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HydroxyChloroQuine ( HCQ ) Patents : Synthesis
& Therapy
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CN108658858 -- Preparing
and refining method for hydroxychloroquine and preparation
method for sulfate of hydroxychloroquine
CN108689929 -- Preparation
method of hydroxychloroquine and sulfate thereof
EP0588430 -- (S)-(+)-Hydroxychloroquine.
CN109280029 -- Preparation
method of hydroxychloroquine sulfate
CN103472154 -- Method
for analysis of hydroxychloroquine sulfate raw material
and preparation by high performance liquid chromatography
KR101115412 -- NEW
PREPARATION OF HYDROXYCHLOROQUINE
CN102050781 -- Industrial
preparation method of hydroxychloroquine sulfate
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method of hydroxychloroquine sulfate
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for simultaneous detection of hydroxychloroquine side
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chromatography
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HIGH-YIELDING CONTINUOUS FLOW SYNTHESIS OF ANTIMALARIAL
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synthesis method of optically pure
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CN108658858 -- Preparing
and refining method for hydroxychloroquine and preparation
method for sulfate of hydroxychloroquine
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Hydroxychloroquine synthetic method
CN109456266 -- Novel
preparation method of hydroxychloroquine sulfate
WO2010027150 -- NEW
PREPARATION OF HYDROXYCHLOROQUINE
CN109928925 -- Sublimation
purification method of 4,7-dichloroquinoline
WO2010027150 -- NEW
PREPARATION OF HYDROXYCHLOROQUINE
CN110627716 -- Preparation
method of 4,7-dichloroquinoline
CN103626699 -- Industrial
preparation method of 4,7-dichloroquinoline
HCQ
Synthesis
CN108658858
Preparing and refining method for hydroxychloroquine
and preparation method for sulfate of hydroxychloroquine
[ PDF ]
Abstract
The invention discloses a preparing and refining method for
hydroxychloroquine and a preparation method for a sulfate of the
hydroxychloroquine. The refining method for the
hydroxychloroquine comprises the following steps: performing
crystallization on a crude product of the hydroxychloroquine in
a mixed solvent of a ketone solvent and an ester solvent to
obtain a refined product of the hydroxychloroquine, wherein a
content of the hydroxychloroquine in the crude product of the
hydroxychloroquine is higher than 92%. According to the method
disclosed by the invention, purity of the refined product of the
hydroxychloroquine prepared by the method can reach 99.9%, a
maximum content of a single impurity is controlled within 0.06%,
and a total content of other impurities is lower than 0.04%;
andpurity of the hydroxychloroquine sulfate prepared from the
hydroxychloroquine can reach 99.8%, and a maximum content of a
single impurity is controlled within 0.06%.
[0001] Technical field
[0002] The invention relates to a method for preparing and
refining hydroxychloroquine and a preparation method thereof.
[0003]
Background technique
[0004] Hydroxychloroquine Sulfate, its chemical name is
2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]-ethanol
sulfate, CAS No. 747-36- 40. Hydroxychloroquine sulfate was
successfully developed by Winthrop and first listed in the
United States in 1956. It has been listed in France, Denmark,
Japan, Germany, Finland and other countries and regions. On May
29, 1998, the US FDA approved hydroxychloroquine sulfate tablets
for the treatment of lupus erythematosus and rheumatoid
arthritis.
[0005] US 2,546,658 discloses a process for the synthesis of
hydroxychloroquine sulfate, the process of which is as follows:
[0006]
[0007] 4,7-Dichloroquinoline is reacted with
5-(N-ethyl-N-2-hydroxyethylenediylamino)-2-pentylamine
(hereinafter referred to as hydroxychloroquine side chain
compound) to give hydroxychloroquine, which is then sulfated to
form a salt. The patent was reported in 1951, the process is
older, the use of equivalent phenol as a solvent, increasing the
difficulty of post-processing. Phenol is toxic and corrosive.
Its concentrated solution is strongly corrosive to the skin.
After treatment, it is converted into sodium phenol wastewater.
The phenol-containing wastewater is a kind of hazardous and
difficult to treat in industrial wastewater. It is the key
control in China. One of the wastewaters has a large
environmental pollution, which causes pressure on the treatment
of the three wastes; the melting point of phenol is 42 ° C,
which is solid at normal temperature. To be successfully fed, it
must be heated and dissolved into liquid to be charged, and the
operation is very cumbersome. The method is complicated and
unsuitable for industrialization, and the yield of the crude
hydroxychloroquine obtained is less than 20%.
[0008] CA2561987 discloses a process for preparing
hydroxychloroquine. Since the reaction is maintained at 120-130
° C for a reaction time of 20-24 h, the impurity content in the
crude product is high and the purification process is very
complicated. In particular, in the post-treatment, in order to
remove the deethylhydroxy chloroquine impurity
(7-chloro-4-(4-N-hydroxyethyl-1-methyl-tertiary amino group) as
shown in Formula I, a complicated post-treatment process is
carried out: An amide group forming agent (for example, an acid
anhydride) is reacted with an impurity of the formula I to form
a compound of the formula II; and an appropriate amount of a
base is added to hydrolyze a compound of the formula III; and
under the same conditions of salt formation using
hydroxychloroquine, the compound III cannot The salt is formed
to remove impurities. In this method, the purification process
of hydroxychloroquine and its sulfate is very complicated, the
reaction time of the whole route is particularly long, and a
large amount of waste water is generated, and complicated
post-treatment is performed in order to remove impurities in the
post-treatment. The process is costly and is not conducive to
industrial production.
[0009] W02010027150 also discloses a method for synthesizing
hydroxychloroquine sulfate, which comprises reacting two raw
materials, after being pressurized with nitrogen or argon to a
pressure of 5-20 bar, stirring at 80 ° C for 30 min, and heating
to 100-120 ° C for reaction 4- 6h. After the reaction is
completed, the hydroxychloroquine is acidified by adding dilute
hydrochloric acid and chloroform. At this time, the
hydroxychloroquine hydrochloride is dissolved in the aqueous
phase, the aqueous phase is collected, alkalized with sodium
hydroxide, hydroxychloroquine is extracted with chloroform, and
the chloroform layer is concentrated and then dichlorocide is
used. The hydroxychloroquine product is obtained after
recrystallization of ethane. Hydroxychloroquine is added to
sulfuric acid under ethanol as a solvent to obtain
hydroxychloroquine sulfate.
[0010] The method still has the following disadvantages: 1. The
condensation reaction is promoted by pressurizing in the
autoclave, but due to the pressure range of 5-20 bar, there is a
great safety hazard in industrial application; The
post-treatment of the reaction is to obtain the
hydroxychloroquine product by recrystallization after
acidification and alkalization, which is equivalent to the use
of two refinings, and the product yield is greatly lost. At the
same time, the extraction and recrystallization are selected
from chloroform and dichloroethane, which are all toxic. Large
reagents should be avoided in the production of APIs.
[0011] CN102050781 discloses an industrial production method of
hydroxychloroquine sulfate: after heating the reaction liquid to
reflux temperature, then gradually raising the temperature for
7-12 hours to 120-125 ° C, distilling off the solvent, and then
maintaining the temperature at 120-125 ° C. 13-18 hours. The
method prolongs the temperature rise time of the solvent by
gradually increasing the temperature during the reaction, and
prolongs the temperature rise reaction time below 120 ° C, and
the high temperature reaction time is slightly reduced. However,
the overall reaction time of the method is still long, the
impurities are still more, and the largest single impurity
cannot be effectively and stably controlled below 0.1%, and the
yield is low. The use of a large amount of organic solvent in
the production process for extraction and crystallization, on
the one hand increases the cost of the product, on the other
hand is not conducive to recycling and environmental protection.
[0012] The method in CN103724261 directly raises the temperature
of the two raw materials under gas protection (13-24 hours), has
a long reaction time, and the reaction is intense, and generates
a large amount of impurities, which is acidified after the
post-treatment, and then a large amount of alkali is alkalized,
and then The organic solvent is added, so that the organic layer
contains a large amount of alkali and inorganic salts, and the
hydroxychloroquine which is crystallized after cooling contains
a large amount of inorganic salts and impurities, so that the
purity of the hydroxychloroquine HPLC is only 96%, so that the
salt is directly obtained by one time. The quality of
hydroxychloroquine sulfate is often unqualified.
[0013] In general, the current method for synthesizing
hydroxychloroquine sulfate uses a highly toxic catalyst and
solvent, which is unfriendly to the environment and increases
the production cost. In addition, the production process is
cumbersome, the reaction selectivity is poor, the reaction
period is long, and special needs are required. The
pressure-resistant equipment, the post-reaction treatment is
cumbersome and difficult to operate, the production cost is
high, and the product impurity content is high. Therefore, it is
necessary to further improve the method for preparing
hydroxychloroquine sulfate in order to obtain a more efficient,
simpler, more selective, environmentally friendly and lower cost
method for preparing high-purity hydroxychloroquine sulfate.
[0014]
Summary of the invention
[0015] The technical problem to be solved by the present
invention is to overcome the defects of the conventional
hydroxychloroquine refining method, such as low purity and
unstable impurity control, and provide a refining method for
effectively controlling the impurity content, greatly improving
the purity, and being environmentally friendly.
[0016] The present invention provides a method for purifying
hydroxychloroquine, which comprises the steps of: crystallizing
a crude hydroxychloroquine in a mixed solvent of a ketone
solvent and an ester solvent to obtain a hydroxychloroquine
product; the hydroxychloroquine The hydroxychloroquine content
in the crude product was >92%.
[0017] The content is calculated by liquid chromatography (HPLC)
and calculated by area normalization.
[0018] The hydroxychloroquine boutique preferably has a purity
of >99.9%, a maximum single heteropoly control of 0.06%, and
a total impurity content of <0.04%.
[0019] The ketone solvent may be conventional in the art, and
particularly preferably a C3 to C9 alkyl ketone in the present
invention, more preferably one of acetone, methyl ethyl ketone,
methyl isobutyl ketone and 2-pentanone or A variety.
[0020] The ester solvent may be conventional in the art, and
particularly preferred in the present invention is an acetate
solvent, more preferably methyl acetate, ethyl acetate, propyl
acetate, isopropyl acetate, butyl acetate and acetic acid. One
or more of isobutyl esters.
[0021] The mixed solvent is preferably one or more of methyl
ethyl ketone and ethyl acetate, acetone and methyl acetate,
2-pentanone and isopropyl acetate, and methyl isobutyl ketone
and butyl acetate.
[0022] The mass ratio of the ketone solvent to the ester solvent
may be from 1:0.5 to 1:1.5, preferably from 1:0.75 to 1:1.25,
more preferably 1:1.
[0023] The mass ratio of the crude hydroxychloroquine to the
mixed solvent may be from 1:2 to 1:10; preferably from 1:2.5 to
1:6, more preferably from 1:2.8 to 1:5.
[0024] The crystal may be a conventional crystal in the art. For
example, after the crude hydroxychloroquine is dissolved, it is
cooled to make the solution supersaturated, and the product is
solid precipitated; in the present invention, 65 to 75 ° C is
particularly preferred. After dissolving, it was cooled to 10 °
C for crystallization.
[0025] After crystallization of the hydroxychloroquine, the
hydroxychloroquine product is preferably obtained by filtration.
[0026] Preferably, the hydroxychloroquine obtained after
filtration is washed with the mixed solvent.
[0027] The method for purifying hydroxychloroquine may further
comprise the steps of: (1) 4,7-dichloroquinoline and
hydroxychloroquine side chain compound (5-(N-ethyl-N) under
inert gas protection 2-hydroxyethylenediylamino)-2-pentylamine),
the temperature is raised to 105 to 120 ° C for 5 to 20 minutes,
and the temperature is raised to 130 to 140 ° C to obtain the
hydroxychloroquine; (2) the step The pH of the
hydroxychloroquine described in (1) is adjusted to >12,
extracted, and washed with water to neutrality to give the crude
hydroxychloroquine.
[0028] In the step (1), the inert gas may be conventional in the
art so as not to participate in the reaction, and one or more of
helium, argon, nitrogen and carbon dioxide are particularly
preferred in the present invention.
[0029] In the step (1), the molar ratio of the
4,7-dichloroquinoline to the hydroxychloroquine side chain
compound may be 1:1.2 to 1:2, preferably 1:1.4 to 1:1.6.
[0030] In the step (1), the progress of the reaction can be
monitored by a conventional monitoring method in the art (for
example, TLC, HPLC or NMR), generally when the compound
4,7-dichloroquinoline disappears or no longer reacts. In the
present invention, it is particularly preferred to carry out the
reaction at 130 to 140 ° C for 3 to 15 hours, more preferably
for 8 to 13 hours.
[0031] In the step (1), after the reaction of the
4,7-dichloroquinoline and the hydroxychloroquine side chain
compound is completed, it is preferably cooled to 80 ° C or
lower.
[0032] In the step (2), the pH adjustment to >12 can be
adjusted conventionally in the art, such as one or more of
sodium hydroxide, sodium carbonate and potassium hydroxide; in
the present invention, the mass percentage is particularly
preferred. The aqueous solution of sodium hydroxide having a
concentration of 6 to 10%, more preferably 7% by mass.
[0033] The invention also provides a preparation method of
hydroxychloroquine, comprising the following steps: (1)
4,7-dichloroquinoline and hydroxychloroquine side chain compound
(5-(N-ethyl-) under the protection of an inert gas
N-2-hydroxyethylenediylamino)-2-pentylamine), the temperature is
raised to 105-120 ° C for 5 to 20 minutes, the temperature is
raised to 130-140 ° C to obtain the hydroxychloroquine; (2) the
step ( The pH of hydroxychloroquine described in 1) is adjusted
to >12, extracted, washed with water to neutrality, and crude
hydroxychloroquine is obtained.
[0034] In the step (1), the inert gas may be conventional in the
art so as not to participate in the reaction, and one or more of
nitrogen, argon, helium and carbon dioxide are particularly
preferable in the present invention.
[0035] In the step (1), the molar ratio of the
4,7-dichloroquinoline to the hydroxychloroquine side chain
compound may be 1:1.2 to 1:2, preferably 1:1.4 to 1:1.6.
[0036] In the step (1), in the reaction, the progress of the
reaction can be monitored by conventional monitoring methods in
the art (for example, TLC, HPLC or NMR), generally disappearing
with the compound 4,7-dichloroquinoline. In the present
invention, it is particularly preferred to carry out the
reaction at 130 to 140 ° C for 3 to 15 hours, and more
preferably for 8 to 13 hours.
[0037] In the step (1), after the reaction of the
4,7-dichloroquinoline and the hydroxychloroquine side chain
compound is completed, it is preferably cooled to 80 ° C or
lower.
[0038] In the step (2), the pH to >12 may be conventionally
determined in the art, such as one or more of sodium hydroxide,
sodium carbonate and potassium hydroxide; in the present
invention, the mass percentage concentration is particularly
preferred. It is a 6 to 10% aqueous sodium hydroxide solution,
and more preferably has a mass percentage concentration of 7%.
[0039] The present invention also provides a process for
preparing hydroxychloroquine sulfate, which comprises the steps
of: reacting sulfuric acid with a hydroxychloroquine as
described above in a solvent to obtain the hydroxychloroquine
sulfate.
[0040] Preferably, the hydroxychloroquine has a purity of
>99.9%, a maximum single impurity control of 0.06%, and a
total impurity content of <0.04%.
[0041] The solvent may be a solvent conventionally used in such
a reaction in the art, for example, an alcohol solvent;
particularly preferably one or more of methanol, ethanol,
isopropanol, propanol, and ethylene glycol;
[0042] The amount of the solvent used in the field is
conventionally used in the field. It is particularly preferred
in the present invention that the mass ratio of the
hydroxychloroquine to the solvent may be from 0.25 g/mL to 0.1
g/mL, preferably 0.2. ~0.15g/mL.
[0043] The amount of the sulfuric acid used may be conventional
in the art, for example, the pH is adjusted to 3.5 to 6. In the
present invention, it is particularly preferred that the molar
ratio of the sulfuric acid to the hydroxychloroquine is 1:0.9 to
1: 1.
[0044] The method for preparing hydroxychloroquine sulfate
preferably comprises the steps of: adding the sulfuric acid to
the mixture of the hydroxychloroquine and the solvent at 20 to
35 ° C, at 45 ° The reaction is carried out at 65 ° C to obtain
the hydroxychloroquine sulfate.
[0045] More preferably, the method for preparing
hydroxychloroquine sulfate comprises the steps of: adding the
sulfuric acid to the mixture of the hydroxychloroquine and the
solvent at 20 to 35 ° C, at 50 The reaction is carried out at
-55 ° C to obtain the hydroxychloroquine sulfate.
[0046] After the reaction of the sulfuric acid with the
hydroxychloroquine is completed, it is preferably cooled to 0 °
C to 20 ° C, more preferably 0 ° C to 20 ° C.
[0047] The hydroxychloroquine sulfate has a purity of >99.8%
and a maximum single impurity of <0.06%.
[0048] The above preferred conditions can be arbitrarily
combined without departing from the ordinary knowledge in the
art, that is, preferred embodiments of the present invention.
[0049] The reagents and starting materials used in the present
invention are commercially available.
[0050] The positive progress of the invention is as follows: 1)
avoiding the use of the toxic catalyst phenol, the reaction is
carried out under normal pressure, avoiding the danger of high
pressure reaction; 2) directly alkalizing in the post-treatment,
easy to operate, reducing the liquid alkali By controlling the
pH value, not only the number of water washings is reduced, the
amount of wastewater is reduced, and the yield is improved; 3)
by using a green mixed solvent crystallization, the impurity
content of the product is low, and the purity of the
hydroxychloroquine obtained by the purification can be Up to
99.9%, the maximum single impurity control is within 0.06%, and
the total impurity content is <0.04%; thus, the purity of
hydroxychloroquine sulfate can be easily obtained up to 99.8%,
and the maximum single impurity control is within 0.06%, which
is stable. Control the impurity content to obtain a high purity
product.
[0051]
DRAWINGS
[0052] Figure 1 is an HPLC chart of crude hydroxychloroquine in
Example 4;
[0053] Figure 2 is a HPLC diagram of the hydroxychloroquine in
Example 4;
[0054] Figure 3 is an HPLC chart of hydroxychloroquine sulfate
in Example 4.
[0055] Detailed ways
[0056] The invention is further illustrated by the following
examples, which are not intended to limit the invention. The
experimental methods in the following examples which do not
specify the specific conditions are selected according to
conventional methods and conditions, or according to the product
specifications.
[0057]
Example 1
[0058] a. Preparation of hydroxychloroquine
[0059] 100 g of 4,7-dichloroquinoline and 110 g of
hydroxychloroquine side chain compound
(5-(N-ethyl-N-2-hydroxyethylenediylamino)-2-pentylamine,
hereinafter referred to as side chain) were added to the
reactor. Into the nitrogen protection, the temperature is raised
at 78 ° C to dissolve 4,7-dichloroquinoline, the temperature is
raised at 120 ° C for 20 minutes, the temperature is raised at
130 ° C for 8 hours, after the reaction is completed, the
temperature is lowered (below 80 ° C), with sodium hydroxide
solution (mass concentration was 7%), the pH was adjusted to 12,
extracted with dichloromethane, washed with water until neutral,
and dichloromethane was evaporated under reduced pressure to
give 154 g of crude chlorochloroquine. The yield was 90.7%, and
the HPLC purity was 92.45%. To the crude hydroxychloroquine, 300
g of methyl ethyl ketone and 300 g of ethyl acetate were added,
and the mixture was heated at 75 ° C to dissolve. After 4 h, the
temperature was slowly lowered to 10 ° C, filtered, and the
filter cake was washed with a mixed solvent of methyl ethyl
ketone and ethyl acetate to obtain hydroxychloroquine. The wet
product was dried at 60 ° C for 4 h to obtain hydroxychloroquine
dry product with a purity of 99.93%, a maximum single impurity
of 0.05%, and a yield of 90.3%.
[0060] b.
Preparation of hydroxychloroquine sulfate
[0061] 100 g of hydroxychloroquine was dissolved in 500 g of
absolute ethanol, and concentrated sulfuric acid was added
dropwise at 20 ° C to adjust the solution to turbidity (pH 3.5
to 5), the temperature was raised at 45 ° C for 10 hours, cooled
to 20 ° C for 1 hour, and filtered to obtain sulfuric acid.
Hydroxychloroquine, purity 99.93%, maximum single impurity
0.05%, yield 94.5%.
[0062]
Example 2: Preparation of hydroxychloroquine sulfate
[0063] a. Preparation of hydroxychloroquine
[0064] 100g of 4,7-dichloroquinoline and 130g side chain were
added to the reactor, protected by argon gas, heated at 70 ° C
to dissolve 4,7-dichloroquinoline, heated at 115 ° C for 10
minutes, and heated at 137 ° C. After 10 hours, after the
reaction is completed, the temperature is lowered (below 80 °
C), adjusted to pH > 12 with sodium hydroxide solution (mass
concentration 6%), extracted with dichloromethane, washed with
water until neutral, and distilled off dichloromethane to obtain
hydroxychloroquine under reduced pressure. The crude product was
157 g, the yield was 92.5%, and the HPLC purity was 93.96%. Add
200g of acetone and 250g of methyl acetate to the whole amount
of hydroxychloroquine and heat to dissolve at 65 °C. After 4h,
slowly cool down to 10 °C, filter, and filter cake washed with
mixed solvent of acetone and methyl acetate to obtain
hydroxychloroquine wet product. After drying at 60 ° C for 4 h,
hydroxychloroquine dry product was obtained, the purity was
99.94%, the maximum single impurity was 0.04%, and the yield was
89.1%.
[0065] b.
Preparation of hydroxychloroquine sulfate
[0066] 100 g of hydroxychloroquine was dissolved in 500 g of
absolute ethanol, and concentrated sulfuric acid was added
dropwise at 25 ° C until the solution became cloudy. The
temperature was raised at 50 ° C for 9 hours, cooled to 20 ° C
for 1 h, and filtered to obtain hydroxychloroquine sulfate. The
purity was 99.94%. Single impurity 0.04%, yield 94.2%.
[0067]
Example 3: Preparation of hydroxychloroquine sulfate
[0068] a. Preparation of hydroxychloroquine
[0069] 100g of 4,7-dichloroquinoline and 130g of side chain were
added to the reactor, protected by helium gas, heated at 70 ° C
to dissolve 4,7-dichloroquinoline, heated at 115 ° C for 15
minutes, and heated at 135 ° C. After 11 hours, after the
reaction is completed, the temperature is lowered (below 80 °
C), adjusted to pH > 12 with sodium hydroxide solution (mass
concentration: 10%), extracted with dichloromethane, washed with
water until neutral, and distilled off dichloromethane to obtain
hydroxychloroquine under reduced pressure. The crude product was
158 g, the yield was 93.1%, and the HPLC purity was 93.73%. Add
400g of 2-pentanone to 350g of isopropyl acetate to the whole
amount of hydroxychloroquine, heat it at 65 °C, slowly cool to
10 °C after 4h, filter, filter cake mixed solvent of 2-pentanone
and isopropyl acetate mixed solution After washing,
hydroxychloroquine wet product was obtained, and dried at 60 ° C
for 4 h to obtain hydroxychloroquine dry product, the purity was
99.93%, the maximum single impurity was 0.04%, and the yield was
89.7%.
[0070] b. Preparation of hydroxychloroquine sulfate
[0071] Dissolve 100g of hydroxychloroquine in 500g of absolute
ethanol, add concentrated sulfuric acid to the solution turbid
at 30 °C, heat up at 55 ° C for 7 hours, cool to 20 ° C for 1 h,
filter to obtain hydroxychloroquine sulfate, purity 99.93%,
maximum The single impurity was 0.04%, and the yield was 94.7%.
[0072]
Example 4: Preparation of hydroxychloroquine sulfate
[0073] a.
Preparation of hydroxychloroquine
[0074] 100g of 4,7-dichloroquinoline and 175g of side chain were
added to the reactor, protected by CO2, heated at 68 ° C to
dissolve 4,7-dichloroquinoline, heated at 105 ° C for 5 minutes,
and heated to 132 ° C. After the reaction is completed, the
temperature is lowered (below 80 ° C), the pH is adjusted to 12
with sodium hydroxide solution (mass concentration 7%),
extracted with dichloromethane, washed with water until neutral,
and dichloromethane is distilled off under reduced pressure to
obtain crude hydroxychloroquine. 156 g, the yield was 96.26%,
and the HPLC purity was 93.36%. Add 400g of methyl isobutyl
ketone to 300g of butyl acetate in the crude amount of
hydroxychloroquine, heat it at 65 °C, slowly cool to 10 °C after
4h, filter, filter cake mixed with methyl isobutyl ketone and
butyl acetate mixed solvent After washing, hydroxychloroquine
wet product was obtained, and dried at 60 ° C for 4 h to obtain
hydroxychloroquine dry product with a purity of 99.92% and a
maximum single impurity of 0.05%.
[0075] Table 1. Contents in crude hydroxychloroquine and HPLC
(Figures 1 and 2)
[0076]
[0077] Note: 1. The relative retention time is based on the
retention time of hydroxychloroquine HPLC; that is, the relative
retention time is “1” for hydroxychloroquine, and the other
relative retention time is impurity.
[0078] b. Preparation of hydroxychloroquine sulfate
[0079] 100 g of hydroxychloroquine was dissolved in 500 g of
absolute ethanol, and concentrated sulfuric acid was added
dropwise at 35 ° C until the solution became cloudy. The
temperature was raised at 65 ° C for 4 hours, cooled to 20 ° C
for 1 h, and filtered to obtain hydroxychloroquine sulfate. The
purity was 99.88%. Single miscellaneous <0.06%, yield 93.6%.
[0080] Table 2. Content in % of hydroxychloroquine sulfate HPLC
(Figure 3)
[0081] Retention time (min) 5.676 7.013 9.998 10.597 12.223
16.655 Content% 0.0527 0.0040 0.0483 0.0074 0.0034 99.8839
[0082]
Comparative Example 1
[0083] 100g side chain, 112g 4.7-dichloroquinoline was added to
a three-necked flask, protected by nitrogen, heated to 100 ° C,
stirred for 1 h, then heated to 120-130 ° C for 20 h, after the
reaction was completed, the temperature was lowered (below 80 °
C), with hydroxide The sodium solution was adjusted to pH >
12, extracted with dichloromethane, washed with water until
neutral, and dichloromethane was evaporated under reduced
pressure to give 147 g of crude chlorochloroquine. The yield was
86.6%, and the HPLC purity was 90.47%. To the crude
hydroxychloroquine, 300 g of methyl ethyl ketone and 300 g of
ethyl acetate were added, and the mixture was heated at 75 ° C
to dissolve. After 4 h, the temperature was slowly lowered to 20
° C, filtered, and the filter cake was washed with a mixed
solvent of methyl ethyl ketone and ethyl acetate to obtain
hydroxychloroquine. The wet product was dried at 60 ° C for 4 h
to obtain hydroxychloroquine dry product with a purity of
99.80%, a maximum single impurity of 0.12%, and a yield of
88.2%.
[0084]
Comparative Example 2
[0085] 100g of 4,7-dichloroquinoline and 110g of side chain were
added to the reactor, protected by nitrogen, heated at 78 ° C to
dissolve 4,7-dichloroquinoline, heated at 120 ° C for 20
minutes, and heated to 140 ° C. After the reaction is completed,
the reaction solution is cooled to 90 ° C ~ 100 ° C, 5% sodium
hydroxide solution is added, alkalized to neutral, extracted
with dichloromethane, and added to the combined organic phase,
250 g of drinking water is added. The layering was repeated
until the pH of the washing water was 7, and methylene chloride
was distilled off under reduced pressure to give 164 g of crude
hydroxy chloroquine. The yield was 96.9%, and the HPLC purity
was 91.78%. To the crude hydroxychloroquine, 300 g of methyl
ethyl ketone and 300 g of ethyl acetate were added, and the
mixture was heated at 75 ° C to dissolve. After 4 h, the
temperature was slowly lowered to 10 ° C, filtered, and the
filter cake was washed with a mixed solvent of methyl ethyl
ketone and ethyl acetate to obtain hydroxychloroquine. The wet
product was dried at 60 ° C for 4 h to obtain hydroxychloroquine
dry product with a purity of 99.70%, a maximum single impurity
of 0.21%, and a yield of 75.3%.
[0086]
Comparative Example 3
[0087] a.
Preparation of hydroxychloroquine
[0088] 100g of 4,7-dichloroquinoline and 110g of side chain were
added to the reactor, protected by nitrogen, heated at 78 ° C to
dissolve 4,7-dichloroquinoline, heated at 120 ° C for 20
minutes, and heated to 140 ° C. After the reaction is completed,
the temperature is lowered (below 80 ° C), the pH is adjusted to
12 with sodium hydroxide solution, extracted with
dichloromethane, washed with water until neutral, and
dichloromethane is evaporated under reduced pressure to give
crude chlorochloroquine 146 g, yield: 86.7%. The HPLC purity was
90.49%. Add 400g of isopropyl acetate to the crude
hydroxychloroquine, then add 5.0g of activated carbon, reflux at
elevated temperature for 1 hour, heat filtration, the filtrate
is cooled to 0 ° C, crystallization for 2 h, filtered, and dried
at 60 ° C for 4 h to obtain hydroxychloroquine dry product. .
The purity was 99.63%, the maximum single impurity was 0.091%,
and the yield was 88.1%.
[0089] b.
Preparation of hydroxychloroquine sulfate
[0090] 100 g of hydroxychloroquine obtained in the previous step
was dissolved in 500 g of absolute ethanol, concentrated
sulfuric acid was added dropwise at 25 ° C until the solution
became cloudy, the temperature was raised at 50 ° C for 9 hours,
cooled to 20 ° C for 1 h, and filtered to obtain
hydroxychloroquine sulfate, purity 99.74. %, the largest single
impurity 0.17%, the yield was 90.2%.
[0091] Comparative Example 4
[0092] a.
Preparation of hydroxychloroquine
[0093] 100g of 4,7-dichloroquinoline and 110g of side chain were
added to the reactor, protected by nitrogen, heated at 78 ° C to
dissolve 4,7-dichloroquinoline, heated at 120 ° C for 20
minutes, and heated to 140 ° C. After the reaction is completed,
the temperature is lowered (below 80 ° C), adjusted to pH >
12 with sodium hydroxide solution, extracted with
dichloromethane, washed with water until neutral, and
dichloromethane is evaporated under reduced pressure to give
crude hydroxychloroquine 149 g, yield 87.8%. The HPLC purity was
90.91%. To the crude hydroxychloroquine, 300 g of ethyl acetate
was added, and the mixture was heated to dissolve, and the
temperature was lowered to 0 to 10 ° C. After incubation for 2
hours, the mixture was filtered and dried to obtain a
hydroxychloroquine dry product. The purity was 99.63%, the
maximum single impurity was 0.095%, and the yield was 89.6%.
[0094] b. Preparation of hydroxychloroquine sulfate
[0095] 100g of hydroxychloroquine obtained in the previous step
is dissolved in 500g of absolute ethanol, concentrated sulfuric
acid is added dropwise at 25 °C until the solution is cloudy,
heated at 50 ° C for 9 hours, cooled to 20 ° C for 1 h, and
filtered to obtain hydroxychloroquine sulfate, purity 99.79 %,
the largest single impurity is 0.18%, and the yield is 89.2%.
[0096]
Comparative Example 5
[0097] In a three-necked round bottom flask,
4,7-dichloroquinoline (198 g, 1.0 mol), hydroxychloroquine side
chain (182 g, 1.05 mol) and isopropyl acetate 1089 g were added,
and sodium ethoxide (13.6 g, 0.2 mol) was slowly added. The
temperature is slowly raised to reflux under stirring
conditions, and then isopropyl acetate is distilled off, and the
temperature is gradually raised to 110 ° C over 9 hours, then
heated to 120-122 ° C for 10 hours, and finally heated at
120-122 ° C for 4 hours, until the reaction is complete.
Thereafter, the reaction solution was cooled to 90 to 100 ° C,
directly added to a 5% sodium hydroxide solution, and alkalized
to neutrality. The distilled isopropyl acetate was extracted
twice, and the layers were separated. 500 g of drinking water
was added to the combined organic phase, washed, layered, and
the above operation was repeated until the pH of the washing
water was 7. After the washing was completed, the water
temperature was controlled to 65 ° C, and isopropyl acetate was
distilled off under reduced pressure to obtain crude
hydroxychloroquine. The HPLC purity was 91.78%. To the crude
hydroxychloroquine, 300 g of methyl ethyl ketone and 300 g of
ethyl acetate were added, and the mixture was heated at 75 ° C
to dissolve. After 4 h, the temperature was slowly lowered to 10
° C, filtered, and the filter cake was washed with a mixed
solvent of methyl ethyl ketone and ethyl acetate to obtain
hydroxychloroquine. The wet product was dried at 60 ° C for 4 h
to obtain hydroxychloroquine dry product with a purity of 99.8%,
a maximum single impurity of 0.17%, and a yield of 87.6%.
[0098]
Comparative Example 6
[0099] 20g side chain, 22.4g 4.7-dichloroquinoline was added to
a three-necked flask, protected by nitrogen, heated to 100 ° C,
stirred for 1 h, then heated to 120-130 ° C for 20 h, the
reaction was completed, slightly cooled (90 ° C ~ 100 ° C) 20 g
of water was added to the reaction solution, and 40 g of
concentrated hydrochloric acid was added. After stirring, 80 g
of liquid alkali was added, and the mixture was stirred for 30
minutes. The aqueous phase was discarded, and the organic
solvent was evaporated under reduced pressure to obtain a crude
product. HPLC purity was 90.2%. The crude product was added with
300 g of methyl ethyl ketone and 300 g of ethyl acetate, and the
mixture was heated at 75 ° C to dissolve. After 4 h, the
temperature was slowly lowered to 10 ° C, filtered, and the
filter cake was washed with a mixed solvent of methyl ethyl
ketone and ethyl acetate to obtain hydroxy chloroquine wet
product, 60 ° C. The dried hydroxychloroquine was dried for 4 h,
the purity was 99.80%, the maximum single impurity was 0.13%,
and the yield was 88.2%.
[0100]
Comparative Example 7
[0101] 100 g of crude hydroxychloroquine (HPLC purity greater
than 92%) obtained in Example 1 was placed in a single-mouth
bottle, and a mixed solvent of 260 g of ethyl acetate and 40 g
of isopropyl alcohol was added thereto, and the mixture was
stirred at a temperature, and slowly heated to 80 ° C, refluxing
1 After the hour, the temperature is lowered to 15-20 ° C, the
crystallization time is started for 5 hours, the temperature is
lowered to 0 to 5 ° C, the crystal is separated by filtration,
and the filter cake is washed with ethyl acetate to obtain
hydroxychloroquine wet product, which is dried to obtain fine
hydroxychloroquine. The HPLC purity was 99.7%, the maximum
single impurity was 0.16%, and the yield was 75%.
[0102]
Comparative Example 8
[0103] 100 g of crude hydroxychloroquine (HPLC purity greater
than 92%) obtained in Example 1 was placed in a single-mouth
bottle, and a mixed solvent of 260 g of ethyl acetate and 40 g
of isopropyl alcohol was added thereto, and the mixture was
stirred and dissolved at a temperature. After completely
dissolved, 4.2 g was added. Activated carbon, slowly warmed to
80 ° C, reflux for 1 hour, hot filtered, filter cake washed with
26g of ethyl acetate and 4g of isopropanol mixed solvent, the
filtrate was combined, cooled to 15 ~ 20 ° C, began
crystallization time 5 hours, cooling to 0 to 5 ° C, after
thermal crystallization, filtration, the filter cake was washed
with ethyl acetate to obtain hydroxy chloroquine wet product,
which was dried to obtain HPLC hydroxychloroquine with a purity
of 99.8%, a maximum single impurity of 0.11%, and a yield of
70%.
[0104] Comparison of Example 1 and Comparative Examples 3 and 4
[0105] table 3.
[0106]
[0107]
[0108] Table 4.
[0109]
[0110] Note: 1. The relative retention time is based on the
retention time of hydroxychloroquine HPLC; that is, the relative
retention time is “1” for hydroxychloroquine, and the other
relative retention time is impurity.
[0111] After refining, in Example 1, the content of impurity 1
was controlled to be <0.06%; the content of the remaining
impurities was one order of magnitude lower than that of the
comparative example, and the total amount of remaining
impurities was <0.04%. The main impurity content in the
comparative example was 0.085-0.1%, both of which were close to
0.1%. The impurity content could not be stably controlled, and
it was easy to be >0.1% in the subsequent storage process.
CN108689929
Preparation method of hydroxychloroquine and sulfate
thereof
[ PDF ]
Abstract
The invention discloses a preparation method of
hydroxychloroquine and sulfate thereof. The preparation method
of the hydroxychloroquine comprises the following steps of step
(1), under the inert gasprotection atmosphere, enabling
4,7-dichloroquine and hydroxychloroquine side chain compounds to
react at the temperature of 134 to 144 DEG C until the content
of 4,7-dichloroquine is smaller than orequal to 10%, so as to
obtain a crude product of the hydroxychloroquine, wherein the
content of the hydroxychloroquine in the crude product of the
hydroxychloroquine is greater than 92%; step (2),
recrystallizing the obtained crude product of the
hydroxychloroquine in step (1) in a mixed solvent of alcohol
solvent and ester solvent, so as to obtain a refined product of
the hydroxychloroquine. Thepurity of the refined product of the
hydroxychloroquine can reach 99.9%, the maximum content of
single impurity is controlled within 0.06%, and the total
content of other impurities is smaller than 0.04%.
[0001] Technical field
[0002] The present invention relates to a process for the
preparation of hydroxychloroquine and its sulfate.
[0003] Background technique
[0004] Hydroxychloroquine Sulfate, its chemical name is
2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]-ethanol
sulfate, CAS No. 747-36- 40. Hydroxychloroquine sulfate was
successfully developed by Winthrop and first listed in the
United States in 1956. It has been listed in France, Denmark,
Japan, Germany, Finland and other countries and regions. On May
29, 1998, the US FDA approved hydroxychloroquine sulfate tablets
for the treatment of lupus erythematosus and rheumatoid
arthritis.
[0005] US 2,546,658 discloses a process for the synthesis of
hydroxychloroquine sulfate, the process of which is as follows:
[0006]
[0007] 4,7-Dichloroquinoline is reacted with
5-(N-ethyl-N-2-hydroxyethylenediylamino)-2-pentylamine
(hereinafter referred to as hydroxychloroquine side chain
compound) to give hydroxychloroquine, which is then sulfated to
form a salt. The patent was reported in 1951, the process is
older, the use of equivalent phenol as a solvent, increasing the
difficulty of post-processing. Phenol is toxic and corrosive.
Its concentrated solution is strongly corrosive to the skin.
After treatment, it is converted into sodium phenol wastewater.
The phenol-containing wastewater is a kind of hazardous and
difficult to treat in industrial wastewater. It is the key
control in China. One of the wastewaters has a large
environmental pollution, which causes pressure on the treatment
of the three wastes; the melting point of phenol is 42 ° C,
which is solid at normal temperature. To be successfully fed, it
must be heated and dissolved into liquid to be charged, and the
operation is very cumbersome. The method is complicated and
unsuitable for industrialization, and the yield of the crude
hydroxychloroquine obtained is less than 20%.
[0008] CA2561987 discloses a method for preparing
hydroxychloroquine. Since the reaction is maintained at 120-130
° C for a reaction time of 20-24 h, the impurity content in the
crude product is high and the purification process is
complicated. In particular, in the post-treatment, in order to
remove the deethylhydroxy chloroquine impurity
(7-chloro-4-(4-N-hydroxyethyl-1-methyl-tertiary amino group) as
shown in Formula I, a complicated post-treatment process is
carried out: An amide group forming agent (for example, an acid
anhydride) is reacted with an impurity of the formula I to form
a compound of the formula II; and an appropriate amount of a
base is added to hydrolyze a compound of the formula III; and
under the same conditions of salt formation using
hydroxychloroquine, the compound III cannot The salt is formed
to remove impurities. In this method, the purification process
of hydroxychloroquine and its sulfate is very complicated, the
reaction time of the whole route is particularly long, and a
large amount of waste water is generated, and complicated
post-treatment is performed in order to remove impurities in the
post-treatment. The process is costly and is not conducive to
industrial production.
[0009] W02010027150 also discloses a method for synthesizing
hydroxychloroquine sulfate, which comprises reacting two raw
materials, after being pressurized with nitrogen or argon to a
pressure of 5-20 bar, stirring at 80 ° C for 30 min, and heating
to 100-120 ° C for reaction 4- 6h. After the reaction is
completed, the hydroxychloroquine is acidified by adding dilute
hydrochloric acid and chloroform. At this time, the
hydroxychloroquine hydrochloride is dissolved in the aqueous
phase, the aqueous phase is collected, alkalized with sodium
hydroxide, hydroxychloroquine is extracted with chloroform, and
the chloroform layer is concentrated and then dichlorocide is
used. The hydroxychloroquine product is obtained after
recrystallization of ethane. Hydroxychloroquine is added to
sulfuric acid under ethanol as a solvent to obtain
hydroxychloroquine sulfate.
[0010] The method still has the following disadvantages: 1. The
condensation reaction is promoted by pressurizing in the
autoclave, but due to the pressure range of 5-20 bar, there is a
great safety hazard in industrial application; The
post-treatment of the reaction is to obtain the
hydroxychloroquine product by recrystallization after
acidification and alkalization, which is equivalent to the use
of two refinings, and the product yield is greatly lost. At the
same time, the extraction and recrystallization are selected
from chloroform and dichloroethane, which are all toxic. Large
reagents should be avoided in the production of APIs.
[0011] CN102050781 discloses an industrial production method of
hydroxychloroquine sulfate: after heating the reaction liquid to
reflux temperature, then gradually raising the temperature for
7-12 hours to 120-125 ° C, distilling off the solvent, and then
maintaining the temperature at 120-125 ° C. 13-18 hours. The
method prolongs the temperature rise time of the solvent by
gradually increasing the temperature during the reaction, and
prolongs the temperature rise reaction time below 120 ° C, and
the high temperature reaction time is slightly reduced. However,
the overall reaction time of the method is still long, the
impurities are still more, and the largest single impurity
cannot be effectively and stably controlled below 0.1%, and the
yield is low. The use of a large amount of organic solvent in
the production process for extraction and crystallization, on
the one hand increases the cost of the product, on the other
hand is not conducive to recycling and environmental protection.
[0012] The method in CN103724261 directly raises the temperature
of the two raw materials under gas protection (13-24 hours), has
a long reaction time, and the reaction is intense, and generates
a large amount of impurities, which is acidified after the
post-treatment, and then a large amount of alkali is alkalized,
and then The organic solvent is added, so that the organic layer
contains a large amount of alkali and inorganic salts, and the
hydroxychloroquine which is crystallized after cooling contains
a large amount of inorganic salts and impurities, so that the
purity of the hydroxychloroquine HPLC is only 96%, so that the
salt is directly obtained by one time. The quality of
hydroxychloroquine sulfate is often unqualified.
[0013] In general, the current method for synthesizing
hydroxychloroquine sulfate has the use of highly toxic catalysts
and solvents, which are environmentally unfriendly and increase
the production cost. In addition, the production process is
cumbersome, the reaction selectivity is poor, the reaction cycle
is long, and special resistance is required. The pressure
equipment, the post-reaction treatment are cumbersome and
difficult to operate, the production cost is high, and the
product impurity content is high. Therefore, it is necessary to
further improve the method for preparing hydroxychloroquine
sulfate in order to obtain a more efficient, simpler, more
selective, environmentally friendly and lower cost method for
preparing high-purity hydroxychloroquine sulfate.
[0014] Summary of the invention
[0015] The technical problem to be solved by the present
invention is the preparation method of the existing
hydroxychloroquine, which has the defects of low purity and
unstable impurity control, and provides a preparation method of
hydroxychloroquine and its sulfate. By adopting the preparation
method, the impurity content can be effectively and stably
controlled, the purity is greatly improved, and the environment
is environmentally friendly.
[0016] The invention provides a preparation method of
hydroxychloroquine sulfate, which comprises the steps of:
forming a salt reaction of a sulfuric acid aqueous solution with
a hydroxychloroquine in a solvent to obtain the
hydroxychloroquine sulfate; the aqueous sulfuric acid solution;
The mass percentage is 30% to 80% aqueous sulfuric acid; the
purity of the hydroxychloroquine is >99.0% by mass.
[0017] Wherein the hydroxychloroquine sulfate is preferably a
crystal; the crystal has an X-ray powder diffraction represented
by a 2θ angle having characteristic peaks at the following
positions: 16.9°, 17.1°, 17.5°, 19.9°, 21.3°, 23.5°, 23.9° and
26.7°. Preferably, the XRPD pattern of the hydroxychloroquine
sulfate form is shown in FIG.
[0018] Wherein the hydroxychloroquine sulfate is preferably
characterized by an infrared absorption spectrum measured by KBr
tableting, which has characteristic peaks at the following
positions: 3424, 3214, 2972, 1613, 1553, 1458, 1366, 1342, 1215
, 1111, 824, 620, and 605 cm-1.
[0019] Wherein the hydroxychloroquine sulfate, preferably
differential scanning calorimetry (DSC), has an endothermic peak
at 246 °C.
[0020] Among them, in the hydroxychloroquine boutique,
preferably, the maximum single heteropoly is controlled within
0.06%, and the total impurity content is <0.04%.
[0021] The aqueous sulfuric acid solution is preferably from 40%
to 60% by mass, more preferably 50% by mass.
[0022] Wherein, the solvent is preferably an alcohol solvent
(for example, one or more of ethanol, methanol and isopropanol),
or an alcohol solvent (for example, one or more of ethanol,
methanol and isopropanol). a mixed solvent with an ester solvent
such as ethyl acetate.
[0023] In the mixed solvent, the weight of the alcohol solvent
and the ester solvent is preferably from 1:0.2 to 1:0.8.
[0024] Wherein, the amount of the solvent is generally such that
the hydroxychloroquine is completely dissolved to form a uniform
solution. The weight of the hydroxychloroquine and the solvent
is preferably from 1:3 to 1:8 (again, for example, from 1:4 to
1:5).
[0025] Wherein, the amount of the sulfuric acid used may be a
conventional amount in the art, for example, the pH is adjusted
to 3.5 to 6. The molar ratio of the sulfuric acid and the
hydroxychloroquine in the present invention is preferably 1:0.9.
1:1.
[0026] The method for preparing hydroxychloroquine sulfate
preferably further comprises the steps of: adding the sulfuric
acid to the mixture of the hydroxychloroquine and the solvent at
20 to 35 ° C; The reaction is carried out at 30 to 55 ° C to
obtain the hydroxychloroquine sulfate. Preferably, after the
sulfuric acid is added dropwise, the reaction is carried out at
50 to 55 °C.
[0027] Wherein, after the reaction of the sulfuric acid with the
hydroxychloroquine is completed, it is preferably cooled to 0 °
C to 20 ° C, more preferably 0 ° C to 20 ° C.
[0028] The preparation method of the hydroxychloroquine sulfate
may further include post-treatment, which may be a conventional
post-treatment in the art, preferably filtration and drying.
[0029] Wherein said drying is conventionally dry in the art,
preferably vacuum drying. The vacuum drying temperature is
preferably from 50 to 80 °C.
[0030] Wherein, the purity of the hydroxychloroquine sulfate can
reach >99.9%, and the maximum single impurity is <0.06%.
[0031] In the method for preparing hydroxychloroquine sulfate,
preferably the hydroxychloroquine is prepared by the following
steps:
[0032] Step (1), 4,7-dichloroquinoline and hydroxychloroquine
side chain compound
(5-(N-ethyl-N-2-hydroxyethylenediylamino)-2-pentylamine) under
inert gas protection , 134 ~ 144 ° C reaction, to
4,7-dichloroquinoline content of less than or equal to 10%, to
obtain crude hydroxychloroquine; the hydroxychloroquine crude
hydroxychloroquine content of > 92%;
[0033] In the step (2), the crude hydroxychloroquine obtained in
the step (1) is recrystallized from a mixed solvent of an
alcohol solvent and an ester solvent to obtain the
hydroxychloroquine fine product.
[0034] In the step (1), the inert gas may be an inert gas
conventional in the art to not participate in the reaction; in
the present invention, preferably one or more of helium, argon,
nitrogen and carbon dioxide. .
[0035] In the step (1), the molar ratio of the
4,7-dichloroquinoline to the hydroxychloroquine side chain
compound may be 1:1.2 to 1:2, preferably 1:1.4 to 1.6 (for
example, 1) :1.5).
[0036] In the step (1), the progress of the reaction can be
monitored by a conventional monitoring method (for example, TLC,
HPLC or NMR) in the art, and in the present invention, the
content of the 4,7-dichloroquinoline is preferably 4 ~6%.
[0037] In the step (1), after the reaction of the
4,7-dichloroquinoline and the hydroxychloroquine side chain
compound is completed, it is preferably cooled to 80 ° C or
lower.
[0038] In the step (1), preferably, after the reaction is
completed, the quenching liquid is quenched to obtain the crude
hydroxychloroquine; more preferably, after the reaction is
finished, the quenching liquid is quenched, and the organic
solvent is extracted. Distillation, removal of the organic
solvent, the crude hydroxychloroquine can be obtained.
[0039] In the step (1), the quenching liquid is preferably water
or an aqueous sodium hydroxide solution having a concentration
by weight of 6 to 10%, more preferably an aqueous sodium
hydroxide solution having a mass percentage of 7%.
[0040] In the step (1), the amount of the quenching liquid may
be a conventional amount in the art, and preferably the mass
ratio of the quenching liquid to the 4,7-dichloroquinoline is
3:1.
[0041] In the step (1), the organic solvent is preferably one or
more of dichloromethane, chloroform and ethyl acetate.
[0042] In the step (2), the ester solvent may be conventional in
the art, and in the present invention, it is preferably an
acetate solvent, more preferably methyl acetate, ethyl acetate,
propyl acetate or acetic acid. One or more of propyl ester,
butyl acetate and isobutyl acetate.
[0043] In the step (2), the alcohol solvent may be conventional
in the art, and in the present invention, preferably one or more
of ethanol, methanol and isopropyl alcohol.
[0044] In the step (2), the mixed solvent is preferably ethanol
and ethyl acetate.
[0045] In the step (2), the weight of the ester solvent and the
alcohol solvent in the mixed solvent is preferably from 1:0.1 to
0.2.
[0046] In the step (2), the weight of the recrystallized mixed
solvent and the crude hydroxychloroquine is preferably from
1:0.3 to 1:0.7.
[0047] In the step (2), the recrystallization may be a
conventional crystal in the art, for example, after the crude
hydroxychloroquine is dissolved, it is cooled to make the
solution into a supersaturated state, and the product is solid
precipitated; Preferably, it is after 65-75 ° C is dissolved; it
is cooled to 10 ° C for crystallization.
[0048] After crystallization of the hydroxychloroquine, the
hydroxychloroquine product is preferably obtained by filtration.
[0049] Preferably, the hydroxychloroquine obtained after
filtration is washed with the mixed solvent.
[0050] The invention also provides a preparation method of
hydroxychloroquine, comprising the following steps:
[0051] Step (1), 4,7-dichloroquinoline and hydroxychloroquine
side chain compound
(5-(N-ethyl-N-2-hydroxyethylenediylamino)-2-pentylamine) under
inert gas protection , 134 ~ 144 ° C reaction, to
4,7-dichloroquinoline content of less than or equal to 10%, to
obtain crude hydroxychloroquine; the hydroxychloroquine crude
hydroxychloroquine content of > 92%;
[0052] In the step (2), the crude hydroxychloroquine obtained in
the step (1) is recrystallized from a mixed solvent of an
alcohol solvent and an ester solvent to obtain a
hydroxychloroquine fine product.
[0053] In the step (1), the inert gas may be conventional in the
art so as not to participate in the reaction, and in the present
invention, preferably one or more of helium, argon, nitrogen and
carbon dioxide.
[0054] In the step (1), the molar ratio of the
4,7-dichloroquinoline to the hydroxychloroquine side chain
compound may be 1:1.2 to 1:2, preferably 1:1.4 to 1.6 (for
example, 1) :1.5).
[0055] In the step (1), the progress of the reaction can be
monitored by a conventional monitoring method (for example, TLC,
HPLC or NMR) in the art, and in the present invention, the
content of the 4,7-dichloroquinoline is preferably 4 ~6%.
[0056] In the step (1), after the reaction of the
4,7-dichloroquinoline and the hydroxychloroquine side chain
compound is completed, it is preferably cooled to 80 ° C or
lower.
[0057] In the step (1), preferably, after the reaction is
completed, the quenching liquid is quenched to obtain the crude
hydroxychloroquine; more preferably, after the reaction is
finished, the quenching liquid is quenched, and the organic
solvent is extracted. Distillation, removal of the organic
solvent, the crude hydroxychloroquine can be obtained.
[0058] In the step (1), the quenching liquid is preferably water
or an aqueous sodium hydroxide solution having a concentration
by weight of 6 to 10%, more preferably an aqueous sodium
hydroxide solution having a mass percentage of 7%.
[0059] In the step (1), the amount of the quenching liquid may
be a conventional amount in the art, and preferably the mass
ratio of the quenching liquid to the 4,7-dichloroquinoline is
3:1.
[0060] In the step (1), the organic solvent is preferably one or
more of dichloromethane, chloroform and ethyl acetate.
[0061] In the step (2), the ester solvent may be conventional in
the art, and in the present invention, it is preferably an
acetate solvent, more preferably methyl acetate, ethyl acetate,
propyl acetate or acetic acid. One or more of propyl ester,
butyl acetate and isobutyl acetate.
[0062] In the step (2), the alcohol solvent may be conventional
in the art, and in the present invention, preferably one or more
of ethanol, methanol and isopropyl alcohol.
[0063] In the step (2), the mixed solvent is preferably ethanol
and ethyl acetate.
[0064] In the step (2), the weight of the ester solvent and the
alcohol solvent in the mixed solvent is preferably from 1:0.1 to
0.2.
[0065] In the step (2), the weight of the recrystallized mixed
solvent and the crude hydroxychloroquine is preferably from
1:0.3 to 1:0.7.
[0066] In the step (2), the recrystallization may be a
conventional crystal in the art, for example, after the crude
hydroxychloroquine is dissolved, it is cooled to make the
solution into a supersaturated state, and the product is solid
precipitated; Preferably, it is after 65-75 ° C is dissolved; it
is cooled to 10 ° C for crystallization.
[0067] After crystallization of the hydroxychloroquine, the
hydroxychloroquine product is preferably obtained by filtration.
[0068] Preferably, the hydroxychloroquine obtained after
filtration is washed with the mixed solvent.
[0069] In the hydroxychloroquine product, the purity of the
hydroxychloroquine is >99.0% by mass; preferably, the maximum
single impurity is controlled within 0.06%, and the total
content of the remaining impurities is <0.04%.
[0070] In the present invention, the contents of the crude
hydroxychloroquine, the hydroxychloroquine, the
hydroxychloroquine sulfate, and the impurities are all
determined by liquid chromatography (HPLC) and the area
normalization method is used.
[0071] The above preferred conditions can be arbitrarily
combined without departing from the ordinary knowledge in the
art, that is, preferred embodiments of the present invention.
[0072] The reagents and starting materials used in the present
invention are commercially available.
[0073] In the present invention: the term "XRPD" means powder
X-ray diffraction;
[0074] The term "IR" means infrared spectroscopy;
[0075] The term "DSC" means differential scanning calorimetry;
[0076] The term "HPLC" means high performance liquid
chromatography;
[0077] In the present invention, if the operating temperature is
not limited, it is carried out at room temperature. The room
temperature is from 0 ° C to 35 ° C, preferably from 20 ° C to
30 ° C.
[0078] The positive progress of the invention is as follows: 1)
The preparation method of the invention is simple,
environmentally friendly and rapid, avoids the use of toxic
catalyst phenol, the reaction is carried out under normal
pressure, avoids the danger of high pressure reaction; 2)
through crystallization, product impurities The content of the
hydroxychloroquine obtained by the purification is as high as
99.9%, the maximum single impurity is controlled within 0.06%,
and the total content of the remaining impurities is <0.04%;
3) the hydroxychloroquine sulfate can be further prepared by
using the aqueous sulfuric acid solution, and the purity can
reach 99.9%. The maximum single impurity control is within
0.06%, and the total impurity content is <0.04%.
[0079] DRAWINGS
[0080] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray
powder diffraction pattern of hydroxychloroquine sulfate Form A
prepared in Example 11 of the present invention.
[0081] 2 is a DSC chart of hydroxychloroquine crystal form A
prepared in Example 11 of the present invention.
[0082] Detailed ways
[0083] The invention is further illustrated by the following
examples, which are not intended to limit the invention. The
experimental methods in the following examples which do not
specify the specific conditions are selected according to
conventional methods and conditions, or according to the product
specifications.
[0084] In the following examples, the content was calculated by
liquid chromatography (HPLC) and the area normalization method
was used. The HPLC method is as follows:
[0085] HPLC model: Aglient 1200
[0086] Column type: Aglient Zorbax XDB-C8 4.6×150mm×5μm
[0087] Detection wavelength: 254nm
[0088] Mobile phase A: 2 mL of triethylamine and 6.8 g of KH2PO4
were dissolved in 900 mL of water, and pH = 8.0 was adjusted
with 1 mol/L KOH. Dilute to 1000 mL and mix well;
[0089] Mobile phase B: methanol;
[0090] Gradient elution:
[0091] Time A(%) B(%) Description 0min 53 47 Equivalence 20min
33 67 Equivalence 20.1min 53 47 Isocratic 30min 53 47 Isocratic
[0092] The model of the powder X-diffraction test instrument
according to the present invention is Bruker D8ADVANCE; the test
conditions are: Voltage, Current is 40Kv, 40 mA, Stand-End
Position is 0-40° 2θ, Increment is 0.02° 2θ, Time per step is
0.5 s. Detection environment: 26 ° C, humidity 44% RH.
[0093] The differential scanning calorimeter model of the
present invention is TA DSC Q2000; the test method is:
Equlibrate at 20 ° C, Ramp at 10.0 ° C/min to 250.0 ° C, N 2
flow is 40 mL / min, aluminum pan, capped. Detection
environment: 25 ° C, humidity 55% RH.
[0094]
Examples 1-8
[0095] Step (1), preparation of crude hydroxychloroquine
[0096] Add 4,7-dichloroquinoline (100g) and side chain to the
reaction flask, stir under nitrogen, raise to a certain
temperature, and react to HPLC to detect 4,7-dichloroquinoline
content below 6%, stop The reaction was quenched with a
quenching liquid, and extracted with an organic solvent. The
extract was washed with purified water to pH 7-8, and distilled
under reduced pressure to give crude chlorochloroquine.
[0097] Table 1. Preparation of crude hydroxychloroquine
[0098]
[0099] Step
(2), preparation of hydroxychloroquine
[0100] The mixed solvent is added to the crude product obtained
in the step (1), dissolved under the conditions of 70±5° C.,
cooled, cooled to 10° C., seeded, crystallized, suction
filtered, and dried to obtain a hydroxychloroquine boutique.
[0101] Table 2. Preparation of hydroxychloroquine
[0102]
[0103]
[0104]
Comparative Example 1:
[0105] 100g side chain, 112g 4.7-dichloroquinoline was added to
a three-necked flask, protected by nitrogen, heated to 100 ° C,
stirred for 1 h, then heated to 120-130 ° C for 20 h, after the
reaction was completed, the temperature was lowered (below 80 °
C), with hydroxide The sodium solution was adjusted to pH >
12, extracted with dichloromethane, washed with water until
neutral, and dichloromethane was evaporated under reduced
pressure to give 147 g of crude chlorochloroquine. The yield was
86.6%, and the HPLC purity was 90.47%. To the crude
hydroxychloroquine, 300 g of methyl ethyl ketone and 300 g of
ethyl acetate were added, and the mixture was heated at 75 ° C
to dissolve. After 4 h, the temperature was slowly lowered to 20
° C, filtered, and the filter cake was washed with a mixed
solvent of methyl ethyl ketone and ethyl acetate to obtain
hydroxychloroquine. The wet product was dried at 60 ° C for 4 h
to obtain hydroxychloroquine dry product with a purity of
99.80%, a maximum single impurity of 0.12%, and a yield of
88.2%.
[0106]
Comparative Example 2
[0107] 100g of 4,7-dichloroquinoline and 110g of side chain were
added to the reactor, protected by nitrogen, heated at 78 ° C to
dissolve 4,7-dichloroquinoline, heated at 120 ° C for 20
minutes, and heated to 140 ° C. After the reaction is completed,
the reaction solution is cooled to 90 ° C ~ 100 ° C, 5% sodium
hydroxide solution is added, alkalized to neutral, extracted
with dichloromethane, and added to the combined organic phase,
250 g of drinking water is added. The layering was repeated
until the pH of the washing water was 7, and methylene chloride
was distilled off under reduced pressure to give 164 g of crude
hydroxy chloroquine. The yield was 96.9%, and the HPLC purity
was 91.78%. To the crude hydroxychloroquine, 300 g of methyl
ethyl ketone and 300 g of ethyl acetate were added, and the
mixture was heated at 75 ° C to dissolve. After 4 h, the
temperature was slowly lowered to 10 ° C, filtered, and the
filter cake was washed with a mixed solvent of methyl ethyl
ketone and ethyl acetate to obtain hydroxychloroquine. The wet
product was dried at 60 ° C for 4 h to obtain hydroxychloroquine
dry product with a purity of 99.70%, a maximum single impurity
of 0.21%, and a yield of 75.3%.
[0108]
Comparative Example 3
[0109] a. Preparation of hydroxychloroquine
[0110] 100g of 4,7-dichloroquinoline and 110g of side chain were
added to the reactor, protected by nitrogen, heated at 78 ° C to
dissolve 4,7-dichloroquinoline, heated at 120 ° C for 20
minutes, and heated to 140 ° C. After the reaction is completed,
the temperature is lowered (below 80 ° C), the pH is adjusted to
12 with sodium hydroxide solution, extracted with
dichloromethane, washed with water until neutral, and
dichloromethane is evaporated under reduced pressure to give
crude chlorochloroquine 146 g, yield: 86.7%. The HPLC purity was
90.49%. Add 400g of isopropyl acetate to the crude
hydroxychloroquine, then add 5.0g of activated carbon, reflux at
elevated temperature for 1 hour, heat filtration, the filtrate
is cooled to 0 ° C, crystallization for 2 h, filtered, and dried
at 60 ° C for 4 h to obtain hydroxychloroquine dry product. .
The purity was 99.63%, the maximum single impurity was 0.091%,
and the yield was 88.1%.
[0111] b.
Preparation of hydroxychloroquine sulfate
[0112] 100 g of hydroxychloroquine obtained in the previous step
was dissolved in 500 g of absolute ethanol, concentrated
sulfuric acid was added dropwise at 25 ° C until the solution
became cloudy, the temperature was raised at 50 ° C for 9 hours,
cooled to 20 ° C for 1 h, and filtered to obtain
hydroxychloroquine sulfate, purity 99.74. %, the largest single
impurity 0.17%, the yield was 90.2%.
[0113]
Comparative Example 4
[0114] a.
Preparation of hydroxychloroquine
[0115] 100g of 4,7-dichloroquinoline and 110g of side chain were
added to the reactor, protected by nitrogen, heated at 78 ° C to
dissolve 4,7-dichloroquinoline, heated at 120 ° C for 20
minutes, and heated to 140 ° C. After the reaction is completed,
the temperature is lowered (below 80 ° C), adjusted to pH >
12 with sodium hydroxide solution, extracted with
dichloromethane, washed with water until neutral, and
dichloromethane is evaporated under reduced pressure to give
crude hydroxychloroquine 149 g, yield 87.8%. The HPLC purity was
90.91%. To the crude hydroxychloroquine, 300 g of ethyl acetate
was added, and the mixture was heated to dissolve, and the
temperature was lowered to 0 to 10 ° C. After incubation for 2
hours, the mixture was filtered and dried to obtain a
hydroxychloroquine dry product. The purity was 99.63%, the
maximum single impurity was 0.095%, and the yield was 89.6%.
[0116] b. Preparation of hydroxychloroquine sulfate
[0117] 100g of hydroxychloroquine obtained in the previous step
is dissolved in 500g of absolute ethanol, concentrated sulfuric
acid is added dropwise at 25 °C until the solution is cloudy,
heated at 50 ° C for 9 hours, cooled to 20 ° C for 1 h, and
filtered to obtain hydroxychloroquine sulfate, purity 99.79 %,
the largest single impurity is 0.18%, and the yield is 89.2%.
[0118]
Comparative Example 5
[0119] In a three-necked round bottom flask,
4,7-dichloroquinoline (198 g, 1.0 mol), hydroxychloroquine side
chain (182 g, 1.05 mol) and isopropyl acetate 1089 g were added,
and sodium ethoxide (13.6 g, 0.2 mol) was slowly added. The
temperature is slowly raised to reflux under stirring
conditions, and then isopropyl acetate is distilled off, and the
temperature is gradually raised to 110 ° C over 9 hours, then
heated to 120-122 ° C for 10 hours, and finally heated at
120-122 ° C for 4 hours, until the reaction is complete.
Thereafter, the reaction solution was cooled to 90 to 100 ° C,
directly added to a 5% sodium hydroxide solution, and alkalized
to neutrality. The distilled isopropyl acetate was extracted
twice, and the layers were separated. 500 g of drinking water
was added to the combined organic phase, washed, layered, and
the above operation was repeated until the pH of the washing
water was 7. After the washing was completed, the water
temperature was controlled to 65 ° C, and isopropyl acetate was
distilled off under reduced pressure to obtain crude
hydroxychloroquine. The HPLC purity was 91.78%. To the crude
hydroxychloroquine, 300 g of methyl ethyl ketone and 300 g of
ethyl acetate were added, and the mixture was heated at 75 ° C
to dissolve. After 4 h, the temperature was slowly lowered to 10
° C, filtered, and the filter cake was washed with a mixed
solvent of methyl ethyl ketone and ethyl acetate to obtain
hydroxychloroquine. The wet product was dried at 60 ° C for 4 h
to obtain hydroxychloroquine dry product with a purity of 99.8%,
a maximum single impurity of 0.17%, and a yield of 87.6%.
[0120]
Comparative Example 6
[0121] 20g side chain, 22.4g 4.7-dichloroquinoline was added to
a three-necked flask, protected by nitrogen, heated to 100 ° C,
stirred for 1 h, then heated to 120-130 ° C for 20 h, the
reaction was completed, slightly cooled (90 ° C ~ 100 ° C) 20 g
of water was added to the reaction solution, and 40 g of
concentrated hydrochloric acid was added. After stirring, 80 g
of liquid alkali was added, and the mixture was stirred for 30
minutes. The aqueous phase was discarded, and the organic
solvent was evaporated under reduced pressure to obtain a crude
product. HPLC purity was 90.2%. The crude product was added with
300 g of methyl ethyl ketone and 300 g of ethyl acetate, and the
mixture was heated at 75 ° C to dissolve. After 4 h, the
temperature was slowly lowered to 10 ° C, filtered, and the
filter cake was washed with a mixed solvent of methyl ethyl
ketone and ethyl acetate to obtain hydroxy chloroquine wet
product, 60 ° C. The dried hydroxychloroquine was dried for 4 h,
the purity was 99.80%, the maximum single impurity was 0.13%,
and the yield was 88.2%.
[0122]
Comparative Example 7
[0123] 100 g of crude hydroxychloroquine (HPLC purity greater
than 92%) obtained in Example 1 was placed in a single-mouth
bottle, and a mixed solvent of 260 g of ethyl acetate and 40 g
of isopropyl alcohol was added thereto, and the mixture was
stirred at a temperature, and slowly heated to 80 ° C, refluxing
1 After the hour, the temperature is lowered to 15-20 ° C, the
crystallization time is started for 5 hours, the temperature is
lowered to 0 to 5 ° C, the crystal is separated by filtration,
and the filter cake is washed with ethyl acetate to obtain
hydroxychloroquine wet product, which is dried to obtain fine
hydroxychloroquine. The HPLC purity was 99.7%, the maximum
single impurity was 0.16%, and the yield was 75%.
[0124]
Comparative Example 8
[0125] 100 g of crude hydroxychloroquine (HPLC purity greater
than 92%) obtained in Example 1 was placed in a single-mouth
bottle, and a mixed solvent of 260 g of ethyl acetate and 40 g
of isopropyl alcohol was added thereto, and the mixture was
stirred and dissolved at a temperature. After completely
dissolved, 4.2 g was added. Activated carbon, slowly warmed to
80 ° C, reflux for 1 hour, hot filtered, filter cake washed with
26g of ethyl acetate and 4g of isopropanol mixed solvent, the
filtrate was combined, cooled to 15 ~ 20 ° C, began
crystallization time 5 hours, cooling to 0 to 5 ° C, after
thermal crystallization, filtration, the filter cake was washed
with ethyl acetate to obtain hydroxy chloroquine wet product,
which was dried to obtain HPLC hydroxychloroquine with a purity
of 99.8%, a maximum single impurity of 0.11%, and a yield of
70%.
[0126] Comparison of Example 1 and Comparative Examples 3 and 4
[0127] Table 3. Comparison of products and impurities in crude
hydroxychloroquine
[0128]
[0129] Table 4. Comparison of products and impurities in
hydroxychloroquine
[0130]
[0131]
[0132] Note: The relative retention time is based on the
hydroxychloroquine HPLC retention time; that is, the relative
retention time of "1" indicates hydroxychloroquine, and the
other relative retention times are impurities.
[0133] After refining, in Example 1, the content of impurity 1
was controlled to be <0.06%; the content of the remaining
impurities was one order of magnitude lower than that of the
comparative example, and the total amount of remaining
impurities was <0.04%. The main impurity content in the
comparative example was 0.085-0.1%, both of which were close to
0.1%. The impurity content could not be stably controlled, and
it was easy to be >0.1% in the subsequent storage process.
[0134] Examples 9 to 17 and Comparative Examples 9 to 11
[0135]
Preparation of Hydroxychloroquine Sulfate - Salt
Crystallization
[0136] Hydroxychloroquine (50 g; obtained in Example 1) was
dissolved in an alcohol solvent, and an aqueous sulfuric acid
solution was added dropwise at 20 to 35 ° C to turbidity, and
the dropwise addition was stopped, and the temperature was
raised to 35 to 55 ° C, and the reaction was kept for 5 hours or
more. After the reaction was completed, the temperature was
lowered to 0 to 20 ° C, and the temperature was kept for 1 hour,
and the filter cake was filtered by suction to obtain a finished
product.
[0137] Table 5. Preparation of hydroxychloroquine sulfate
[0138]
[0139]
[0140] The HPLC data of Example 11 and Comparative Example 9
were analyzed as follows:
[0141] Table 6. Comparison of products and impurities in
hydroxychloroquine sulfate
[0142]
[0143] Note: The relative retention time is based on the HPLC
retention time of hydroxychloroquine sulfate; that is, the
relative retention time is “1” for hydroxychloroquine sulfate,
and the other relative retention time is impurity.
EP0588430A1
(S)-(+)-Hydroxychloroquine
[ PDF ]
Abstract
The present invention provides (S)-(+)-Hydroxychloroquine
substantially free of (R)-(-)-hydroxychloroquine, or a
pharmaceutically acceptable acid-addition salt thereof, the use
in the manufacture of a medicament for treatment of malaria,
lupus erythematosus or rheumatoid arthritis and a composition
containing it for the treatment of such diseases. The weight
ratio of (S)-(+)-Hydroxychloroquine to
(R)-(-)-hydroxychloroquine is preferably at least 90:10, most
preferably at least 98:2.
0001] The invention relates to
(S)-(+)-2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol
[hereinafter (S)-(+)-hydroxychloroquine] which is useful in the
treatment of acute attacks and suppression of malaria due to
Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and
susceptible strains of Plasmodium falciparum, systemic and
discoid lupus erythematosus, and rheumatoid arthritis.
[0002] Racemic hydroxychloroquine, which is
2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol
(Surrey U.S. Patent 2,546,658), and which is sold as the sulfate
salt by Sanofi Winthrop Pharmaceuticals under the tradename
Plaquenil® Sulfate, is primarily useful as an antimalarial agent
and is also used in treating lupus erythematosus and rheumatoid
arthritis.
[0003] A.J. McLachlan et al ., J. Chromatogr., 570 (No. 1),
119-127, September 18, 1991, disclose the high-performance
liquid chromatographic separation of the enantiomers of
hydroxychloroquine and its major metabolites in biological
fluids. The authors acknowledge a gift of
S(+)-hydroxychloroquine from Sterling Pharmaceuticals.
[0004] J. Iredale et al. , J. Chromatogr., 573 (No. 2), 253-258,
January 17, 1992, disclose the development of a sequential
achiral-chiral high-performance liquid chromatographic system
for the determination of the enantiomers of hydroxychloroquine
and its three major metabolites.
[0005] S.E. Tett et al ., Br. J. Clin. Pharmac., 26 , 303-313
(1988), disclose a dose-ranging study of the pharmacokinetics of
racemic hydroxychloroquine following intravenous administration
to healthy volunteers. The authors state that the
pharmacokinetics of hydroxychloroquine are similar to those of
chloroquine.
[0006] Chem. Abstr. 92 , 69587p (1980) discloses that when
administered orally daily for four days beginning at two hours
after Plasmodium bergher infestation in mice, doses of 5 and 20
mg/kg of the d-enantiomer of chloroquine diphosphate were more
effective than corresponding doses of the 1-enantiomer in
antimalarial parameters measured, including percentage of cured
mice at >7.5 mg/kg; and that the d-enantiomer was also more
active than the racemate, but only at subcurative doses.
[0007] Chem. Abstr. 90 , 132863b (1979) discloses the results of
a study of the activity of chloroquine enantiomers against
rodent malaria in which it was found that (+)-chloroquine
diphosphate was a more active antiplasmodial agent than
(―)-chloroquine diphosphate in Plasmodium vinckei-infected mice,
and that the activity of (±)-chloroquine diphosphate was between
that the the two enantiomers.
[0008] J.C. Craig et al ., J. Org. Chem., 53 , 1167-1170 (1988),
disclose the absolute configuration of the enantiomers of
chloroquine and the synthesis of (R)-(―)-chloroquine by
condensation of (R)-(―)-4-amino-1-(diethylamino)pentane of
>90% purity with 4,7-dichloroquinoline.
[0009] G. Blaschke et al. , Chem. Ber., 111 , 2732-2734 (1978)
disclose the chromatographic separation of the enantiomers of
chloroquine as well as their preparation by condensation of (+)-
and (―)-4-amino-1-(diethylamino)pentane with
4,7-dichloroquinoline.
[0010] H.N. Bernstein, Annals of Ophthalmology, 23 , 292-296
(1991), presents an analysis of all published cases and Food and
Drug Administration reports of retinopathy induced by
hydroxychloroquine. The author states that antimalarial therapy,
because of a relative lack of systemic side effects compared
with other immunomodulating drugs, has been used increasingly
over the past 15 years for the treatment of rheumatoid
arthritis, discoid and systemic lupus erythematosus, and other
predominantly autoimmune diseases, and that in the United
States, hydroxychloroquine is preferred to chloroquine because
it is considered significantly less retinotoxic at the current
recommended maximum dose (400 mg/day, according to the FDA and
the manufacturer). The author nevertheless notes that physicians
are concerned about using drugs with retinotoxic potential at
higher dose levels. He then suggests, inter alia , that the risk
of true retinopathy is nullified when the maintenance daily dose
is based on ≦6.5 mg/kg body weight and states that even in the
absence of a real toxicity risk, it is recommended that a
periodic ocular examination program be followed because of the
retinotoxic history associated with hydroxychloroquine.
[0011] Drugs having an asymmetric center are, in most instances,
administered as racemates consisting of a 1:1 mixture of two
enantiomers. However, since there often are pharmacodynamic and
pharmacokinetic differences between the two enantiomers,
therapeutic efficacy may reside entirely or for the most part in
one of the two enantiomers and therefore may be diluted by the
other enantiomer in the racemate and, moreover, any adverse
effect which may be associated with the racemate may be
attributable to the other enantiomer. In such cases it would be
desirable to administer the single enantiomer in which the
therapeutic efficacy resides.
[0012] Plaquenil® Sulfate (hydroxychloroquine sulfate) is a
racemic mixture (1:1) of 2 enantiomers. The manufacturer of this
drug contraindicates its use, inter alia , in the presence of
retinal or visual field changes attributable to any
4-amino-quinoline compound and warns that irreversible retinal
damage has been observed in some patients who had received long
term or high-dosage 4-aminoquinoline therapy for discoid and
systemic lupus erythematosus or rheumatoid arthritis and notes
that retinopathy has been reported to be dose-related. Adverse
reactions discussed by the manufacturer include a small number
of cases of retinal changes which have been reported as
occurring in patients who received only hydroxychloroquine.
[0013] Although Plaquenil® Sulfate has an excellent ocular
safety record when the maintenance dose levels recommended by
the manufacturer (310 mg base/day) for the treatment of malaria,
discoid and systemic lupus erythematosus and rheumatoid
arthritis are not exceeded, nevertheless, because cases of
retinal changes in patients receiving only hydroxychloroquine
have been reported and physicians are concerned about using
drugs with retinotoxic potential at higher doses (see H.N.
Bernstein, supra ), it would be highly desirable if the risk of
retinopathy in the use of hydroxychloroquine could be
substantially reduced, particularly for that segment of the
population which could benefit from hydroxychloroquine therapy
but where such therapy is contraindicated because of the
presence of retinal or visual field changes attributable to any
4-aminoquinoline compound.
[0014] Unexpectedly, it has now been found that when
(S)-(+)-hydroxychloroquine and its (R)-(―)-antipode were
compared in the Rat Pleurisy Macrophage Model, which model is
used to identify disease modifying antirheumatic drugs [see Z.E.
Mielens et al ., J. Rheumatol., 12 , 1083-1087 (1985)],
(S)-(+)-hydroxychloroquine was approximately 70% more active
than the corresponding (R)-(―)-enantiomer in decreasing the
accumulation of cells (monocytes) to the pleural cavity.
Furthermore, it was found that in a study wherein racemic
hydroxychloroquine was administered either intravenously,
subcutaneously or orally to rabbits, there was an
enantioselective accumulation of (R)-(―)-hydroxychloroquine in
the ocular tissue. The ratio of the (R)-(―)-enantiomer to the
(S)-(+)-enantiomer in this study was 1.58 ± 0.24. These results
were consistent with the results of pharmacokinetic studies in
humans treated with racemic hydroxychloroquine in which it was
found that for (R)-(―)-hydroxychloroquine, the fraction absorbed
was approximately two times greater, the systemic clearance was
more than two fold greater and the apparent half life was
significantly faster than for the corresponding
(S)-(+)-enantiomer. These differences are attributed to
enantioselective distribution into various tissue compartments
such as the retina.
[0015] These unexpected discoveries have important clinical
implications for hydroxychloroquine therapy in that malaria,
lupus erythematosus and rheumatoid arthritis may now be
effectively treated with (S)-(+)-hydroxychloroquine
substantially free of (R)-(―)-hydroxychloroquine with
concomitant lower adverse effects attributable to the
corresponding (R)-(―)-enantiomer with the result that it will be
possible, where indicated, to administer
(S)-(+)-hydroxychloroquine at higher dose levels and/or longer
periods of times than is now recommended for administration of
equivalent dose levels of racemic hydroxychloroquine.
[0016] Therefore, in one aspect of the invention there is
provided (S)-(+)-hydroxychloroquine substantially free of
(R)-(―)-hydroxychloroquine, or a pharmaceutically acceptable
acid-addition salt thereof.
[0017] In another aspect there is provided a method for the
treatment of malaria, lupus erythematosus or rheumatoid
arthritis in a human which comprises administering to the human
an amount effective to treat malaria, lupus erythematosus or
rheumatoid arthritis of (S)-(+)-hydroxychloroquine substantially
free of (R)-(―)-hydroxychloroquine or a pharmaceutically
acceptable acid-addition salt thereof.
[0018] In another aspect the invention provides a composition
for treating malaria, lupus erythematosus or rheumatoid
arthritis in a human comprising (S)-(+)-hydroxychloroquine
substantially free of (R)-(―)-hydroxychloroquine or a
pharmaceutically acceptable acid-addition salt thereof in an
amount effective for the treatment of malaria, lupus
erythematosus or rheumatoid arthritis and a pharmaceutically
acceptable vehicle.
[0019] A further aspect of the invention provides the use in the
manufacture of a medicament for treating malaria, lupus
erythematosus or rheumatoid arthritis in a human of
(S)-(+)-hydroxychloroquine substantially free of
(R)-(―)hydroxychloroquine, or a pharmaceutically acceptable
acid-addition salt thereof. The (S)-(+)-hydroxychloroquine
substantially free of (R)-(―)-hydroxychloroquine, or a
pharmaceutically acceptable acid-addition salt thereof, is
preferably present in the medicament in therapeutic amounts
effective for the treatment of such diseases.
[0020] In order to avoid or minimize adverse effects associated
with the enantioselective accumulation of
(R)-(―)-hydroxychloroquine in ocular tissue, it is preferable in
practising the invention to use as the active ingredient
(S)-(+)-hydroxychloroquine substantially free of
(R)-(―)-hydroxychloroquine. In this context, the expression
"substantially free" means that the active ingredient should
contain at least 90% by weight of (S)-(+)-hydroxychloroquine and
10% by weight or less of (R)-(―)-hydroxychloroquine, preferably
at least 95% by weight of the (S)-(+)-enantiomer and 5% by
weight or less of the (R)-(―)-enantiomer and more preferably at
least 98% by weight and 2% by weight or less of the
(R)-(―)-enantiomer. Ideally the (S)-(+)-hydroxychloroquine
should be free of (R)-(―)-hydroxychloroquine.
[0021] Included within the purview of this invention in addition
to (S)-(+)-hydroxychloroquine are its pharmaceutically
acceptable acid-addition salts such as those derived from
nontoxic inorganic acids, including hydrochloric acid, sulfuric
acid, sulfamic acid and the like, and nontoxic organic acids,
including tartaric acid, citric acid, acetic acid and the like.
[0022] The composition of the invention can be formulated for
oral or parenteral administration in solid, liquid or other
appropriate dosage forms including tablets, capsules and
solutions, using conventional pharmaceutically acceptable
vehicles and techniques.
The invention will now be described with reference to the
following Example but is in no way to be construed as limited
thereto.
EXAMPLE Preparation of (S)-(+)-Hydroxychloroquine
[0023] (S)-(+)-Hydroxychloroquine was prepared by condensing
(S)-(+)-2-[(4-aminopentyl)ethylamino]ethanol with
4,7-dichloroquinoline. The latter compound is known. The
(S)-(+)-2-[(4-aminopentyl)ethylamino]ethanol was prepared by
resolving known racemic 2-[(4-aminopentyl)ethylamino]ethanol by
forming a salt thereof with known (S)-(+)-mandelic acid and
separating the (S)-(+)-mandelic acid salts of the two
enantiomers by crystallization.
[0024] The
following example illustrates the method of preparation.
a) (S)-(+)-2-[(4-Aminopentyl)ethylamine]ethanol.
[0025] A solution of (S)-(+)-mandelic acid (15.9 g, 105 mmol,
0.60 equivalents) in ethyl alcohol was added to a solution of
racemic 2-[(4-aminopentyl)ethylamino]ethanol (30.37 g, 174 mmol,
1.00 equivalents) in ethyl ether. The solvents were evaporated
and the resulting white solid was recrystallized from ethyl
alcohol, washed with a little ethyl ether, recrystallized again
from ethyl alcohol and washed with a little ethyl alcohol and
then ethyl ether. The crystals were dried in vacuo overnight to
give 7.45 g of salt of the title compound with (S)-(+)-mandelic
acid, m.p. 126-127°C. This salt was dissolved in water and the
resulting solution was made basic with 35% sodium hydroxide and
extracted three times with methylene chloride. The combined
extracts were dried (K₂CO₃), filtered and evaporated. The
residue was distilled (Kugelrohr; 80-100°C/0.020 tort) to yield
the title compound as a colorless oil (approximately 3.7 g)
which was used as such in the next step.
b) (S)-(+)-Hydroxychloroquine.
[0026] A mixture of the product from (a) above (approximately
3.7 g, 19.0 mmol, 1.00 equivalents). N-ethyldiisopropylamine
(2.45 g, 20.9 mmol, 1.10 equivalents) and 4,7-dichloroquinoline
(3.31 g, 19.0 mmol, 1.00 equivalents) was heated at reflux under
nitrogen for 48 hours and cooled. The excess base was poured off
and the residue was taken up in methyl alcohol and excess
aqueous sodium hydroxide. The mixture was diluted with water and
extracted three times with methylene dichloride. The combined
organic extracts were washed two times with water, once with
brine, dried (K₂CO₃), filtered and evaporated to dryness. The
residue was filtered through silica gel with
tetrahydrofuran:diethylamine (95:5) to give 4.12 g of material.
This material was subjected to fractional distillation
(Kugelrohr). A white crystalline solid was obtained at
approximately 130°C and 0.010 torr. The receiver bulb was
changed and the distillation temperature was increased to
approximately 200°C. This provided 2.93 g of the title compound
which was converted to its sulfate salt by treatment with one
equivalent of 1 molar sulfuric acid in methyl alcohol and
evaporation to a sticky oil. The oily salt was dissolved in 5 ml
methyl alcohol and acetone was added slowly until the solution
turned a little murky. This solution was allowed to stand
overnight at room temperature and the resulting crystalline salt
was collected and washed with acetone and dried at 50°C (0.01
torr) for twenty-four hours to give approximately 390 mg of
(S)-(+)-hydroxychloroquine sulfate as an off-white solid, m.p.
235-238°C(dec.); [α]D = +105.9 (1% in H₂O). It was determined by
direct chromatographic resolution via high performance liquid
chromatography using a chiral stationary phase that this
material contained 98.4% by weight of the (S)-(+)-enantiomer and
1.6% by weight of the (R)-(―)-enantiomer.
CN109280029
Preparation method of hydroxychloroquine sulfate
[ PDF ]
Abstract
The invention discloses a preparation method of high-purity
hydroxychloroquine sulfate. The method uses
4,7-dichloroquinoline and hydroxychloroquine side chain as raw
materials to directly prepare hydroxychloroquine hydrochloride,
hydroxychloroquine hydrochloride is neutralized with sodium
alcoholate or potassium alcoholate, filtered, concentrated,
beaten and crystallized to obtain hydroxychloroquine refined
product, and the hydroxychloroquine refined product finally is
subjected to salifying reaction with sulfuric acid in a certain
proportion of pure aqueous solution to obtain hydroxychloroquine
sulfate. The method avoids the use of phenol or its catalyst in
the process of preparing hydroxychloroquine, avoids the
extraction operation in the post-treatment, has high product
purity, and basically does not generate waste water in the
production process. The method is convenient to operate and has
high yield, the HPLC purity of prepared hydroxychloroquine
sulfate is more than or equal to99.6%, and maximum single
impurity is less than or equal to 0.1%, and that method is more
suitable for industrial production.
[0002] The invention belongs to the technical field of medicinal
chemistry, and in particular relates to a preparation method of
hydroxychloroquine sulfate.
[0003]
Background technique
[0004] Hydroxychloroquine Sulfate, chemical name
2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]-ethanol
sulfate is a quinoline drug, clinical For rheumatoid arthritis,
juvenile chronic arthritis, discoid and systemic lupus
erythematosus, and skin lesions caused or exacerbated by
sunlight.
[0005] Chinese patent CN 103724261B discloses an
industrialization method of hydroxychloroquine sulfate: the
temperature reaction is directly added to the side chain of
4,7-dichloroquinoline and hydroxychloroquine under the
protection of inert gas, and the reaction is gradually heated to
120-130 ° C during the reaction. After 13-24 hours, the reaction
is completed, the temperature is lowered, water is added to the
reaction system to dissolve, and the alkalization layer is
separated, the aqueous phase is discarded, and the organic phase
is crystallized by adding an organic solvent to obtain
hydroxychloroquine. In the method, hydroxychloroquine is easily
precipitated as an oil during the acid-base treatment, and a
large amount of alkali and inorganic salts are easily mixed, so
that the purity of the crude hydroxychloroquine is not high, and
the quality of hydroxychloroquine sulfate obtained directly for
salt formation is often unqualified.
[0006] Chinese patent CN104230803B provides a preparation method
of hydroxychloroquine sulfate, which dissolves
4,7-dichloroquinoline and hydroxychloroquine side chain in an
acetate solvent, and adds sodium alkoxide as a catalyst to
gradually heat up the acetate solvent by distillation. The
condensation reaction is carried out in a manner, and after the
reaction is completed, the pH is adjusted to 9-10 by adding a 5%
aqueous sodium hydroxide solution, extracted with an organic
solvent of an acetate, washed, crystallized to obtain
hydroxychloroquine, and then a mixture solvent of
hydroxychloroquine and sulfuric acid in an alcohol-water mixture
is obtained. The salt formation reaction is carried out in the
system. In comparison, the method described in this patent is
simpler, and its main disadvantage is that the solubility of
hydroxychloroquine in the acetate solvent is small, and the
solvent required for extracting hydroxychloroquine using an
acetate solvent in the post-treatment is used. Great amount.
[0007] In the preparation method of the above-disclosed
hydroxychloroquine sulfate, there are some disadvantages which
are not favorable for industrial production. Therefore, it is
necessary to solve the above problems and further improve the
synthesis process of hydroxychloroquine sulfate.
[0008]
Summary of the invention
[0009] The object of the present invention is to overcome the
above problems and to provide a novel green environmentally
friendly, simple and convenient method for synthesizing
high-purity hydroxychloroquine sulfate.
[0010] The invention provides a preparation method of
hydroxychloroquine sulfate, and the specific steps are as
follows:
[0011] (1)After mixing 4,7-dichloroquinoline with
hydroxychloroquine side chain, the mixture is heated and
condensed without solvent and without catalyst to prepare
hydroxychloroquine hydrochloride;
[0012] (2)Hydroxychloroquine hydrochloride is dissolved in an
anhydrous alcohol solvent, neutralized with sodium alkoxide or
potassium alkoxide, and the resulting potassium chloride or
sodium chloride is removed by filtration, and the filtrate is
concentrated to obtain crude hydroxychloroquine;
[0013] (3)The crude hydroxychloroquine is firstly pretreated
with acetate and then crystallized with a mixed solvent of
acetate and alcohol to obtain a hydroxychloroquine product
having a purity greater than 99.5% and a maximum single impurity
of less than 0.1%;
[0014] (4)The hydroxychloroquine product is dissolved in
ethanol, and an equimolar aqueous solution of sulfuric acid or
an ethanol-water solution of sulfuric acid is added dropwise
thereto, and the internal temperature of the reaction is
controlled to be below 40 ° C during the dropwise addition, and
the mixture is stirred at room temperature after the dropwise
addition. 10-24h, filtration, drying, that is,
hydroxychloroquine sulfate, its HPLC purity>99.6%, the
maximum single impurity <0.1%; the reaction equation is as
follows:
[0015]
[0016] In the above step (1), the molar ratio of the
4,7-dichloroquinoline to the hydroxychloroquine side chain is
1:1 to 1:1.2; the reaction temperature is 110-130 ° C, and the
reaction time is 18-48 h.
[0017] In the above step (2), the alcohol solvent is selected
from any one or more of methanol, ethanol or isopropanol; and
the sodium alkoxide or potassium alkoxide reagent is selected
from the group consisting of sodium methoxide, sodium ethoxide
and sodium isopropoxide. Any one of sodium t-butoxide, potassium
methoxide, potassium ethoxide, potassium propoxide or potassium
t-butoxide.
[0018] In the above step (2), the volume-to-mass ratio of the
theoretical yield of the alcohol solvent and hydroxychloroquine
hydrochloride is 3-8 mL/g.
[0019] In the above step (2), the molar ratio of the amount of
sodium alkoxide or potassium alkoxide added to the theoretical
yield of hydroxychloroquine hydrochloride is from 1.0:1 to
1.1:1.
[0020] In the above step (3), the acetate is selected from any
one of methyl acetate, ethyl acetate, isopropyl acetate or
t-butyl acetate; the alcohol is selected from the group
consisting of methanol, ethanol, propanol and isopropyl alcohol.
Any of alcohol or n-butanol.
[0021] In the above step (3), the volume ratio of the acetate to
the alcohol is from 4:1 to 8:1.
[0022] In the above step (4), the mass concentration of the
aqueous solution of sulfuric acid or the ethanol-water solution
of sulfuric acid is less than 35%.
[0023] The 4,7-dichloroquinoline and hydroxychloroquine side
chains used in the present invention are industrial raw
materials which are commercially available on a large scale, and
the solvents used are industrial raw materials.
[0024] The "hydroxychloroquine side chain" referred to in the
present invention means the starting material
"5-(N-ethyl-N-2-hydroxyethylamine-2-pentylamine); "sodium
alkoxide" means an alkyl alcohol A base formed by substituting
hydrogen for sodium; "acetate" means an ester of acetic acid
with a monohydric alcohol.
[0025] Compared with the prior art, the beneficial effects of
the present invention are:
[0026] 1)4，7- The condensation of dichloroquinoline with the
hydroxychloroquine side chain is a solventless reaction,
avoiding the use of highly polluting catalyst phenol, and does
not require the use of other catalysts. The reaction is carried
out under normal pressure and does not require protection with
an inert gas. simple.
[0027] 2)After the reaction, the anhydrous alcohol is used as a
solvent to dissolve hydroxychloroquine hydrochloride,
neutralized with sodium alkoxide and potassium alkoxide, and the
resulting inorganic salt, sodium chloride and potassium chloride
can be removed by filtration, concentrated to recover alcohol
solvent, and then acetic acid. The ester solvent is beaten to
obtain crude hydroxychloroquine. The extraction operation is
avoided, no waste water is generated, and the labor intensity is
greatly reduced.
[0028] 3)The crude hydroxychloroquine which has been subjected
to acetate-based beating has a high purity, and is further
crystallized by a mixed solvent of an acetate and an alcohol,
and the purity of the obtained hydroxychloroquine is further
improved, and the content of the single impurity is easily
reduced to 0.1% or less.
[0029] 4)Hydroxychloroquine and sulfuric acid salt are formed in
an ethanol-water mixed solvent, avoiding the risk of producing
toxic substances under anhydrous conditions, the product has
good crystallinity, and the obtained quality index of
hydroxychloroquine sulfate (HPLC purity is 99.6% or more, the
largest single Miscellaneous less than 0.1%)
[0030]
Detailed ways
[0031] The preparation of the hydroxychloroquine sulfate
industrialization of the present invention is further
illustrated and explained below by way of examples without
limiting the scope of the invention.
[0032]
Example 1 Synthesis of Hydroxychloroquine
[0033] In a 500 mL four-necked flask, 4,7-dichloroquinoline: 100
g (0.51 mol) and hydroxychloroquin side chain: 89 g (0.51 mol),
heated to 110 ° C for 1 hour, and then heated to 120 ° C for 24
hours. The plate was monitored until the 4,7-dichloroquinoline
disappeared. The mixture was cooled slightly. Anhydrous methanol
(600 mL) was added, stirred and dissolved. 1.0 eq of sodium
methoxide (27.5 g) was added in portions, stirred for 2 h,
filtered to remove insolubles, filtrate It was concentrated to
dryness under reduced pressure, and then ethyl acetate (300 mL)
was added and then filtered to afford 169 g of crude
chlorochloroquine.
[0034] The above crude hydroxychloroquine was added to a mixed
solvent of methanol-methyl acetate (1:4, v/v, 600 mL), dissolved
by heating, and then naturally cooled to room temperature,
stirred and crystallized for 5 h, filtered, and the filter cake
was run with methyl acetate. Washing, drying at 50 ° C to
constant weight, hydroxychloroquine product about 145g, yield of
85.1%, HPLC purity > 99.5%, the maximum single impurity
<0.1%.
[0035]
Example 2 Synthesis of Hydroxychloroquine
[0036] In a 500 mL four-necked flask, 4,7-dichloroquinoline: 100
g (0.51 mol) and hydroxychloroquin side chain: 92 g (0.53 mol),
heated to 110 ° C for 1 hour, and then heated to 125 ° C for 20
hours. The plate was monitored until 4,7-dichloroquinoline
disappeared, cooled to room temperature, dissolved in ethanol
(800 mL), 1.1 eq sodium ethoxide (38.15 g) was added in
portions, stirred for 1-2 h, filtered to remove insolubles, and
the filtrate was reduced. The mixture was concentrated to
dryness, then EtOAc EtOAc (EtOAc)
[0037] The above crude hydroxychloroquine was added to a mixed
solvent of ethanol-ethyl acetate (1:5, v/v, 800 mL), dissolved
by heating, and then naturally cooled to room temperature,
stirred and crystallized for 8 hours, filtered, and the filter
cake was isopropyl acetate. Rinse, dry at 50 ° C to constant
weight, hydroxychloroquine product about 146g, yield of 86.0%,
HPLC purity > 99.5%, the largest single impurity <0.1%.
[0038]
Example 3 Synthesis of Hydroxychloroquine
[0039] In a 500 mL four-necked flask, 4,7-dichloroquinoline: 100
g (0.51 mol) and hydroxychloroquine side chain: 95 g (0.55 mol),
heated to 110 ° C for 1 hour, and then heated to 130 ° C for 18
hours. The plate was monitored until 4,7-dichloroquinoline
disappeared, cooled to room temperature, dissolved in absolute
ethanol (1000 mL), 1.05 eq of potassium t-butoxide (59.9 g) was
added in portions, stirred for 1-2 h, filtered to remove
insoluble The filtrate was concentrated to dryness under reduced
pressure, and then ethyl acetate was added and then filtered to
afford crude hydroxy chloroquine (167.9 g).
[0040] The above crude hydroxychloroquine was added to a mixed
solvent of ethanol-ethyl acetate (1:6, v/v, 1000 mL), dissolved
by heating, and then naturally cooled to room temperature,
stirred and crystallized for 6 h, filtered, and the filter cake
was evaporated with ethyl acetate. Washing, drying at 50 ° C to
constant weight, hydroxychloroquine product about 148g, yield of
87.2%, HPLC purity > 99.5%, maximum single impurity <0.1%.
[0041]
Example 4 Synthesis of Hydroxychloroquine
[0042] In a 500 mL four-necked flask, 4,7-dichloroquinoline: 100
g (0.51 mol) and hydroxychloroquin side chain: 100 g (0.57 mol),
heated to 110 ° C for 1 hour, and then heated to 130 ° C for 18
hours. The plate was monitored until 4,7-dichloroquinoline
disappeared, cooled to room temperature, dissolved in
isopropanol (1200 mL), 1.0 eq of sodium tert-butylate (48.96 g)
was added in portions, stirred for 1-2 h, cooled, insoluble The
precipitate was separated, and the insoluble material was
filtered, and the filtrate was concentrated to dryness under
reduced pressure, and then isopropyl acetate was used to be
pulverized and filtered to obtain 167.8 g of crude
hydroxychloroquine.
[0043] The above crude hydroxychloroquine was added to a mixed
solvent of isopropyl alcohol-isopropyl acetate (1:7, v/v, 1200
mL), heated to 80 ° C to dissolve, and then naturally cooled to
room temperature, stirred for 8 h, filtered, filtered. The cake
was rinsed with a small amount of isopropyl acetate, and dried
at 50 ° C to constant weight to obtain about 150 g, the yield
was 88.3%, the HPLC purity was >99.5%, and the maximum single
impurity was <0.1%.
[0044]
Example 5 Synthesis of Hydroxychloroquine
[0045] In a 500 mL four-necked flask, 4,7-dichloroquinoline was
added: 100 g (0.51 mol) and hydroxychloroquine side chain: 104 g
(0.60 mol), and the temperature was raised to 110 ° C for 48
hours, and the spot plate was monitored for 4, 7-two.
Chloroquinoline disappeared, cooled to room temperature,
dissolved in ethanol (1500 mL), 1.0 eq of potassium methoxide
was added in portions, stirred for 2 h, insoluble matter was
precipitated, and insolubles were removed by filtration, and the
filtrate was concentrated to dryness under reduced pressure,
then isopropyl acetate was added. The ester was beaten and
filtered to obtain 168.5 g of crude hydroxychloroquine.
[0046] The above crude hydroxychloroquine was added to a mixed
solvent of isopropyl alcohol-isopropyl acetate (1:8, v/v, 1500
mL), heated to 80 ° C to dissolve, and then naturally cooled to
room temperature, stirred for 5 h, filtered, filtered. The cake
was rinsed with a small amount of isopropyl acetate, and dried
at 50 ° C to constant weight to obtain about 145 g, the yield
was 85.4%, the HPLC purity was >99.5%, and the maximum single
impurity was <0.1%.
[0047]
Example 6 Synthesis of Hydroxychloroquine Sulfate
[0048] 10.0 g of hydroxychloroquine product was added to a 250
mL four-necked flask, 100 mL of ethanol was added, and the
mixture was stirred and dissolved at room temperature, and an
equivalent amount of dilute sulfuric acid (2.97 g of
concentrated sulfuric acid + 7 mL of water) was added dropwise
to control the dropping rate, and the internal temperature of
the reaction liquid was not higher than After 40 ° C, the
mixture was stirred at room temperature for 18 hours, filtered,
rinsed with 10 mL×2 ethanol, and dried at 50 ° C for 2 hours to
obtain 12.2 g of white crystalline powder, HPLC purity
>99.6%, maximum single impurity <0.1%.
[0049]
Example 7 Preparation of Hydroxychloroquine Sulfate
[0050] Take 10.0g of hydroxychloroquine product into a 250mL
four-necked flask, add 90mL of ethanol, stir to dissolve at room
temperature, add equivalent amount of dilute sulfuric acid
(2.97g concentrated sulfuric acid + 7mL water + 10mL ethanol),
control the drop rate, the internal temperature of the reaction
solution Not higher than 40 ° C, added, stirred at room
temperature for 18 hours, filtered, rinsed with 10 mL × 2
ethanol, blasted at 50 ° C for 2 hours to obtain 12.0 g of white
crystalline powder, HPLC purity > 99.6%, maximum single
impurity <0.1 %.
[0051]
Example 8 Synthesis of Hydroxychloroquine Sulfate
[0052] 10.0 g of hydroxychloroquine product was added to a 250
mL four-necked flask, 80 mL of ethanol was added, and the
solution was dissolved at room temperature, and an equivalent
amount of dilute sulfuric acid (2.97 g of concentrated sulfuric
acid + 7 mL of water + 20 mL of ethanol) was added dropwise to
control the drop rate and the internal temperature of the
reaction solution. Not higher than 40 ° C, added, stirred at
room temperature for 18 hours, filtered, rinsed with 10 mL × 2
ethanol, blasted at 50 ° C for 2 hours, to obtain 12.2 g of
white crystalline powder, HPLC purity > 99.6%, maximum single
impurity <0.1 %.
[0053]
Example 9 Synthesis of Hydroxychloroquine Sulfate
[0054] 10.0 g of hydroxychloroquine product was added to a 250
mL four-necked flask, 70 mL of ethanol was added, and the
mixture was stirred and dissolved at room temperature, and an
equivalent amount of dilute sulfuric acid (2.97 g of
concentrated sulfuric acid + 7 mL of water) was added dropwise
to control the dropping rate, and the internal temperature of
the reaction liquid was not higher than After addition at 40 °
C, the mixture was stirred at room temperature for 18 hours,
filtered, rinsed with 10 mL of 2 ethanol, and dried at 50 ° C
for 2 hours to obtain 12.3 g of white crystalline powder, HPLC
purity >99.6%, maximum single impurity <0.1%.
[0055]
Example 10 Synthesis of Hydroxychloroquine Sulfate
[0056] Take 10.0g of hydroxychloroquine product into a 250mL
four-necked flask, add 60mL of ethanol, stir to dissolve at room
temperature, add equivalent amount of dilute sulfuric acid
(2.97g concentrated sulfuric acid + 7mL water + 40mL ethanol),
control the drop rate, the reaction liquid internal temperature
Not higher than 40 ° C, added, stirred at room temperature for
18 hours, filtered, rinsed with 10 mL × 2 ethanol, and dried by
air at 50 ° C for 2 hours to obtain 12.1 g of white crystalline
powder, HPLC purity > 99.6%, maximum single impurity < 0.1
%.
CN103472154
Method for analysis of hydroxychloroquine sulfate raw
material and preparation by high performance liquid
chromatography
[ PDF ]
Abstract
The invention belongs to the field of drug analysis and
discloses a method for analysis of a hydroxychloroquine sulfate
raw material and preparation by high performance liquid
chromatography. The method can realize effective separation of
related substances in hydroxychloroquine sulfate so that
hydroxychloroquine sulfate quality is controlled,
hydroxychloroquine sulfate raw material and preparation content
is accurately determined, and hydroxychloroquine sulfate
stability is indicated. The method has the advantages of strong
specificity, high accuracy and simple operation.
The invention belongs to the field of drug analysis, and
specifically relates to an analysis by high performance liquid
chromatography Hydroxychloroquine sulfate raw materials and
preparation methods.
Background technique
Hydroxychloroquine sulfate is used to treat discoid lupus
erythematosus and systemic lupus erythematosus, and similar
Rheumatoid arthritis and other drugs. Its structural formula is:
The chemical name is
2-[[4-[(7-chloro-4-quinoline)amino]pentyl]ethylamino]-ethanolsulfur
Acid salt. For the related substances introduced in the
synthesis of synthetic hydroxychloroquine sulfate and degraded
in storage, Whether it is in the bulk drug or the preparation,
it needs to be controlled. Therefore, to achieve The separation
of chloroquine and its related substances is used in the quality
control of the synthesis and preparation of hydroxychloroquine
sulfate The system has important practical significance.
At present, the national standards and ministerial standards of
the People’s Republic of China, BP (2012), USP （36）Among them,
thin layer chromatography is used. After research, it is found
that thin layer chromatography is used to detect The related
substances of hydroxychloroquine sulfate have the problems of
not strong specificity, low sensitivity, and thin Layer
chromatography can only detect the limits of related substances,
but cannot determine the exact amount of impurities. and In the
content determination method of hydroxychloroquine sulfate and
its preparations, chloroform is often used to extract
hydroxychloroquine, Measured by non-aqueous titration method.
Because chloroform is more toxic, it is easy to cause
experimental operators Harm and easily pollute the environment.
Summary of
the invention
The innovation of the present invention lies in the
development of high performance liquid chromatography for the
detection of hydroxychloroquine sulfate Related substances and
content in raw materials and preparations, high performance
liquid chromatography as a chromatographic analysis The method
has the advantages of good separation effect, high sensitivity
and fast analysis speed.
The invention overcomes the lack of specificity, low sensitivity
and poor use of existing detection methods. Disadvantages of
toxic agents. The chromatographic conditions are:
Stationary phase: octadecyl silane bonded silica gel or octane
silane bonded silica gel
Mobile phase: mixed solvent composed of water-soluble organic
solvent and buffer solution; using isocratic Or gradient
elution.
Flow rate: 0.5～2.0ml/min
Detection wavelength: 220～300nm
Among them, the salt for preparing the buffer solution includes
acetate, phosphate, cation pair reagent, etc. Among them,
phosphates are preferred, mainly selected from potassium
dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium
hydrogen phosphate, Disodium phosphate. The mobile phase
contains a certain amount of triethylamine, which helps reduce
the main component chromatographic peaks The amount of
triethylamine is 0.01%～1%V/V of the buffer solution, and the
mobile phase is slow The pH selection range of the rinse is
7.2-8.2, preferably pH 8.0.
Wherein, the water-soluble organic solvent in the mixed solvent
of the mobile phase is: methanol or ethyl Nitrile, or other
water-soluble organic solvents acceptable for liquid
chromatography.
In the quality control method of the present invention, the
wavelength 220～ 270nm; When performing content determination, a
wavelength of 245-300 nm can be selected; among them, 254 nm is
preferred.
This method overcomes the lack of specificity, sensitivity and
use of existing detection methods. Disadvantages of toxic
agents.
Figure 1 shows that the impurities 1, 2, and 3 in the raw
material of hydroxychloroquine sulfate are hydroxyquinoline,
LC45-1, dichloroquinoline (retention times are 7.833, 13.547,
24.820min), It is well separated from the peak of
hydroxychloroquine sulfate (retention time 20.447min).
Description of the drawings
Figure 1: Related substances detected in specific embodiment 1
of the present invention Product related substance detection
map. Impurities 1, 2, 3 are hydroxyquinoline, LC45-1, two
Chloroquinoline (retention time is 7.833, 13.547, 24.820min),
hydroxychloroquine sulfate Peak (retention time 20.447min)
Figure 2: A comparative map of related substances detected in
specific embodiment 1 of related substances of the present
invention, Related substance control solution map.
Hydroxychloroquine sulfate peak (retention time 20.573min)
Figure 3: The chromatogram of the test solution in the content
specific example 1 of the present invention, the content is
measured Set, the chromatogram of the test solution.
Hydroxychloroquine sulfate peak (retention time 20.084min)
Figure 4: The chromatogram of the reference substance solution
in the content specific example 1 of the present invention, and
the content is measured In the calibration, the chromatogram of
the reference solution: hydroxychloroquine sulfate peak
(retention time 20.103min)
detailed
description
The present invention will be further described in detail
below through specific embodiments, but it should not be
understood In order to limit the scope of protection of the
present invention, based on the above-mentioned technical ideas,
common use in the field Modifications, replacements, and
alterations made by common technical knowledge and conventional
means fall within the scope of the present invention.
Specific
Example 1: Detection of Related Substances:
Use octyl silane-bonded silica gel as filler, and use
phosphoric acid buffer solution (take dihydrogen phosphate
Potassium 2.72g, put in 1000ml water, add 2ml triethylamine,
adjust with 1mol potassium hydroxide pH to 8.0±0.05 is mobile
phase A, methanol is mobile phase B, and gradient elution is
performed according to the following table:
The detection wavelength is 254nm.
The number of theoretical plates should not be lower than the
peak of hydroxychloroquine sulfate 2000。
Take an appropriate amount of hydroxychloroquine sulfate raw
material and add a solvent [mobile phase A-methanol (53:47)] to
dissolve it Dissolve and dilute to make a solution containing
0.5mg per 1ml as the test solution; take an appropriate amount
accurately The amount, diluted with the above solvent to make a
solution containing 5μg per 1ml as a control solution.
respectively Precisely measure 20μl each of the test solution
and the control solution, inject into the liquid chromatograph,
and record the color Spectrogram. Calculate the content of
related substances according to its own low concentration
control method.
Specific Example 2: Detection of Related Substances:
Use octyl silane-bonded silica gel as filler, and use phosphoric
acid buffer solution (take dihydrogen phosphate Sodium 3.12g,
put in 1000ml water, add 5ml triethylamine, adjust with 1mol
potassium hydroxide pH to 8.0±0.05) is mobile phase A,
acetonitrile is mobile phase B, and gradient elution is
performed according to the following table:
The detection wavelength is 254nm.
The number of theoretical plates should not be lower than the
peak of hydroxychloroquine sulfate
2000。
Take an appropriate amount of hydroxychloroquine sulfate raw
material and add a solvent [mobile phase A-acetonitrile (60:40)]
to dissolve it Dissolve and dilute to make a solution containing
0.5mg per 1ml as the test solution; take an appropriate amount
accurately The amount, diluted with the above solvent to make a
solution containing 5μg per 1ml as a control solution.
respectively Precisely measure 20μl each of the test solution
and the control solution, inject into the liquid chromatograph,
and record the color Spectrogram. Calculate the content of
related substances according to its own low concentration
control method.
Specific Example 3: Detection of Related Substances:
Use octadecyl silane-bonded silica gel as a filler, and use a
phosphoric acid buffer solution 5.44g potassium hydrogen, put in
1000ml water, add 3ml triethylamine, dissolve it with 1mol/L
potassium hydroxide Adjust the pH to 8.0±0.05)-methanol (60:40)
as the mobile phase, the detection wavelength is 254 nm. The
number of theoretical plates should not be less than 2000 based
on the peak of hydroxychloroquine sulfate.
Take an appropriate amount of hydroxychloroquine sulfate raw
material, dissolve and dilute it with mobile phase to make it
contain per 1ml 0.4mg solution is used as the test solution;
accurately measure an appropriate amount, dilute with mobile
phase to make
A solution containing 4μg in ml was used as a control solution.
Precisely take the test solution and control separately 20μl
each of the solution was injected into the liquid chromatograph,
and the chromatogram was recorded. According to its own low
concentration control method Calculate the content of related
substances.
Specific Example 4: Detection of Related Substances:
Use octadecyl silane-bonded silica gel as a filler, and use a
phosphoric acid buffer solution 5.44g potassium hydrogen, put in
1000ml water, add 2ml triethylamine, and dissolve it with 1mol/L
potassium hydroxide Adjust the pH to 8.0±0.05)-methanol (60:40)
as the mobile phase, the detection wavelength is 254 nm. The
number of theoretical plates should not be less than 2000 based
on the peak of hydroxychloroquine sulfate.
Take an appropriate amount of hydroxychloroquine sulfate raw
material, dissolve and dilute it with mobile phase to make it
contain per 1ml 0.4mg solution is used as the test solution;
accurately measure an appropriate amount, dilute with mobile
phase to make 1 A solution containing 4μg in ml was used as a
control solution. Precisely take the test solution and control
separately 20μl each of the solution was injected into the
liquid chromatograph, and the chromatogram was recorded.
According to its own low concentration control method Calculate
the content of related substances.
Specific Example 5 for Detection of Related Substances:
Use octadecyl silane-bonded silica gel as a filler, and use a
phosphoric acid buffer solution 5.44g potassium hydrogen, put in
1000ml water, add 1ml triethylamine, and dissolve it with 1mol/L
potassium hydroxide Adjust the pH to 8.0±0.05)-methanol (60:40)
as the mobile phase, the detection wavelength is 254 nm. The
number of theoretical plates should not be less than 2000 based
on the peak of hydroxychloroquine sulfate.
Take an appropriate amount of hydroxychloroquine sulfate tablet
powder, dissolve it with mobile phase and dilute it to make the
content per 1ml 0.4mg of the solution, filter, take the
continued filtrate as the test solution; accurately measure an
appropriate amount, use The mobile phase was diluted to make a
solution containing 4μg per 1ml as a control solution.
Respectively accurately measure 20μl each of the test solution
and the control solution were injected into the liquid
chromatograph, and the chromatogram was recorded. press
Calculate the content of related substances by its own low
concentration control method.
Specific Example of Assay 1:
Use octyl silane-bonded silica gel as filler, and use phosphoric
acid buffer solution (take dihydrogen phosphate Potassium 2.72g,
put in 1000ml water, add 2ml triethylamine, adjust with 1mol
potassium hydroxide (pH to 8.0±0.05) is mobile phase A, methanol
is mobile phase B, perform gradient washing according to the
following table Off:
The detection wavelength is 254nm.
The number of theoretical plates should not be lower than the
peak of hydroxychloroquine sulfate 2000。
Take an appropriate amount of hydroxychloroquine sulfate raw
material, accurately weigh it, and add solvent [mobile phase-A
methanol (53：47)] Dissolve and dilute quantitatively to make a
solution containing 0.1mg per 1ml as a test Product solution;
another appropriate amount of hydroxychloroquine acid reference
substance dried at 105°C, accurately weighed, plus The solvent
is dissolved and diluted to prepare a solution containing
approximately 0.1 mg per 1 ml as a reference solution; Measure
20μl of the above test solution and reference solution and
inject into the liquid chromatograph, record Chromatogram.
Calculate the peak area according to the external standard
method to obtain.
Specific example of content determination 2:
Use octadecyl silane-bonded silica gel as a filler, and use a
phosphoric acid buffer solution 2.72g potassium hydride, put in
1000ml water, add 2ml triethylamine, adjust with 1mol potassium
hydroxide PH to 8.0±0.05)-methanol (60:40) is the mobile phase,
and the detection wavelength is 329nm. The number of theoretical
plates should not be less than 2000 based on the peak of
hydroxychloroquine sulfate.
Take an appropriate amount of hydroxychloroquine sulfate raw
material, accurately weigh it, add mobile phase to dissolve and
dilute quantitatively Make a solution containing 0.1mg per 1ml
as the test solution; take another after drying at 105℃ An
appropriate amount of hydroxychloroquine acid reference
substance, accurately weighed, dissolved in mobile phase and
diluted to make each 1ml The solution containing about 0.1mg in
the medium is used as the reference solution; respectively
measure the above-mentioned test solution and the Inject 20μl of
the product solution into the liquid chromatograph and record
the chromatogram. Calculate by peak area according to external
standard method Count, get it.
Specific example of content determination 3:
Use octyl silane-bonded silica gel as filler, and use phosphoric
acid buffer solution (take hydrogen phosphate dibasic Sodium
4.0g, put in 1000ml water, add 2ml triethylamine, adjust with
1mol potassium hydroxide (pH to 8.0±0.05)-acetonitrile (70:30)
is the mobile phase, and the detection wavelength is 254nm. The
number of theoretical plates should not be less than 2000 based
on the peak of hydroxychloroquine sulfate.
Take 20 hydroxychloroquine sulfate tablets, accurately weigh,
grind finely, take an appropriate amount of fine powder, and add
flow Dissolve the phases and dilute quantitatively to make a
solution containing 0.1mg per 1ml, filter, and take the
subsequent filtrate as It is the test solution; another
appropriate amount of hydroxychloroquine acid reference
substance dried at 105°C, accurately weighed, Add mobile phase
to dissolve and dilute to make a solution containing about 0.1mg
per 1ml as a reference solution Solution; respectively measure
20μl of the above-mentioned test solution and reference solution
and inject into the liquid chromatograph, Record the
chromatogram. Calculate the peak area according to the external
standard method to obtain.
KR101115412
NEW PREPARATION OF HYDROXYCHLOROQUINE
[ PDF ]
PURPOSE: A method for
preparing hydroxychloroquine is provided to suppress generation
of by-product by reducing reaction temperature and time and
prepare the hydroxychloroquine with high yield and purity.
CONSTITUTION: A hydroxychloroquine of chemical formula 1 is
prepared by reacting... step of reacting sulfuric acid with
hydroxychloroquine to obtain hydroxychloroquine sulfate.
The present invention relates to a method for producing
hydroxychloroquine which is a therapeutic agent for malaria.
Hydroxychloroquine has the structure of the following formula 1
and its chemical name is 2 - [[4- [7-chloro-4-quinolinyl] amino]
pentyl] 4- [7-chloro-4-quinolinyl] amino] pentyl] -ethylamino]
ethanol} was first disclosed in U.S. Patent No. 2,546,658.
N'-N'-hydroxyethyl-1,4-pentanediamine {N'ethyl-N ',
N'-tetramethyluronium hexafluorophosphate)
β-hydroxyethyl-1,4-pentadiamine} was reacted with potassium
iodide (KI) and a phenol solvent at 125-130 ° C. for 18 hours or
longer to prepare crude hydroxychloroquine, (S) -N'ethyl-N
'[beta] -hydro-quinoline in the case of U.S. Pat. No. 5,314,894,
(S) - (+) - hydroxycroquinoline {(R) - (R) -methyl-2- S) - (+) -
hydroxychloroquine}. In Canadian patent CA 2,561,987,
4,7-dichloroquinoline (2) and N'ethyl- After reacting
cyethyl-1,4-pentadiyimine (3) at 120-130 ° C for 20-24 hours, a
protecting group is introduced into the reaction product as
follows to easily remove the impurities, and then the protecting
group is hydrolyzed (PG in formula (A), (B) and (C) means a
protecting group). However, the known processes for preparing
hydroxychloroquine and its acid addition salt include a method
of producing toxic phenol Use of the same solvent or a reagent
such as N, N-diisopropylethylamine having a high boiling point
and a similar form to the final product makes it difficult to
remove by-products during the production of the acid salt.
Moreover, since the long reaction time at high temperature
increases the production cost and increases the production of
by-products, there is a demand for a method of synthesizing
hydroxychloroquine and dicellulose salt, which is more efficient
in the industrial field. It is necessary to develop new
synthesis method of hydroxychloroquine which overcomes various
disadvantages and shows high purity and yield.
An object of the present invention is to provide a novel process
for the production of hydroxychloroquine which suppresses the
production of by-products and reduces the production cost by
significantly lowering the reaction temperature and the reaction
time by using a pressure without using a catalyst and a reaction
solvent The present invention relates to a novel process for the
preparation of hydroxychloroquine using pressure, which
comprises reacting 4,7-dichloroquinoline and N'-ethyl-N '?
-Hydroxyethyl-1,4-pentanediamine at high pressure The process of
the present invention can be carried out by reacting
4,7-dichloroquinoline with N, N'-ethyl-N'-tetrachloroquinoline
without using a catalyst and a solvent, In the present
invention, the high pressure means a pressure exceeding 1 atm
(about 1 bar) higher than the atmospheric pressure, and a
pressure of 5 bar to 30 b The high pressure in the present
invention is due to inert gas such as nitrogen gas or argon gas
or air without moisture. In the present invention, the reaction
time is preferably 10 to 20 bar, The reaction temperature may be
varied within a range of 80 to 150 ° C. and more preferably 100
to 120 ° C. In the present invention, 4, The reaction molar
ratio of 7-dichloroquinoline and N'-ethyl-N '?
-Hydroxyethyl-1,4-pentadiamine can be varied, but is preferably
1: 1.05 to 1.5, more preferably 1: 1.05-1.1 The present
invention also provides a process for preparing hydroxy
chloroquinone represented by the following formula (1): (a)
reacting 4,7-dichloroquinoline with N'ethyl-N '?
-Hydroxyethyl-1,4- And (b) reacting the hydroxides prepared in
step (a) The present invention also provides a process for
preparing hydroxychloroquine sulfate comprising reacting
chloroquine with sulfuric acid (H2SO4) to prepare
hydroxychloroquine sulfate. The reaction conditions of step (a)
are as described above. The method for preparing
hydroxychloroquine according to the present invention is
characterized in that 4,7-dichloroquinoline and N'-ethyl-N '?
-Hydroxyethyl-1,4-pentanediamine are reacted with 1 : 1.1 molar
ratio, put into a high-pressure reactor and pressurize with
nitrogen pressure from 5 bar to 20 bar, preferably from 10 bar
to 15 bar. The mixture is stirred at 80 ° C for 30 minutes until
the 4,7-dichloroquinoline is dissolved, and then stirred at 100
° C to 120 ° C for 4 hours to 6 hours. , The reaction
temperature and the reaction time are remarkably lowered to
inhibit the production of by-products, and hydroxychloroquine is
produced at a high purity and a high yield, and the production
cost is reduced.
Hereinafter, preferred embodiments of the present invention will
be described in order to facilitate understanding of the present
invention. However, the following examples are provided only for
the purpose of easier understanding of the present invention,
and the contents of the present invention are not limited by the
examples. Example 1 Preparation of Hydroxychloroquine Using 20
Bar Pressure 10 Kg of 4,7-dichloroquinoline and 10 g of
N'-ethyl-N '? - hydroxy 11.4 Kg (1.0 eq) of
ethyl-1,4-pentadiamine was charged into a high-pressure reactor
and charged with 20 bar of nitrogen gas. The mixture was stirred
at 80 ° C for 30 minutes and then at 100 ° C to 110 ° C for 4
hours. 30Kg of 3N HCl aqueous solution and 20Kg of chloroform
were added thereto. The mixture was cooled to room temperature
and stirred for 1 hour. After the mixture was allowed to stand,
the resulting product was transferred to an aqueous layer and
the remaining by-products to a chloroform layer. This procedure
was repeated three times and an aqueous layer with the desired
compound was collected. The collected water layer was extracted
with 40Kg of 2N NaOH and chloroform solvent, and the aqueous
layer was removed. 5Kg of activated carbon and 5Kg of alumina
were added, and the mixture was stirred at 40 ° C for 6 hours
and then filtered. The filtrate was concentrated under reduced
pressure and 60 Kg of ethylene glycol (EDC) was added thereto to
crystallize the crystals. After filtration and vacuum drying at
40 DEG C, 14 Kg (yield 78.2%) of the title compound was
obtained. 1H NMR (500 MHz) (d), 7.32 (d), 6.38 (d), 5.09 (d),
3.50-3.80 (m), 2.40-2.70 (m), 1.50-1.80 (m), 1.30 (d), 1.00 (t)
Example 2 Preparation of Hydroxychloroquine (Formula 1) Using 10
bar Pressure 10 kg of 4,7-dichloroquinoline and N'-
-1,4-pentadiamine (11 eq.) Was charged into a high-pressure
reactor and charged with nitrogen gas at 10 bar. The mixture was
stirred at 80 ° C for 30 minutes and then at 100 ° C to 110 ° C
for 6 hours. 30Kg of 3N HCl aqueous solution and 20Kg of
chloroform were added thereto. The mixture was cooled to room
temperature, stirred and allowed to stand, and the resulting
product was transferred to an aqueous layer and the remaining
by-products to a chloroform layer. This procedure was repeated
three times and an aqueous layer with the desired compound was
collected. The collected water layer was extracted with 40 Kg
aqueous solution of 2N NaOH and 20 Kg of chloroform solvent to
remove the aqueous layer. 5 Kg of activated carbon and 5 Kg of
alumina were added and stirred at 40 ° C for 6 hours and
filtered. The filtrate was concentrated under reduced pressure,
60 Kg of EDC was added to crystallize, followed by filtration
and vacuum drying at 40 DEG C to obtain 14.5 g (yield 75.5%) of
the title compound. 1H NMR (500 MHz) Example 3 Preparation of
Hydroxychloroquine Sulfate 10 Kg of hydroxychloroquine prepared
in Example 1 was dissolved in 100 Kg of ethanol and then cooled
to 10 ° C. To this solution was added 1.58 Kg of concentrated
sulfuric acid (1.0 eq) dissolved in 50 kg of ethanol was stirred
for 12 hours while slowly adding thereto. (D2) 8.08 (d), 7.95
(d), 7.53 (d), 7.35 (dd), 6.64 (d, d), 3.94 (d), 3.60-3.70 (m),
2.90-3.30 (m), 1.50-1.80 (m), 1.23 (d), 1.09 (t) Example 4
Preparation of Hydroxychloroquine Sulfate 10 Kg of the
hydroxychloroquine prepared in Example 1 was dissolved in 100 Kg
of ethyl acetate, and a solution prepared by dissolving 1.58 Kg
(1.0 eq) of concentrated sulfuric acid in 50 Kg of ethyl acetate
was added to the solution at 30 ° C while stirring slowly. After
stirring for 12 hours at 0 ° C, 10.0 Kg (77.5%) of the title
compound was obtained by filtration.
CN102050781A
Industrial preparation method of hydroxychloroquine
sulfate
[ PDF ]
Abstract
The invention relates to an industrial preparation method of
hydroxychloroquine sulfate, which comprises heating 4,
7-dichloroquinoline and hydroxychloroquine side chain at
refluxing temperature to 120-125 DEG C, allowing reaction to
obtain hydroxychloroquine, and reacting with sulfuric acid to
obtain hydroxychloroquine sulfate. The method can obtain
high-purity hydroxychloroquine sulfate with single impurity less
than or equal to 0.1% and purity higher than or equal to 99.5%;
and has less preparation procedures, simple process, high
product yield, good quality, low environmental pollution, no use
of highly toxic solvent, and is easy for industrial production.
[0001]
Technical field
[0002] The invention belongs to the field of chemistry or
medicinal chemistry, and particularly relates to an industrial
preparation method of hydroxychloroquine sulfate. The side chain
of 4,7-dichloroquinoline and hydroxychloroquine is heated at a
reflux temperature and slowly heated to 120 ° C-125 ° C The
hydroxychloroquine is prepared, and then reacted with sulfuric
acid to obtain hydroxychloroquine sulfate. This method can
obtain high purity hydroxychloroquine sulfate with single
impurity ≤0.1% and purity ≥99.5%.
[0003]
Background technique
[0004] The structure of hydroxychloroquine sulfate is shown
below. Its chemical name is 2-[[4-[(7-chloro-4-quinolinyl)
amino] pentyl] ethylamino] -ethanol sulfate, CAS number is
747-36- 4. Hydroxychloroquine sulfate was successfully developed
by Winthrop Corporation. It was first listed in the United
States in 1956 and has been listed in many countries and regions
such as France, Denmark, Japan, Germany, and Finland. The US FDA
approved hydroxychloroquine sulfate tablets for the treatment of
lupus erythematosus and rheumatoid arthritis on May 29, 1998.
[0005]
[0006] CA2561987 discloses a method for preparing
hydroxychloroquine, the method is as follows,
[0007]
[0008] The method includes sequentially adding isopropyl alcohol
(2vol), 4-amino-N-ethyl- (2-hydroxyethyl) -pentylamine (1.5eq,
0.75mol), 4,7-dichloroquinoline (1.0eq, 0.5mol), stir, heat,
stir at 120-130 ℃ for 20-24h, then cool to 70-80 ℃, add water
(2vol) and methyl isobutyl ketone (3vol), adjust the pH at
10-11, min Liquid, add acetic anhydride (0.1eq) to the organic
layer, stir at room temperature overnight, then add LiOH-H2O
(0.25eq), water (0.5vol) and methanol (0.5vol) in sequence, the
mixture was stirred at room temperature overnight, Wash again
with water. Add methanol (5vol) and sulfuric acid (1.0eq,
0.5mol) to the organic layer, heat to 35-45 ° C and stir for
3-4h, then cool to 20-25 ° C, filter, and wash the filter cake
with methanol to obtain hydroxychloroquine sulfate Crude
product, yield 80%, chromatographic purity greater than 99.5%.
The impurity 7-chloro-4- (4-N-hydroxyethyl-1-methyl tertiary
amino) quinoline is less than 0.1%. Add the crude product
obtained above (200.0g), water (1L) and methyl isobutyl ketone
(800ml), stir to dissolve, cool to 0-5 ℃, add 5N sodium
hydroxide until the pH is 10.5-11.0, Stir at room temperature
for 0.5-1h, separate the liquid, add 5% sodium chloride solution
(200ml) to the organic layer and wash with activated carbon
(20.0g), stir at room temperature, filter, wash the filter cake
with methanol (200ml), spin-dry the filtrate, Get
hydroxychloroquine. The purification process of
hydroxychloroquine and its sulfate in this method is very
complicated, especially in the post-treatment to remove ethyl
impurities (7-chloro-4- (4-N-hydroxyethyl-1-methyl tertiary
amino) After a complicated post-processing process, the
impurities are finally controlled to less than 0.1%, which has
high cost and long time, which is not conducive to industrial
production.
[0009] US2546658 (equivalent to GB680255, DE838142) discloses a
synthesis method of hydroxychloroquine. The reaction process of
this method is as follows:
[0010]
[0011] The operation of this method is as follows:
4,7-dichloroquinoline (90g), phenol (90g), potassium iodide
(1.0g), 5- (N-ethyl-N-2-hydroxyethylamino) -2 -Pentylamine
(132g), stirred, heated, stirred at 125-130 ° C for 18h, after
which the reaction solution was cooled, methanol (1.9L) was
added, the reaction solution was filtered with charcoal, and the
clear filtrate was added to methanol (300ml) Phosphoric acid
(100g), wipe the wall with a glass rod and let it stand for 2
days, suction filtration, washing the filter cake with methanol
and drying to obtain hydroxychloroquine diphosphate (10lg),
yield 41.9%, melting point 155-156 ° C. The obtained phosphate
was dissolved in water, completely dissociated with ammonium
hydroxide, extracted with chloroform, distilled off chloroform,
and the residue was recrystallized with ether to obtain crude
hydroxychloroquine (30g), melting point 77-82 ° C, yield 44.3%.
Dichloromethane and ethyl acetate can be further added to
recrystallize to obtain pure hydroxychloroquine, melting point
89-91 ° C.
[0012] The method of US2546658 uses phenol with a weight ratio
of 1: 1 as the reaction catalyst. Phenol is toxic and corrosive.
Its concentrated solution is strongly corrosive to the skin.
After treatment, it is converted into sodium phenol wastewater.
Phenol-containing wastewater is one of the most harmful and
difficult to treat in industrial wastewater. It is one of the
wastewaters that are currently controlled in China. It has a
large environmental pollution; phenol has a melting point of 42
° C and is solid at room temperature. To successfully feed, it
must be heated to dissolve into a liquid In order to feed, the
operation is very cumbersome, and industrial production is
difficult; the reaction does not involve the solvent, the
material is very viscous, and the selectivity of mass transfer,
heat transfer, transmission, and reaction is very poor. It is
necessary to remove impurities by forming phosphate, 4, 7-two
The yield of chloroquinoline to crude hydroxychloroquine is
44.3%, the production cost is high, and it is difficult to
implement industrial production. At the same time, this method
is not suitable for industrial production.
[0013] WO2010027150 also discloses a method for synthesizing
hydroxychloroquine sulfate, whose reaction circuit is as
follows:
[0014]
[0015] The method includes sequentially adding
4,7-dichloroquinoline, 4-amino-N-ethyl- (2-hydroxyethyl)
-pentylamine, pressurizing with nitrogen or argon to maintain
the pressure at 5-20bar Stir at 30 ° C for 30min, warm to
100-120 ° C and react for 4-6h. After the reaction is complete,
add dilute hydrochloric acid and chloroform to acidify
hydroxychloroquine. At this time, hydroxychloroquine forms a
hydrochloride and dissolves in the aqueous phase. After
collecting the aqueous phase, add sodium hydroxide to alkalinize
and extract hydroxychloroquine with chloroform. The chloroform
layer is concentrated and dichloromethane is used after
concentration. The hydroxychloroquine product is obtained after
crystallization of ethane. Hydroxychloroquine is added with
sulfuric acid under the condition of ethanol as a solvent to
obtain hydroxychloroquine sulfate.
[0016] The method of WO2010027150 still has the
following disadvantages:
[0017] 1、Promote the condensation reaction by pressurizing in
the autoclave, but because the pressure range is 5-20 bar, it
has great safety risks in industrial applications;
[0018] 2、The post-treatment of the reaction is to obtain
hydroxychloroquine product by recrystallization after
acidification and alkalization, which is equivalent to two
refinings, and the product yield is greatly lost. At the same
time, chloroform and dichloroethane are selected for extraction
and recrystallization, which are both toxic Very large reagents
should be avoided in the production of APIs.
[0019] According to the three methods disclosed above, the
method of CA2561987 has certain advantages in environmental
protection and reaction conditions compared to other methods. No
toxic reagents and high pressure are used. However, the reaction
time is maintained at 120-130 ° C for up to 20 -24h, it will
cause the impurity content in the crude product to be too high,
increasing the post-treatment pressure, and also has the
following prominent shortcomings:
[0020] 1、The control of the reaction also needs to be refined.
If the temperature rise process of the reaction is strictly
controlled, the content of by-products in the crude product will
be further reduced, and at the same time, the conversion rate of
the product will be improved and the production cost will be
reduced.
[0021] 2、5-(N-ethyl-N-2-hydroxyethylamino) -2-pentylamine
(referred to as "hydroxychloroquine side chain" in the present
invention) is used in a large amount, and the amount of
hydroxychloroquine side chain is 4,7-di The 2-3 times of
chloroquinoline makes the hydroxychloroquine side chain account
for a large proportion of the cost, resulting in too high
production costs.
[0022] 3、In order to remove 7-chloro-4-
(4-N-hydroxyethyl-1-methyl tertiary amino) quinoline during the
post-treatment of the reaction, a more expensive methyl isobutyl
ketone was used, and the steps were complicated , Increasing
production costs.
[0023] 4、There are many overnight treatment operations in
post-processing, and there will be uncertainty in the operation
time when applied to production, resulting in production
deviations.
[0024] In general, the current methods of synthesizing
hydroxychloroquine sulfate use highly toxic catalysts and
solvents, the synthesis route is lengthy, the reaction
selectivity is poor, the reaction period is long, special
pressure-resistant equipment is required, the post-reaction
treatment is cumbersome and difficult to operate, and the
production cost is high , Insufficient product content, etc.
Therefore, it is necessary to further improve the method for
preparing hydroxychloroquine sulfate in order to obtain a more
efficient, simpler, more selective, more environmentally
friendly, and lower cost method for preparing high-purity
hydroxychloroquine sulfate.
[0025]
Summary of the invention
[0026] The purpose of the present invention is to provide an
industrial preparation method for hydroxychloroquine sulfate.
This method can increase the purity of hydroxychloroquine in the
reaction solution by controlling the temperature and time of
distilling off the solvent by gradually raising the temperature
during the reaction process and the reaction time. With regard
to the content of related impurities, hydroxychloroquine sulfate
with higher yield and high purity is obtained, with a purity ≥
99.7% and a single impurity ≤ 0.1%. The method also avoids the
use of toxic solvents and catalysts, which is beneficial to
environmental protection. The reaction conditions are mild, high
pressure is avoided, the amount of hydroxychloroquine side
chains is reduced, the post-processing is simple, and the
production cost is significantly reduced. Therefore, it is
particularly suitable for industrial production.
[0027] To achieve the purpose of the present invention, the
following embodiments are provided:
[0028] In one embodiment, an industrial preparation method of
hydroxychloroquine sulfate of the present invention includes:
[0029] Condensation reaction of 4,7-dichloroquinoline and
hydroxychloroquine side chain in an organic solvent by heating
and gradually distilling off the solvent to obtain crude
hydroxychloroquine, which is recrystallized to obtain
hydroxychloroquine, which is then converted into sulfuric acid
Salt reaction to produce hydroxychloroquine sulfate,
[0030]
[0031] The method is characterized in that: the method of
gradually raising the temperature to distill off the solvent
includes: after heating the reaction solution to the initial
reflux temperature, then distilling off the solvent by gradually
raising the temperature for 7-12 hours to 120-125 ° C,
preferably 9-10 hours, and then maintaining The reaction
temperature is 120 ° C to 125 ° C for 13 to 18 hours, preferably
14 to 16 hours.
[0032] In the above embodiment, the organic solvent is selected
from propanol, isopropanol, n-butanol and their mixed solvents,
preferably isopropanol.
[0033] In the above scheme, the molar ratio of
4,7-dichloroquinoline to hydroxychloroquine side chain is 1:
1.2.
[0034] In the above embodiment, the recrystallization is
performed in an organic solvent selected from the group
consisting of ethanol, isopropanol, ethyl acetate, and mixed
solvents thereof, preferably ethyl acetate and isopropanol.
[0035] In the above embodiment, the hydroxychloroquine reacts
with concentrated sulfuric acid to form a salt, wherein the
weight ratio of hydroxychloroquine to concentrated sulfuric acid
is 1: 0.25 to 0.30.
[0036] In the above embodiment, the hydroxychloroquine reacts
with concentrated sulfuric acid to form a salt, and the
appropriate solvent is selected from ethanol, isopropanol, ethyl
acetate and their mixed solvents, preferably ethyl acetate and
ethanol.
[0037] In the above embodiment, after the reaction of
4,7-dichloroquinoline and hydroxychloroquine side chain is
completed, the reaction product is extracted with
dichloromethane, and the extract is distilled by heating to
remove the dichloromethane to obtain crude hydroxychloroquine.
[0038] The term "hydroxychloroquine side chain" refers to the
starting material "5- (N-ethyl-N-2-hydroxyethylamino)
-2-pentylamine".
[0039] In the industrial preparation method of
hydroxychloroquine sulfate of the present invention, in
optimizing the preparation process of hydroxychloroquine
sulfate, the inventors were surprised to find that the
temperature in the reaction mixture of 4,7-dichloroquinoline and
hydroxychloroquine side chain was controlled by stage heating
The temperature and time for the organic solvent to evaporate,
that is, during the evaporation of the organic solvent, it takes
7-12 hours to gradually increase the temperature from the
temperature at the beginning of the reflux to 120-125 ℃, and the
reaction under the conditions of 120 ℃ ~ 125 ℃ The time is
shortened to 13-18 hours. At the same time, the lower molar
ratio of 4,7-dichloroquinoline and hydroxychloroquine side chain
can achieve the best balance between cost and yield, thereby
reducing the amount of hydroxychloroquine side chain. The
hydroxychloroquine with purity ≥ 99.5% can be obtained only by
recrystallization during treatment. The purity of
hydroxychloroquine sulfate after salt formation can reach 99.7%
or more (determined by HPLC external standard method), and its
single impurity ≤ 0.1%.
[0040] The industrial preparation method of hydroxychloroquine
sulfate of the invention has few preparation steps, simple
process, high product purity, ideal yield, mild reaction
conditions (no pressurized conditions), and avoids the use of
corrosive reagents, which is less harmful to the environment and
more suitable For industrial production.
[0041] Through the follow-up monitoring of the reaction state,
we found that the condensation reaction is the main temperature
range for the production of by-products at 125-130 ° C. If the
reaction time is too long within this temperature range, the
by-products of the product will increase, resulting in an
increase in the content of impurities The inventors found that
the conversion of raw materials and the control of impurities
achieved the best balance by exploring the reaction temperature
and time, and found that by controlling the heating method of
the temperature-increasing reaction, first, by extending the
temperature-rising reaction time below 120 ° C, the reaction was
promoted as much as possible The conversion at this temperature
improves the conversion rate of the raw material
4,7-dichloroquinoline; then the reaction time is reduced to
120-125 ° C and the reaction time is shortened to 13-18 hours in
order to minimize side reactions at this high temperature
Production, reduce the impurity content in the product. Due to
the greatly reduced content of impurities, there is no need to
use methyl isobutyl ketone, only one-step recrystallization
using low-cost common solvents to obtain high-purity
hydroxychloroquine products, its purity can reach more than
99.5%, while a single impurity ≤0.1%. By using this purity
hydroxychloroquine to form a salt, hydroxychloroquine sulfate
with a purity greater than 99.7% and a single impurity ≤0.1% can
be obtained.
[0042] In short, the beneficial effects of the present invention
are as follows: The present invention discloses a method for
preparing hydroxychloroquine sulfate, using
4,7-dichloroquinoline as the starting material, and
hydroxychloroquine sulfate is prepared by condensation and salt
formation in two steps; The condensation reaction uses propanol,
isopropanol, one or more of n-butanol as a solvent, and
gradually increases the conversion rate and yield of the
reaction by means of stage heating. For the crude product of
hydroxychloroquine, ethanol, isopropanol, and ethyl acetate are
used Recrystallization of esters or their mixed solvents
improves the purity of hydroxychloroquine and keeps its purity
above 99.5%; selecting a suitable solvent as a solvent in the
salt formation reaction can further purify the product, improve
product yield and quality, and reduce The production cost makes
the purity of hydroxychloroquine sulfate HPLC external standard
method above 99.7%, and the single impurity below 0.1%.
[0043] The method of the present invention does not use highly
toxic reagents, the reaction and post-treatment processes are
simple and controllable, no special pressure equipment is used,
the environmental pollution is small, and it is very suitable
for industrial production.
[0044]
detailed description
[0045] The following examples are used to further explain the
present invention, but do not limit the scope of the present
invention.
[0046]
Example 1. Preparation of hydroxychloroquine sulfate
[0047] a. Preparation of hydroxychloroquine
[0048] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine 153g; in a 1000mL
three-necked round bottom flask, add 4,7-dichloroquinoline 90g
and isopropanol 141g, and heat to 60 ° C under stirring to
completely dissolve slowly 95.13g of hydroxyquine side chain was
added dropwise, and the timing was started after the addition
was completed. The temperature was gradually increased to
120-125 ° C over 7 hours, and then kept at 120 ° C-125 ° C for
16 hours until the high-performance liquid detection reached the
end of the reaction, waiting for the reaction After completion,
the reaction solution was cooled to a temperature of 50-60 ° C,
and a 6% sodium hydroxide solution was added. After
alkalization, the pH value was> 12, while continuing to lower
the temperature to 20-25 ° C. After the temperature was reached,
279 g of dichloromethane was added for the first time and
stirred for 10 minutes. After standing for 15 minutes, the
liquid was separated and the organic phase was stored. Add 198g
of dichloromethane to the water phase for the second time and
stir for 10 minutes. After standing for 15 minutes, separate the
liquid and combine the organic phase with the previous one. Add
120g of dichloromethane to the water phase for the third time
and stir for 10 minutes. After standing for 15 minutes, separate
the liquid. The organic phase is combined with the previous one,
and the water phase is treated as waste water. To the combined
organic phase, 500 g of drinking water was added, stirred for 5
minutes, and allowed to stand for 15 minutes, and then
separated. The organic phase is continuously washed with water,
and the above operation is repeated several times until the pH
value of the washing water is 7-8. After washing, the water
temperature is controlled to 60 ° C, the internal temperature
does not exceed 50 ° C, dichloromethane is distilled at
atmospheric pressure, and oil is obtained after no dripping. A
mixed solvent of 398 g of ethyl acetate and 61 g of isopropyl
alcohol was added, and the mixture was heated and stirred to
dissolve. After the dissolution is complete, 6.4 g of activated
carbon is added and the temperature is slowly raised to 80 ° C.
and refluxed for 1 hour. The filter cake is washed with a mixed
solvent of 39 g of ethyl acetate and 6.3 g of isopropanol, and
combined with the previous one. The filtrate was slowly cooled
to 15-20 ° C, and the crystallization was started for 5 hours.
The temperature was lowered to 0-5 ° C. After 4 hours of
incubation and filtration, the filter cake was washed with a
small amount of ethyl acetate to obtain a hydroxychloroquine wet
product. The vacuum oven was 40 ° C. Drying within to obtain a
dry product, hydroxychloroquine HPLC purity 99.5%, maximum
single impurity 0.12%, yield 58%;
[0049] b.
Preparation of hydroxychloroquine sulfate
[0050] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine sulfate 129g; in a
1000mL three-necked round bottom flask, add 100g of
hydroxychloroquine obtained in step a, 100g of ethyl acetate,
and 500g of ethanol to stir to completely dissolve. After the
dissolution is complete, the mechanical impurities are removed
by filtration. The temperature was lowered to below 5 ° C, and
26g of concentrated sulfuric acid was added dropwise, and the
temperature was controlled within 20 ° C. Slowly warm to 61 ° C
and react for 6 hours. After the reaction is completed, the
temperature is lowered to 0 ~ 5 ° C, the crystallized material
is kept for 4 hours and then filtered. The filter cake is washed
with a small amount of ethyl acetate to obtain
hydroxychloroquine sulfate wet product, and dried in a vacuum
oven at 40 ° C to obtain a dry product. The purity is 99.6%, the
largest single impurity is below 0.1%, and the yield is 92%.
[0051] There are two steps from the starting material to the
final product, and the total yield is 53.36%.
[0052]
Example 2. Preparation of hydroxychloroquine sulfate
[0053] a. Preparation of hydroxychloroquine
[0054] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine 153g; in a 1000mL
three-necked round bottom flask, add 4,7-dichloroquinoline 90g
and isopropanol 141g, and heat to 60 ° C under stirring to
completely dissolve slowly 95.13g of hydroxyquine side chain was
added dropwise, and the timing was started after the addition
was completed. The temperature was gradually increased to
120-125 ° C over 10 hours, and then kept at 120 ° C-125 ° C for
16 hours until the high-performance liquid detection reached the
end of the reaction, waiting for the reaction After completion,
the reaction solution was cooled to a temperature of 50-60 ° C,
and a 6% sodium hydroxide solution was added. After
alkalization, the pH value was> 12, while continuing to lower
the temperature to 20-25 ° C. After the temperature was reached,
279 g of dichloromethane was added for the first time and
stirred for 10 minutes. After standing for 15 minutes, the
liquid was separated and the organic phase was stored. Add 198g
of dichloromethane to the water phase for the second time and
stir for 10 minutes. After standing for 15 minutes, separate the
liquid and combine the organic phase with the previous one. Add
120g of dichloromethane to the water phase for the third time
and stir for 10 minutes. After standing for 15 minutes, separate
the liquid. The organic phase is combined with the previous one,
and the water phase is treated as waste water. To the combined
organic phase, 500 g of drinking water was added, stirred for 5
minutes, and allowed to stand for 15 minutes, and then
separated. The organic phase is continuously washed with water,
and the above operation is repeated several times until the pH
value of the washing water is 7-8. After washing, the water
temperature is controlled to 60 ° C, the internal temperature
does not exceed 50 ° C, dichloromethane is distilled at
atmospheric pressure, and oil is obtained after no dripping. A
mixed solvent of 398 g of ethyl acetate and 61 g of isopropyl
alcohol was added, and the mixture was heated and stirred to
dissolve. After the dissolution is complete, 6.4 g of activated
carbon is added and the temperature is slowly raised to 80 ° C.
and refluxed for 1 hour. The filter cake is washed with a mixed
solvent of 39 g of ethyl acetate and 6.3 g of isopropanol, and
combined with the previous one. The filtrate was slowly cooled
to 15-20 ° C, and the crystallization was started for 5 hours.
The temperature was lowered to 0-5 ° C. After 4 hours of
incubation and filtration, the filter cake was washed with a
small amount of ethyl acetate to obtain a hydroxychloroquine wet
product. The vacuum oven was 40 ° C. Drying within to obtain a
dry product, hydroxychloroquine HPLC purity 99.8%, maximum
single impurity 0.05%, yield 70%;
[0055] b. Preparation of hydroxychloroquine sulfate
[0056] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine sulfate 129g; in a
1000mL three-necked round bottom flask, add 100g of
hydroxychloroquine obtained in step a, 100g of ethyl acetate,
and 500g of ethanol to stir to completely dissolve. After the
dissolution is complete, the mechanical impurities are removed
by filtration. The temperature was lowered to below 5 ° C, and
26g of concentrated sulfuric acid was added dropwise, and the
temperature was controlled within 20 ° C. Slowly warm to 61 ° C
and react for 6 hours. After the reaction is completed, the
temperature is lowered to 0 ~ 5 ° C, the crystallized material
is kept for 4 hours and then filtered. The filter cake is washed
with a small amount of ethyl acetate to obtain
hydroxychloroquine sulfate wet product, and dried in a vacuum
oven at 40 ° C to obtain a dry product. The purity is 99.85%,
the largest single impurity is below 0.1%, and the yield is 92%.
[0057] There are two steps from the starting material to the
final product, and the total yield is 64.4%.
[0058]
Example 3. Preparation of hydroxychloroquine sulfate
[0059] a. Preparation of hydroxychloroquine
[0060] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine 153g; in a 1000mL
three-necked round bottom flask, add 4,7-dichloroquinoline 90g
and isopropanol 141g, and heat to 60 ° C under stirring to
completely dissolve slowly 95.13g of hydroxyquine side chain was
added dropwise, and the timing was started after the addition
was completed. The temperature was gradually increased to
120-125 ° C over 12 hours, and then kept at 120 ° C to 125 ° C
for 16 hours until the high-performance liquid detection reached
the end of the reaction, waiting for the reaction After
completion, the reaction solution was cooled to a temperature of
50-60 ° C, and a 6% sodium hydroxide solution was added. After
alkalization, the pH value was> 12, while continuing to lower
the temperature to 20-25 ° C. After the temperature was reached,
279 g of dichloromethane was added for the first time and
stirred for 10 minutes. After standing for 15 minutes, the
liquid was separated and the organic phase was stored. Add 198g
of dichloromethane to the water phase for the second time and
stir for 10 minutes. After standing for 15 minutes, separate the
liquid and combine the organic phase with the previous one. Add
120g of dichloromethane to the water phase for the third time
and stir for 10 minutes. After standing for 15 minutes, separate
the liquid. The organic phase is combined with the previous one,
and the water phase is treated as waste water. To the combined
organic phase, 500 g of drinking water was added, stirred for 5
minutes, and allowed to stand for 15 minutes, and then
separated. The organic phase is continuously washed with water,
and the above operation is repeated several times until the pH
value of the washing water is 7-8. After washing, the water
temperature is controlled to 60 ° C, the internal temperature
does not exceed 50 ° C, dichloromethane is distilled at
atmospheric pressure, and oil is obtained after no dripping. A
mixed solvent of 398 g of ethyl acetate and 61 g of isopropyl
alcohol was added, and the mixture was heated and stirred to
dissolve. After the dissolution is complete, 6.4 g of activated
carbon is added and the temperature is slowly raised to 80 ° C.
and refluxed for 1 hour. The filter cake is washed with a mixed
solvent of 39 g of ethyl acetate and 6.3 g of isopropanol, and
combined with the previous one. The filtrate was slowly cooled
to 15-20 ° C, and the crystallization was started for 5 hours.
The temperature was lowered to 0-5 ° C. After 4 hours of
incubation and filtration, the filter cake was washed with a
small amount of ethyl acetate to obtain a hydroxychloroquine wet
product. The vacuum oven was 40 ° C. Drying within to obtain a
dry product, hydroxychloroquine HPLC purity 99.5%, maximum
single impurity 0.08%, yield 65%;
[0061] b. Preparation of hydroxychloroquine sulfate
[0062] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine sulfate 129g; in a
1000mL three-necked round bottom flask, add 100g of
hydroxychloroquine obtained in step a, 100g of ethyl acetate,
and 500g of ethanol to stir to completely dissolve. After the
dissolution is complete, the mechanical impurities are removed
by filtration. The temperature was lowered to below 5 ° C, and
26g of concentrated sulfuric acid was added dropwise, and the
temperature was controlled within 20 ° C. Slowly warm to 61 ° C
and react for 6 hours. After the reaction is completed, the
temperature is lowered to 0 ~ 5 ° C, the crystallized material
is kept for 4 hours and then filtered. The filter cake is washed
with a small amount of ethyl acetate to obtain
hydroxychloroquine sulfate wet product, and dried in a vacuum
oven at 40 ° C to obtain a dry product. The purity is 99.7%, the
largest single impurity is below 0.1%, and the yield is 92%.
[0063] There are two steps from the starting material to the
final product, and the total yield is 59.8%.
[0064]
Example 4. Preparation of hydroxychloroquine sulfate
[0065] a. Preparation of hydroxychloroquine
[0066] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine 153g; in a 1000mL
three-necked round bottom flask, add 4,7-dichloroquinoline 90g
and isopropanol 141g, and heat to 60 ° C under stirring to
completely dissolve slowly 95.13g of hydroxyquine side chain was
added dropwise, and the timing was started after the addition
was completed. The temperature was gradually increased to
120-125 ° C over 10 hours, and then kept at 120 ° C-125 ° C for
13 hours until the high-performance liquid detection reached the
end of the reaction, waiting for the reaction After completion,
the reaction solution was cooled to a temperature of 50-60 ° C,
and a 6% sodium hydroxide solution was added. After
alkalization, the pH value was> 12, while continuing to lower
the temperature to 20-25 ° C. After the temperature was reached,
279 g of dichloromethane was added for the first time and
stirred for 10 minutes. After standing for 15 minutes, the
liquid was separated and the organic phase was stored. Add 198g
of dichloromethane to the water phase for the second time and
stir for 10 minutes. After standing for 15 minutes, separate the
liquid and combine the organic phase with the previous one. Add
120g of dichloromethane to the water phase for the third time
and stir for 10 minutes. After standing for 15 minutes, separate
the liquid. The organic phase is combined with the previous one,
and the water phase is treated as waste water. To the combined
organic phase, 500 g of drinking water was added, stirred for 5
minutes, and allowed to stand for 15 minutes, and then
separated. The organic phase is continuously washed with water,
and the above operation is repeated several times until the pH
value of the washing water is 7-8. After washing, the water
temperature is controlled to 60 ° C, the internal temperature
does not exceed 50 ° C, dichloromethane is distilled at
atmospheric pressure, and oil is obtained after no dripping. A
mixed solvent of 398 g of ethyl acetate and 61 g of isopropyl
alcohol was added, and the mixture was heated and stirred to
dissolve. After the dissolution is complete, 6.4 g of activated
carbon is added and the temperature is slowly raised to 80 ° C.
and refluxed for 1 hour. The filter cake is washed with a mixed
solvent of 39 g of ethyl acetate and 6.3 g of isopropanol, and
combined with the previous one. The filtrate was slowly cooled
to 15-20 ° C, and the crystallization was started for 5 hours.
The temperature was lowered to 0-5 ° C. After 4 hours of
incubation and filtration, the filter cake was washed with a
small amount of ethyl acetate to obtain a hydroxychloroquine wet
product. The vacuum oven was 40 ° C. Drying within to obtain a
dry product, hydroxychloroquine HPLC purity 99.6%, maximum
single impurity 0.11%, yield 55%;
[0067] b. Preparation of hydroxychloroquine sulfate
[0068] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine sulfate 129g; in a
1000mL three-necked round bottom flask, add 100g of
hydroxychloroquine obtained in step a, 100g of ethyl acetate,
and 500g of ethanol to stir to completely dissolve. After the
dissolution is complete, the mechanical impurities are removed
by filtration. The temperature was lowered to below 5 ° C, and
26g of concentrated sulfuric acid was added dropwise, and the
temperature was controlled within 20 ° C. Slowly warm to 61 ° C
and react for 6 hours. After the reaction is completed, the
temperature is lowered to 0 ~ 5 ° C, the crystallized material
is kept for 4 hours and then filtered. The filter cake is washed
with a small amount of ethyl acetate to obtain
hydroxychloroquine sulfate wet product, and dried in a vacuum
oven at 40 ° C to obtain a dry product. The purity is 99.7%, the
largest single impurity is 0.087%, and the yield is 92%.
[0069] There are 2 steps from the starting material to the final
product, and the total yield is 50.6%.
[0070]
Example 5. Preparation of hydroxychloroquine sulfate
[0071] a. Preparation of hydroxychloroquine
[0072] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine 153g; in a 1000mL
three-necked round bottom flask, add 4,7-dichloroquinoline 90g
and isopropanol 141g, and heat to 60 ° C under stirring to
completely dissolve slowly 95.13g of hydroxyquine side chain was
added dropwise, and the timing was started after the addition
was completed. The temperature was gradually increased to
120-125 ° C over 10 hours, and then maintained at 120 ° C-125 °
C for 18 hours until the high-performance liquid detection
reached the end of the reaction, waiting for the reaction After
completion, the reaction solution was cooled to a temperature of
50-60 ° C, and a 6% sodium hydroxide solution was added. After
alkalization, the pH value was> 12, while continuing to lower
the temperature to 20-25 ° C. After the temperature was reached,
279 g of dichloromethane was added for the first time and
stirred for 10 minutes. After standing for 15 minutes, the
liquid was separated and the organic phase was stored. Add 198g
of dichloromethane to the water phase for the second time and
stir for 10 minutes. After standing for 15 minutes, separate the
liquid and combine the organic phase with the previous one. Add
120g of dichloromethane to the water phase for the third time
and stir for 10 minutes. After standing for 15 minutes, separate
the liquid. The organic phase is combined with the previous one,
and the water phase is treated as waste water. To the combined
organic phase, 500 g of drinking water was added, stirred for 5
minutes, and allowed to stand for 15 minutes, and then
separated. The organic phase is continuously washed with water,
and the above operation is repeated several times until the pH
value of the washing water is 7-8. After washing, the water
temperature is controlled to 60 ° C, the internal temperature
does not exceed 50 ° C, dichloromethane is distilled at
atmospheric pressure, and oil is obtained after no dripping. A
mixed solvent of 398 g of ethyl acetate and 61 g of isopropyl
alcohol was added, and the mixture was heated and stirred to
dissolve. After the dissolution is complete, 6.4 g of activated
carbon is added and the temperature is slowly raised to 80 ° C.
and refluxed for 1 hour. The filter cake is washed with a mixed
solvent of 39 g of ethyl acetate and 6.3 g of isopropanol, and
combined with the previous one. The filtrate was slowly cooled
to 15-20 ° C, and the crystallization was started for 5 hours.
The temperature was lowered to 0-5 ° C. After 4 hours of
incubation and filtration, the filter cake was washed with a
small amount of ethyl acetate to obtain a hydroxychloroquine wet
product. The vacuum oven was 40 ° C. Drying within to obtain a
dry product, hydroxychloroquine HPLC purity 98.7%, maximum
single impurity 0.13%, yield 60%;
[0073] b. Preparation of hydroxychloroquine sulfate
[0074] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine sulfate 129g; in a
1000mL three-necked round bottom flask, add 100g of
hydroxychloroquine obtained in step a, 100g of ethyl acetate,
and 500g of ethanol to stir to completely dissolve. After the
dissolution is complete, the mechanical impurities are removed
by filtration. The temperature was lowered to below 5 ° C, and
26g of concentrated sulfuric acid was added dropwise, and the
temperature was controlled within 20 ° C. Slowly warm to 61 ° C
and react for 6 hours. After the reaction is completed, the
temperature is lowered to 0 ~ 5 ° C, the crystallized material
is kept for 4 hours and then filtered. The filter cake is washed
with a small amount of ethyl acetate to obtain
hydroxychloroquine sulfate wet product, and dried in a vacuum
oven at 40 ° C to obtain a dry product. The purity is 99.4%, the
largest single impurity is 0.1%, and the yield is 92%.
[0075] There are 2 steps from the starting material to the final
product, and the total yield is 55.2%.
[0076]
Comparative Example 1. Preparation of hydroxychloroquine
sulfate
[0077] a. Preparation of hydroxychloroquine
[0078] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine 153g; in a 1000mL
three-necked round bottom flask, add 4,7-dichloroquinoline 90g
and isopropanol 141g, and heat to 60 ° C under stirring to
completely dissolve slowly 95.13g of hydroxyquine side chain was
added dropwise, and the timing was started after the addition
was completed. The temperature was gradually increased to
120-125 ° C over 6 hours, and then kept at 120 ° C-125 ° C for
12 hours until the high-performance liquid detection reached the
end of the reaction, waiting for the reaction After completion,
the reaction solution was cooled to a temperature of 50-60 ° C,
and a 6% sodium hydroxide solution was added. After
alkalization, the pH value was> 12, while continuing to lower
the temperature to 20-25 ° C. After the temperature was reached,
279 g of dichloromethane was added for the first time and
stirred for 10 minutes. After standing for 15 minutes, the
liquid was separated and the organic phase was stored. Add 198g
of dichloromethane to the water phase for the second time and
stir for 10 minutes. After standing for 15 minutes, separate the
liquid and combine the organic phase with the previous one. Add
120g of dichloromethane to the water phase for the third time
and stir for 10 minutes. After standing for 15 minutes, separate
the liquid. The organic phase is combined with the previous one,
and the water phase is treated as waste water. To the combined
organic phase, 500 g of drinking water was added, stirred for 5
minutes, and allowed to stand for 15 minutes, and then
separated. The organic phase is continuously washed with water,
and the above operation is repeated several times until the pH
value of the washing water is 7-8. After washing, the water
temperature is controlled to 60 ° C, the internal temperature
does not exceed 50 ° C, dichloromethane is distilled at
atmospheric pressure, and oil is obtained after no dripping. A
mixed solvent of 398 g of ethyl acetate and 61 g of isopropyl
alcohol was added, and the mixture was heated and stirred to
dissolve. After the dissolution is complete, 6.4 g of activated
carbon is added and the temperature is slowly raised to 80 ° C.
and refluxed for 1 hour. The filter cake is washed with a mixed
solvent of 39 g of ethyl acetate and 6.3 g of isopropanol, and
combined with the previous one. The filtrate was slowly cooled
to 15-20 ° C, and the crystallization was started for 5 hours.
The temperature was lowered to 0-5 ° C. After 4 hours of
incubation and filtration, the filter cake was washed with a
small amount of ethyl acetate to obtain a hydroxychloroquine wet
product. The vacuum oven was 40 ° C. Drying within to obtain a
dry product, hydroxychloroquine HPLC purity 99.3%, maximum
single impurity 0.23%, yield 45%;
[0079] b. Preparation of hydroxychloroquine sulfate
[0080] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine sulfate 129g; in a
1000mL three-necked round bottom flask, add 100g of
hydroxychloroquine obtained in step a, 100g of ethyl acetate,
and 500g of ethanol to stir to completely dissolve. After the
dissolution is complete, the mechanical impurities are removed
by filtration. The temperature was lowered to below 5 ° C, and
26g of concentrated sulfuric acid was added dropwise, and the
temperature was controlled within 20 ° C. Slowly warm to 61 ° C
and react for 6 hours. After the reaction is completed, the
temperature is lowered to 0 ~ 5 ° C, the crystallized material
is kept for 4 hours and then filtered. The filter cake is washed
with a small amount of ethyl acetate to obtain
hydroxychloroquine sulfate wet product, and dried in a vacuum
oven at 40 ° C to obtain a dry product. The purity is 99.5%, the
largest single impurity is 0.20%, and the yield is 92%.
[0081] There are two steps from the starting material to the
final product, and the total yield is 41.4%.
[0082]
Comparative Example 2. Preparation of hydroxychloroquine
sulfate
[0083] a. Preparation of hydroxychloroquine
[0084] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine 153g; in a 1000mL
three-necked round bottom flask, add 4,7-dichloroquinoline 90g
and isopropanol 141g, and heat to 60 ° C under stirring to
completely dissolve slowly 95.13g of hydroxyquine side chain was
added dropwise, and the timing was started after the addition
was completed. The temperature was gradually increased to
120-125 ℃ over 14 hours, and then kept at 120 ℃ ～ 125 ℃ for 20
hours until the high-performance liquid detection reached the
end of the reaction, waiting for the reaction After completion,
the reaction solution was cooled to a temperature of 50-60 ° C,
and a 6% sodium hydroxide solution was added. After
alkalization, the pH value was> 12, while continuing to lower
the temperature to 20-25 ° C. After the temperature was reached,
279 g of dichloromethane was added for the first time and
stirred for 10 minutes. After standing for 15 minutes, the
liquid was separated and the organic phase was stored. Add 198g
of dichloromethane to the water phase for the second time and
stir for 10 minutes. After standing for 15 minutes, separate the
liquid and combine the organic phase with the previous one. Add
120g of dichloromethane to the water phase for the third time
and stir for 10 minutes. After standing for 15 minutes, separate
the liquid. The organic phase is combined with the previous one,
and the water phase is treated as waste water. To the combined
organic phase, 500 g of drinking water was added, stirred for 5
minutes, and allowed to stand for 15 minutes, and then
separated. The organic phase is continuously washed with water,
and the above operation is repeated several times until the pH
value of the washing water is 7-8. After washing, the water
temperature is controlled to 60 ° C, the internal temperature
does not exceed 50 ° C, dichloromethane is distilled at
atmospheric pressure, and oil is obtained after no dripping. A
mixed solvent of 398 g of ethyl acetate and 61 g of isopropyl
alcohol was added, and the mixture was heated and stirred to
dissolve. After the dissolution is complete, 6.4 g of activated
carbon is added and the temperature is slowly raised to 80 ° C.
and refluxed for 1 hour. The filter cake is washed with a mixed
solvent of 39 g of ethyl acetate and 6.3 g of isopropanol, and
combined with the previous one. The filtrate was slowly cooled
to 15-20 ° C, and the crystallization was started for 5 hours.
The temperature was lowered to 0-5 ° C. After 4 hours of
incubation and filtration, the filter cake was washed with a
small amount of ethyl acetate to obtain a hydroxychloroquine wet
product. The vacuum oven was 40 ° C. Drying within to obtain a
dry product, hydroxychloroquine HPLC purity 97.8%, maximum
single impurity 0.88%, yield 55%;
[0085] b. Preparation of hydroxychloroquine sulfate
[0086] Calculate the amount of raw materials based on the
theoretical amount of hydroxychloroquine sulfate 129g; in a
1000mL three-necked round bottom flask, add 100g of
hydroxychloroquine obtained in step a, 100g of ethyl acetate,
and 500g of ethanol to stir to completely dissolve. After the
dissolution is complete, the mechanical impurities are removed
by filtration. The temperature was lowered to below 5 ° C, and
26g of concentrated sulfuric acid was added dropwise, and the
temperature was controlled within 20 ° C. Slowly warm to 61 ° C
and react for 6 hours. After the reaction is completed, the
temperature is lowered to 0 ~ 5 ° C, the crystallized material
is kept for 4 hours and then filtered. The filter cake is washed
with a small amount of ethyl acetate to obtain
hydroxychloroquine sulfate wet product, and dried in a vacuum
oven at 40 ° C to obtain a dry product. The purity is 98.4%, the
largest single impurity is 0.67%, and the yield is 92%.
[0087] There are 2 steps from the starting material to the final
product, and the total yield is 50.6%.
[0088] Investigation table of reaction time and
hydroxychloroquine quality:
[0089]
[0090] It can be seen from the table above that the temperature
rise time under the control temperature below 120 ° C is 7-12h,
and the reaction time at 120-125 ° C is 13-18h, which can ensure
that hydroxychloroquine obtains a higher or relatively high
purity and yield.
[0091] It should be noted that the above embodiments are only
used to illustrate the technical solutions of the present
invention and not to limit them. Although the present invention
has been described by referring to the preferred embodiments of
the present invention, those of ordinary skill in the art should
understand that Various changes are made to it in detail and in
detail without departing from the spirit and scope of the
present invention.
CN104230803
Preparation method of hydroxychloroquine sulfate
[ PDF ]
Abstract
The invention discloses a preparation method of
hydroxychloroquine sulfate. The preparation method is
characterized by comprising the following steps: condensing
4,7-dichloroquinoline serving as an initial raw material and a
hydroxychloroquine side chain under the action of a catalyst, so
as to obtain hydroxychloroquine; and reacting hydroxychloroquine
with sulfuric acid, so as to prepare the hydroxychloroquine
sulfate. According to the method disclosed by the invention, the
defects in the prior art are overcome. The method has the
advantages that the yield of the prepared hydroxychloroquine
sulfate crude product is greater than or equal to 85%, the yield
of hydroxychloroquine sulfate is greater than or equal to 94%;
the total yield is greater than or equal to 80%; the purity of
the prepared hydroxychloroquine sulfate HPLC is greater than or
equal to 99.6%; the maximum single impurity is smaller than
0.1%; the method accords with the requirements of United States
pharmacopeia, is short in reaction step, and simple in the whole
technological operation; and the obtained product is high in
quality, high in yield, and relatively suitable for industrial
production.
[0002] The invention belongs to the technical field of medicine
and chemical industry, and particularly relates to
hydroxychloroquine sulfate for treating discoid lupus
erythematosus and systemic lupus erythematosus.
[0003]
Background technique
[0004] Hydroxychloroquine Sulfate is chemically known as
2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]-ethanol
sulfate, CAS No. 747-36-4, The chemical structure is as follows:
[0005]
[0006] Hydroxychloroquine sulfate was successfully developed by
Winthrop and first listed in the United States in 1956. It was
later listed in France, Denmark, Japan, Germany, Finland and
other countries and regions. On May 29, 1998, the US FDA
approved hydroxychloroquine sulphate tablets for the treatment
of lupus erythematosus and rheumatoid arthritis.
[0007] US 2,546,658 discloses a process for the
synthesis of hydroxychloroquine sulfate, the process of which is
as follows:
[0008]
[0009] The patent was reported in 1951, using a large amount of
phenol as a reaction catalyst. Phenol is toxic and corrosive.
Its concentrated solution is highly corrosive to the skin. The
post-treatment wastewater causes great pressure on the treatment
of three wastes, and the phenol-containing wastewater It is a
kind of waste that is very hazardous in industrial wastewater
and difficult to handle. It is one of the wastewaters that are
currently controlled in China, and the environmental pollution
is particularly large. The melting point of phenol is 42 ° C,
which is solid at normal temperature, and must be heated to
liquid to be fed. This process is very cumbersome, unsuitable
for industrialization, and the yield is also low.
[0010] CA2561987 discloses a method for preparing
hydroxychloroquine sulfate, which comprises adding
4,7-dichloroquinoline, hydroxychloroquine side chain and
isopropanol in sequence, followed by stirring and heating,
stirring at 120 ° C ~ 130 ° C for 20-24 hours, then Add water
and methyl isobutyl ketone, adjust pH=10~11, separate the
liquid, add acetic anhydride and stir at room temperature
overnight, then add LiOH-H2O, water and methanol in turn, stir
again at room temperature overnight, then wash once, organic
layer Add methanol and sulfuric acid, stir at 35 ° C ~ 45 ° C
for 3-4 hours, then cool to 20 ° C ~ 25 ° C, filtered to obtain
crude hydroxychloroquine sulfate, yield 80%; then add the crude
product obtained above, Water and methyl isobutyl ketone, stir
and dissolve, cool to 0 ° C ~ 5 ° C, add sodium hydroxide
solution to pH = 10.5 ~ 11.0, stir at room temperature for 0.5 ~
1 hour, liquid separation, organic layer added 5% After washing
with sodium chloride solution, activated carbon was added,
stirred at room temperature, filtered, and the filtrate was
evaporated to give hydroxychloroquine. Then, it is salted with
concentrated sulfuric acid in an anhydrous alcohol solvent to
obtain a hydroxychloroquine sulfate product. The purification
process of hydroxychloroquine and its sulfate in this method is
very complicated, the reaction time of the whole route is
particularly long, and a large amount of waste water is
generated. In the post-treatment, a complicated post-treatment
process is carried out in order to remove impurities, and
finally the single impurity is controlled at 0.1. Below %, there
are cumbersome operations, high cost, and long time, which is
not conducive to industrial production. The salt forming process
is to directly add concentrated sulfuric acid to an anhydrous
alcohol solvent, and there is a risk of producing toxic
substances such as dimethyl sulfate and diethyl sulfate.
[0011] W02010027150 also discloses a method for
synthesizing hydroxychloroquine sulfate, the reaction route of
which is as follows:
[0012]
[0013] The method comprises the steps of sequentially adding
4,7-dichloroquinoline and hydroxychloroquine side chain, and
applying nitrogen or argon gas to a pressure of 5 to 20 bar, and
then reacting at 100 ° C to 120 ° C for 4 to 6 hours. After the
reaction is completed, the product is dissolved in dilute
hydrochloric acid and chloroform, and the product is dissolved
in an aqueous phase, and the liquid phase is collected. The
aqueous phase is collected, alkalized with sodium hydroxide,
extracted with chloroform, and the chloroform layer is
concentrated and then recrystallized from dichloroethane.
Hydroxychloroquine products. Hydroxychloroquine is then added to
the concentrated sulfuric acid under anhydrous ethanol as a
solvent to obtain hydroxychloroquine sulfate. The method is
carried out under high pressure, and there is a certain safety
hazard, and the alkalization loss is great after acidification
first, and a highly toxic solvent such as chloroform and
dichloroethane is also used, which is difficult to remove in the
hydroxychloroquine sulfate product. According to the ICH
(International Coordinating Committee for the Registration of
Technical Requirements for Human Drugs), the requirements for
the Guideline for Residual Solvents, dichloroethane is the first
type of solvent and should be strictly prohibited. Chloroform is
the second type of solvent and should be controlled. Moreover,
the limit is 60 ppm, and it is difficult to completely remove
the two types of solvents in the finished product.
[0014] CN 103724261 A discloses an industrialization
method of hydroxychloroquine sulfate: the temperature reaction
is directly added to the side chain of 4,7-dichloroquinoline and
hydroxychloroquine under the protection of an inert gas, and the
reaction is gradually heated to 120 ° C to 130 ° C during the
reaction. After 13 to 24 hours, the mixture is acidified, and
the excess liquid is alkalized and then layered, and
crystallized by adding an organic solvent to obtain
hydroxychloroquine. The method directly raises the temperature
of the two raw materials, and the reaction is too strong, and a
large amount of impurities are generated. After the
post-treatment, acidification, a large amount of liquid alkali
alkalization, and then an organic solvent is added, so that the
organic layer contains a large amount of alkali liquid and
inorganic The salt, the crude hydroxychloroquine crystallized
after cooling, contains a large amount of inorganic salts and
impurities, so that the crude purity of hydroxychloroquine is
only 96%, so that the quality of hydroxychloroquine obtained
directly through one salt formation is often unqualified.
[0015] In the preparation method of the above-disclosed
hydroxychloroquine sulfate, there are some insufficient factors,
and it is not suitable for industrial production; and most
processes use toxic solvents such as chloroform and
dichloroethane to obtain hydroxychloroquine sulfate, which leads
to The product contains halogenated hydrocarbon genotoxic
impurities such as chloroform and dichloroethane, which does not
meet the requirements of the ICH Guidelines for Residual
Solvents. In the case of hydroxychloroquine sulfate formation,
most of the process uses concentrated sulfuric acid under
anhydrous alcohol conditions, which may present the risk of
producing dimethyl sulfate and diethyl sulfate. Therefore, it is
very necessary to find an industrial preparation method which is
simple in operation, high in efficiency, safe and
environmentally friendly, high in yield and quality, and low in
production cost. The invention has been completed for this
purpose.
[0016]
Summary of the invention
[0017] The object of the present invention is to provide a
method for preparing hydroxychloroquine sulfate, wherein
4,7-dichloroquinoline and hydroxychloroquine side chain are
condensed by distillation of an acetate-based organic solvent
under the action of a sodium alkoxide catalyst. The reaction is
subjected to alkalization, extraction with an organic solvent of
an acetate, washing, and crystallization to obtain
hydroxychloroquine, and then hydroxychloroquine is reacted with
sulfuric acid in a mixed solvent system containing at least
water and an alcohol to obtain hydroxychloroquine sulfate. The
reaction route is as follows:
[0018]
[0019] 1、The molar ratio of 4,7-dichloroquinoline to
hydroxychloroquine side chain is 1:1.05.
[0020] 2、The catalyst is sodium alkoxide, such as sodium
methoxide, sodium ethoxide, sodium t-butoxide, sodium t-amylate,
etc., and the molar ratio of the catalyst to
4,7-dichloroquinoline is 0.2:1.
[0021] 3、The acetate organic solvent is isopropyl acetate or
t-butyl acetate, and among them, isopropyl acetate is preferred.
(Amount: 5-6 times the weight of 4,7-dichloroquinoline)
[0022] 4、The heating method is: after heating the reaction
liquid to the reflux temperature, the solvent is distilled off,
and the temperature is gradually raised to 110 ° C for 9 to 10
hours, then the temperature is raised to 120 ° C to 122 ° C for
10 to 12 hours, and finally the temperature is maintained at 120
° C to 122 ° C. 4~5 hours.
[0023] 5、The alkalization mode is as follows: the reaction
solution is slightly cold and directly alkalized with a 5%
sodium hydroxide solution.
[0024] 6、The crystallization method is: after the extracted
acetate solvent is washed with water, the total addition amount
is 20% to 30%, and then the crystal is naturally cooled, and the
crystallization temperature is 0 ° C to 30 ° C.
[0025] 7、The process of forming a salt of hydroxychloroquine and
sulfuric acid in a dilute alcohol solution is as follows:
hydroxychloroquine is dissolved in a mixed solvent containing at
least 4 times of water and an alcohol, and concentrated sulfuric
acid is added dropwise at 0° C. to 10° C. to pH=4.5~ 5.5, keep
warm at 20 ° C ~ 30 ° C for 2 ~ 3 hours, cool to 0 ° C ~ 10 ° C
filtered to obtain hydroxychloroquine sulfate.
[0026] The 4,7-dichloroquinoline and hydroxychloroquine side
chains used in the present invention are industrial raw
materials which are commercially available on a large scale; and
the solvents used are industrial raw materials.
[0027] The "hydroxychloroquine side chain" referred to in the
present invention means the starting material
"5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine"; "sodium
alkoxide" means an alkane A base formed by replacing a hydrogen
of a base alcohol with sodium; "acetate" means an ester of
acetic acid with a monohydric alcohol. "95% ethanol" means that
the volume ratio of absolute ethanol to purified water is 95:5,
and industrial 95% ethanol can be directly purchased on the
market.
[0028] The advantages of the invention are as follows:
[0029] 1)In the production process, a single organic solvent is
used for reaction, extraction and crystallization, which avoids
the use of toxic solvents such as chloroform and dichloroethane.
On the one hand, it saves production costs, can be recycled, and
on the other hand reduces environmental pollution.
[0030] 2)Avoid the use of toxic catalyst phenol, the reaction is
carried out under normal pressure, avoiding the danger of high
pressure reaction.
[0031] 3)In the post-reaction treatment, direct alkalization,
simple operation, reducing the amount of liquid alkali, reducing
the number of water washing, reducing the amount of wastewater
generated.
[0032] 4)Crystallized by isopropyl acetate or tert-butyl
acetate, the granular crystals are precipitated at room
temperature, the melting point is 89 ° C ~ 91 ° C, the crystal
habit is good, the product impurity content is low, filtration
and drying fast, avoiding the crystallization after mixing
solvent Solvents are not well recycled, and many solvents
crystallize without crystals.
[0033] 5)The crude hydroxychloroquine is directly salted with
sulfuric acid, using an aqueous mixed solvent of alcohol to
avoid the risk of producing toxic substances under anhydrous
conditions.
[0034] 6)The yield of the crude hydroxychloroquine obtained by
the invention is ≥85% (based on 4,7-dichloroquinoline, the same
below), the purity of hydroxychloroquine HPLC is ≥99.0%; the
yield of salt formation is ≥94% (according to
hydroxychloroquine, the same The purity of hydroxychloroquine
sulfate is HPLC≥99.6%, the maximum single impurity is <0.1%,
and the melting point is 239°C~241°C.
[0035] The preparation of the hydroxychloroquine sulfate
industrialization of the present invention is further
illustrated and explained below by way of examples without
limiting the scope of the invention.
[0036]
Detailed ways
[0037] Example 1 Preparation of Hydroxychloroquine
Sulfate
[0038] 1.1 Preparation of hydroxychloroquine
[0039] In a three-necked round
bottom flask, 4,7-dichloroquinoline (198.0 g, 1.0 mol),
hydroxychloroquine side chain (182.7 g, 1.05 mol) and isopropyl
acetate 1089 g were added, and sodium ethoxide (13.6 g, was
slowly added. 0.2mol), slowly heated to reflux under stirring
conditions, then distilled off isopropyl acetate, gradually
heated to 110 ° C over 9 hours, then heated to 120 ° C ~ 122 ° C
10 hours, and finally 120 ° C ~ 122 ° C reaction After 4 hours,
after the reaction was completed, the reaction solution was
cooled to 90 ° C to 100 ° C, directly added to a 5% sodium
hydroxide solution, and alkalized to pH = 9 to 10. The distilled
isopropyl acetate was extracted twice, and the layers were
separated. 500 g of drinking water was added to the combined
organic phase, washed, layered, and the above operation was
repeated until the pH of the washing water was 7. After the
washing was completed, the water temperature was controlled to
65 ° C, and 200 to 300 g of isopropyl acetate was distilled off
under reduced pressure. Then, 9.9 g of activated carbon was
added, and the mixture was heated under reflux for 1 hour,
filtered while hot, the filtrate was cooled to 0 ° C, and the
mixture was filtered for 2 hours, filtered, and dried at 60 ° C
for 4 hours to obtain 294.6 g of crude hydroxychloroquine. The
melting point is 89.2 ° C ~ 91.3 ° C, HPLC purity 99.3%, the
largest single impurity <0.1%, the yield of 87.7%.
[0040] 1.2
Preparation of hydroxychloroquine sulfate
[0041] In a three-necked round bottom flask, 100 g of
hydroxychloroquine obtained in Example 1.1 and 500 g of 95%
ethanol were added. After the dissolution was completed, the
temperature was lowered to 0 ° C to 10 ° C, and concentrated
sulfuric acid was slowly added thereto to adjust the pH to 4.5
to 5.5, and the temperature was controlled. Within 10 °C. Then,
the reaction was kept at 20 ° C to 30 ° C for 3 hours. After the
reaction was completed, the temperature was lowered to 0 ° C to
10 ° C for 2 hours, and then filtered, and dried under reduced
pressure to obtain 123.0 g of hydroxychloroquine sulfate,
melting point of 239.8 ° C to 240.5 ° C, HPLC purity. 99.6%, the
largest single impurity <0.1%, the yield is 95.2%.
[0042] Example 2 Preparation of Hydroxychloroquine Sulfate
[0043] 2.1 Preparation of hydroxychloroquine
[0044] According to the embodiment 1.1, the type of the catalyst
is changed, the reaction effect after the dosage is not changed,
and other conditions are unchanged, and the obtained results are
as follows:
[0045] table 2-1
[0046]
[0047] 2.2 Preparation of hydroxychloroquine sulfate
[0048] Based on Example 1.2, the salt formation reaction was
carried out using the hydroxychloroquine obtained in Example
2.1, and the other conditions were unchanged. The results are as
follows:
[0049] Table 2-2
[0050]
[0051] Example 3 Preparation of Hydroxychloroquine Sulfate
[0052]
3.1Preparation of hydroxychloroquine
[0053] In a three-necked round bottom flask,
4,7-dichloroquinoline (198.0 g, 1.0 mol), hydroxychloroquine
side chain (182.7 g, 1.05 mol) and tert-butyl acetate 1089 g
were added, and sodium ethoxide (13.6 g, 0.2mol), slowly heated
to reflux under stirring conditions, then by distillation of
t-butyl acetate, gradually heated to 110 ° C over 9 hours, then
heated to 120 ° C ~ 122 ° C 10 hours, and finally 120 ° C ~ 122
° C reaction After 4 hours, after the reaction was completed,
the reaction solution was cooled to 90 ° C to 100 ° C, and 5%
sodium hydroxide solution was added thereto, and alkalized to pH
= 9 to 10. The distilled t-butyl acetate was extracted twice,
and the layers were separated. 500 g of drinking water was added
to the combined organic phase, washed, layered, and the above
operation was repeated until the pH of the washing water was 7.
After the completion of the washing, the temperature of the
water was controlled to 65 ° C, and 200 to 300 g of t-butyl
acetate was distilled off under reduced pressure. Then, 9.9 g of
activated carbon was added, and the mixture was heated under
reflux for 1 hour, and filtered hot. The filtrate was naturally
cooled to 30 ° C, and after crystallization for 2 hours, it was
filtered, and dried at 65 ° C for 4 hours to obtain 285.3 g of
crude hydroxychloroquine. The melting point is 89.4 ° C ~ 91.0 °
C, HPLC purity 99.1%, the maximum single impurity <0.1%, the
yield of 85.1%.
[0054] 3.2 Preparation of hydroxychloroquine sulfate
[0055] In a three-necked round
bottom flask, 100 g of hydroxychloroquine obtained in Example
3.1 and 400 g of 95% ethanol were added. After the dissolution
was completed, the temperature was lowered to 0 ° C to 10 ° C,
and concentrated sulfuric acid was slowly added dropwise to
adjust the pH to 4.5 to 5.5, and the temperature was controlled.
Within 10 °C. Then, the reaction was kept at 20 ° C to 30 ° C
for 3 hours. After the reaction was completed, the temperature
was lowered to 0 ° C to 10 ° C for 2 hours, and then filtered,
and dried under reduced pressure to give 122.7 g of
hydroxychloroquine sulfate. The melting point is 239.4 ° C ~
240.6 ° C, the HPLC purity is 99.6%, the maximum single impurity
is <0.1%, and the yield is 95.0%.
[0056] Example 4 Preparation of Hydroxychloroquine Sulfate
[0057] 4.1 Preparation of hydroxychloroquine
[0058] According to the embodiment 3.1, the type of the catalyst
is changed, the reaction effect after the dosage is not changed,
and other conditions are unchanged, and the obtained results are
as follows:
[0059] Table 4-1
[0060]
[0061] 4.2 Preparation of hydroxychloroquine sulfate
[0062] Based on Example 3.2, the salt formation reaction was
carried out using the hydroxychloroquine obtained in Example
4.1, and the other conditions were unchanged. The results are as
follows:
[0063] Table 4-2
[0064]
[0065] Example 5 Preparation of Hydroxychloroquine Sulfate
[0066]
5.1Preparation of hydroxychloroquine
[0067] In a three-necked round bottom flask,
4,7-dichloroquinoline (99. 0 g, 0.5 mol), hydroxychloroquine
side chain (91.5 g, 0.525 mol) and isopropyl acetate 545 g were
added, and sodium t-amylate was slowly added ( 11.0g, 0.1mol),
slowly heated to reflux under stirring conditions, and then
distilled isopropyl acetate, gradually heated to 110 ° C over 9
hours, then heated to 120 ° C ~ 122 ° C 10 hours, and finally
maintained 120 ° C ~ After reacting at 122 ° C for 4 hours,
after the reaction was completed, the reaction solution was
cooled to 90 ° C to 100 ° C, and 5% sodium hydroxide solution
was added thereto to alkalinize to pH = 9 to 10. The distilled
isopropyl acetate was extracted twice, and the layers were
separated. 250 g of drinking water was added to the combined
organic phase, washed, layered, and the above operation was
repeated until the pH of the washing water was 7. After the
washing was completed, the temperature of the water was
controlled to 65 ° C, and 100 to 150 g of isopropyl acetate was
distilled off under reduced pressure. Then, 5.0 g of activated
carbon was added, and the mixture was heated under reflux for 1
hour, and filtered while hot. The filtrate was naturally cooled
to 15 ° C, and the mixture was allowed to stand for 2 hours,
filtered, and dried at 65 ° C for 4 hours to obtain 149.0 g of
crude hydroxychloroquine. The melting point is 89.4 ° C ~ 91.5 °
C, HPLC purity 99.5%, the largest single impurity <0.1%,
yield 88.9%.
[0068] 5.2 Preparation of hydroxychloroquine sulfate
[0069] In a three-necked round
bottom flask, 10.0 g of hydroxychloroquine obtained in Example
5.1 and 40.0 g of 95% ethanol were added. After the dissolution
was completed, the temperature was lowered to 0 ° C to 10 ° C,
and concentrated sulfuric acid was slowly added thereto to
adjust the pH to 4.5 to 5.5. The temperature is within 10 °C.
Then, the reaction was kept at 20 ° C to 30 ° C for 3 hours, and
after the reaction was completed, the temperature was lowered to
0 ° C to 10 ° C for 2 hours, and then filtered, and dried under
reduced pressure to obtain 12.4 g of hydroxychloroquine sulfate,
melting point of 239.5 ° C to 240.5 ° C, HPLC purity. 99.8%, the
largest single impurity <0.1%, the yield is 96.1%.
[0070] Example 6 Preparation of Hydroxychloroquine Sulfate
[0071] Based on Example 5.2, the hydroxychloroquine obtained in
Example 5.1 was used to carry out the salt formation reaction,
and the solvent was changed. The other conditions were
unchanged, and the results were as follows:
[0072] Table 6-1
[0073]
[0074] The invention has been described in detail above,
including its preferred embodiments. It is to be understood,
however, that the invention may be modified and/or modified
within the spirit and scope of the appended claims.
CN107266323
Side chain, synthesis method thereof, and method for
synthesizing hydroxychloroquine sulfate from side chain
[ PDF ]
Abstract
The invention discloses a side chain, a synthesis method
thereof, and a method for synthesizing hydroxychloroquine
sulfate from the side chain. The synthesis method of the side
chain comprises the following steps: 1, condensing
N-ethylethanolamine and 5-chloro-2-pentanone to obtain a
condensation product; 2, esterifying the condensation product
and an acetyl reagent to obtain an esterification product; 3,
reducing the esterification product to obtain a reduction
product; and 4, reacting the reduction product with a
halogenating agent to obtain the side chain. The synthesis
method of the hydroxychloroquine sulfate comprises the following
steps: 1, reacting 4-amino-7-chloroquinoline with
paratoluensulfonyl chloride to obtain
4-Tos-amino-7-chloroquinoline; 2, reacting the side chain with
the 4-Tos-amino-7-chloroquinoline to obtain a hydroxyquine base;
and 3, reacting the hydroxyquine base with sulfuric acid to
obtain the hydroxychloroquine sulfate. The synthesis method of
the new side chain avoids the ammonification process and the
catalytic hydrogenation process, and is safe and environmentally
friendly, and the hydroxychloroquine sulfate can be obtained
through low-temperature condensation of the side chain, so the
quality of the above products is remarkably improved, and the
production flow is simplified.
[0001] Technical field
[0002] The invention belongs to the field of medicine and
chemical industry, in particular to a side chain and a synthesis
method thereof, and a method for synthesizing hydroxychloroquine
sulfate using the side chain.
[0003]
Background technique
[0004] Hydroxychloroquine sulfate, chemical name 2-4-
(7-chloro-4-quinolyl) aminopentylethylamino-ethanol sulfate,
English name: Hydroxychloroquine Sulfate, the chemical structure
is as follows:
[0005]
[0006] Hydroxychloroquine (HCQ) is an anti-malarial drug
consisting of 4-aminoquinoline compounds, synthesized in 1946 by
Surrey and Hammer. Clinic for the treatment of discoid lupus
erythematosus and systemic lupus erythematosus, has also been
widely used in rheumatoid-related diseases.
[0007] Discoid lupus erythematosus (DLE) is a common skin and
mucous membrane connective tissue disease, 25% -35% have oral
damage, can be issued in the mouth without incidental skin
damage, and more no obvious systemic symptoms. The etiology and
pathogenesis is not yet clear, the treatment is more difficult,
easy to relapse and cancer. Traditional application of
chloroquine phosphate (CQ) for the treatment of DLE, but the
side effects. HCQ has anti-inflammatory, anti-amine and
immunosuppressive effects, reducing lymphocyte conversion,
inhibiting vascular permeability, stabilizing lysosomal
membranes, so the treatment of DLE with HCQ targeted. So far,
HCQ is considered more secure than CQ. A large number of
clinical and literature reports confirmed the use of
hydroxychloroquine sulfate (HCQ) treatment of DLE obtained
satisfactory results.
[0008] Systemic Lupus Erythematosus (SLE) is a multi-systemic
disease with many kinds of antibodies in the body. The etiology
and treatment are difficult and difficult to treat. While
antimalarial drugs used to treat SLE began in 1950, Dobois found
that after 75% -80% of SLE patients were treated with
antimalarial drugs, rashes, fever, and joint symptoms improved,
especially for skin lesions. Subsequent research found that
anti-malarial drugs can reduce or stop the use of
corticosteroids in patients with SLE and have anti-allergic
effects. A double-blind controlled study by Hydroxychloro in
Canada showed that HCQ can stabilize SLE patients and
significantly reduce recurrence. Wallace et al found that HCQ
treatment can reduce the level of blood lipid in patients with
corticosteroid-dependent, can significantly reduce the incidence
of thrombosis. Given that HCQ can have a beneficial effect on
SLE, most scholars advocate that HCQ is used in patients with
mild to moderate SLE, combined with hormones and
immunosuppressants for adjuvant treatment of severe SLE.
[0009] 90% of foreign countries choose hydroxychloroquine when
applying anti-malarial drugs to treat SLE, while domestic may be
affected by such factors as cognition and drug source, and most
choose chloroquine. In fact, from a security point of view, if
the patient's condition allows, do not need to rely on
antimalarial drugs in a short period of time to play a curative
effect, should try to choose hydroxychloroquine.
[0010] As scientists further study found that hydroxychloroquine
can play a variety of immune regulation in rheumatic diseases,
the preferred hydroxychloroquine has a significant
anti-inflammatory effect, it can stabilize the lysosome, inhibit
enzyme activity, thereby inhibiting the activation of
inflammatory mediators , While inhibiting the chemotaxis and
infiltration of inflammatory cells such as neutrophils and
significantly reducing the production of proinflammatory
cytokines such as TNF-ɑ, IL-1 and IL-6; second,
hydroxychloroquine can inhibit the growth of fibroblasts And
connective tissue deposition and thus inhibit synovial
hyperplasia in patients with arthritis; hydroxychloroquine can
inhibit the interaction of antigen and antibody and immune
complex synthesis, to reduce the titer of rheumatoid factor;
hydroxychloroquine can also affect the absorption of ultraviolet
light and block UV damage to the skin. All of the above are
hydroxychloroquine in clinical treatment of rheumatic diseases
provide a large number of basis. In addition, many centers of
large-scale clinical studies also confirmed hydroxychloroquine
in the treatment of rheumatism play a significant therapeutic
effect.
[0011] At present, the synthesis of hydroxychloroquine sulfuric
acid generally take the following synthetic route:
[0012]
[0013] The core of this route is that 5-
(N-ethyl-N-2-hydroxyethylamine) -2-pentanamine (hereinafter
abbreviated hydroxychloroquine side chain) and 4,7- Preparation
of hydroxychloroquine base reaction, and then salt with sulfuric
acid. US2546658 discloses a method for synthesizing
hydroxychloroquine sulfate, the reaction process is as follows:
[0014]
[0015] The process is older, the use of phenol as a solvent,
phenol is toxic and corrosive, serious environmental pollution,
post-processing complex, not suitable for industrial production,
and the yield is relatively low, below 20%.
[0016] CA2561987 discloses a method for synthesizing
hydroxychloroquine sulfate, the reaction process is as follows:
[0017]
[0018] The method establishes the basic conditions for improving
the yield of hydroxyquinoline base of hydroxychloroquine side
chain and 4,7-dichloroquinoline, ie high temperature reaction.
Although the purity of the product is above 99.5%, the solvent
isobutyl Ketones and reagents Lithium hydroxide high prices,
high cost of raw materials, and cumbersome methods of operation,
a long time, is not conducive to industrial production.
[0019] WO2010027150 also discloses a method for
synthesizing hydroxychloroquine sulfate. The reaction process is
as follows:
[0020]
[0021] The law is still high temperature reaction, and the need
for high-pressure reaction, a higher security risk.
[0022] CN103724261A discloses a new industrial hydroxy
hydroxy quinoline sulfate method, the reaction process is as
follows:
[0023]
[0024] The method uses inert gas to reduce the risk of oxidation
impurities, but it is still a high temperature reaction. The
side reactions such as dehydration and condensation can not be
avoided and the corresponding impurities still exist. The purity
of the reported HPLC can only ensure ≧ 99.2%.
[0025] Hydroxychloroquine side chain is the synthesis of
hydroxychloroquine sulfate key intermediates, reported in the
literature there are two synthetic methods: Route one is the
first 5-chloro-2-pentanone first prepared as a ketal, and then
N-ethyl ethanolamine Reaction to give 5-
(N-ethyl-N-2-hydroxyethylamine) -2-pentanone, and then by
ammoniation, hydrogenation hydroxychloroquine side chain; Route
two, Reaction of pentanone with N-ethylethanolamine gives 5-
(N-ethyl-N-2-hydroxyethylamine) -2-pentanone, which is then
aminated and hydrogenated to reduce the hydroxychloroquine side
chain. Ammonia or high concentration of liquid ammonia is
required for both routes. Ammonia or high concentration of
liquid ammonia is required, and the odor is heavy, adversely
affecting the environment. Simultaneously, the imine is
subjected to high pressure hydrogenation to prepare an amino
group, which has a high safety risk. In 2015, CN104803859A
disclosed a method for synthesizing 5-
(N-ethyl-N-2-hydroxyethylamine) -2-pentylamine, that is, a
method for synthesizing hydroxychloroquine side chain. The
synthetic route is as follows:
[0026]
[0027] In summary, the current synthesis of hydroxychloroquine
sulfate there are two main adverse factors: First,
hydroxychloroquine side chain preparation: the need to use
ammonia or high concentrations of liquid ammonia, heavy smell,
the adverse impact on the environment, while imine Need
high-pressure hydrogenation to reduce the amino group, the
safety risk is high; Second, hydroxychloroquine base
preparation: 4,7-Dichloroquinoline 4 chlorine activity is
relatively low, and can not only use catalysts such as potassium
bromide, potassium iodide catalytic , Therefore, it is necessary
to react under high temperature. During the reaction of high
temperature, -NH2 and -OH at the end of hydroxychloroquine side
chain are easily oxidized, dehydrated, condensed and so on.
Therefore, if it is necessary to ensure the product quality, a
relatively complicated post-treatment process And use a lot of
organic solvents. In addition, the existing synthetic route also
has the defects of long production cycle, high impurity content,
low yield and high raw material cost. Therefore, it is of great
social significance and significant economic value to design an
industrialized synthetic route with simple process, mild
reaction conditions, high safety and environmental protection,
high yield and high quality, and low manufacturing cost.
[0028] Content of the invention
[0029] The purpose of the present invention is to provide a side
chain and a method for synthesizing the same, and a method for
synthesizing hydroxychloroquine sulfate using the side chain.
The method for synthesizing the side chain can avoid the use of
ammonia or high-concentration liquid ammonia on the one hand and
does not require high pressure On the other hand, the
synthesized new side chain replaces the hydroxychloroquine side
chain, and the hydroxychloroquine sulfate can be synthesized at
the lower reaction temperature, which can avoid
hydroxychloroquine side chain -NH2 and -OH reaction occurs under
high temperature conditions, help to ensure product quality, and
does not require cumbersome after-treatment process.
[0030] The technical solution adopted by the present invention
is as follows:
[0031] A side chain of the formula:
[0032] Where R is Cl, Br or I.
[0033] A side chain synthesis method, comprising the following
steps:
[0034] (1)Condensation reaction: adding N-ethylethanolamine,
phase transfer catalyst, inorganic alkali and organic solvent to
water, controlling the temperature to be 20-30 DEG C, adding
dropwise 5-chloro-2-pentanone for 2-6 hours, Layer, take the
organic layer was dried to obtain the condensation product of
the organic phase, the chemical name of the condensation product
is: 5- (N-ethyl-N-2-hydroxyethyl amine) -2-pentanone;
[0035] (2)Esterification reaction: the condensation product is
cooled to 0 to 10 DEG C in an organic phase, and incubated for 1
to 3 hours under the condition of dropwise addition of an acetyl
reagent for incubation. After the reaction is completed, the
organic layer is layered and washed with water, and the organic
phase of the esterified product is obtained. The chemical name
of the product is: 5- (N-ethyl-N-2-acetoxyamine) -2-pentanone;
[0036] (3)Reduction reaction: the esterified product was cooled
to -5 ~ 0 ° C in an organic phase, reacted with a reducing agent
for 1 to 4 hours, added with water, layered, and the organic
layer was dried to obtain the chemical product of the reduced
product Is: 5- (N-ethyl-N-2-acetoxyamine) -2-methylpentanol;
[0037] (4)Halogenation reaction: Adding the catalyst into the
organic phase of the reduction product, controlling the
temperature to 25-40 DEG C, reacting the halogenated reagent
dropwise for 3 to 8 hours while keeping the temperature,
delaminating and washing with water, and taking the organic
layer to dry to obtain the side chain organic phase; The
chemical name of the chain is: 5- (N-ethyl-N-2-acetoxyamine)
-2-chloropentane.
[0038] Further, before the esterification reaction and the
halogenation reaction are stratified by the completion of the
reaction, it is necessary to add the reaction system to an
aqueous solution of an inorganic alkali to neutralize the acid
formed during the esterification reaction and the halogenation
reaction, , Washed with water to ensure that the finally
generated side chain organic phase does not contain acid, alkali
and other impurities, preferably 0 to 5 ° C., and can cool the
reaction system for the subsequent reaction.
[0039] In the step (1), the molar ratio of 5-chloro-2-pentanone
to N-ethylethanolamine is 0.8 to 1.2, and the molar ratio of the
inorganic base to 5-chloro-2-pentanone is 1.2 to 1.8.
[0040] More preferably, the molar ratio of 5-chloro-2-pentanone
to N-ethylethanolamine is from 0.8 to 1.0 and the molar ratio of
inorganic base to N-ethylethanolamine is from 1.2 to 1.5. In
this step, the molar ratio of 5-chloro-2-pentanone and
N-ethylethanolamine is designed to be 0.8-1.0, which is
favorable for the complete conversion of 5-chloro-2-pentanone,
the reduction of the residue in the organic phase and the
increase of the condensation Product purity and content, reduce
the formation of impurities, the molar amount of inorganic base
slightly more than 5-chloro-2-pentanone molar amount can be,
both to ensure the catalytic, the amount of acid, but also not
waste, but also reduce waste emission.
[0041] In the step (1), the phase transfer catalyst is
tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate,
tetrabutylammonium chloride, trioctylmethylammonium chloride,
dodecyltrimethyl Ammonium chloride or
tetradecyltrimethylammonium chloride. In this step,
N-ethylethanolamine is dissolved in water and
5-chloro-2-pentanone is dissolved in organic solvent. Therefore,
the reaction system is a mixed system of aqueous phase and
organic phase and belongs to the heterophasic system. In the ion
binding, and use their own affinity for organic solvents, the
N-ethyl ethanolamine in the aqueous phase transferred to the
organic phase, prompting the reaction to occur, thereby
accelerating the heterogeneous system reaction rate.
[0042] More preferably, the phase transfer catalyst is
tetrabutylammonium bromide.
[0043] In the step (1), the organic solvent is dichloromethane,
chloroform or chlorobenzene.
[0044] More preferably, the organic solvent is chloroform.
[0045] Further, in the step (2), the molar ratio of the acetyl
reagent to the condensation product is from 1.0 to 1.5.
[0046] In the step (2), the acetyl reagent is acetyl chloride or
acetic anhydride. Acetylation is the condensation of the end
product - OH introduction of acetyl CH3CO- reaction, with high
product conversion, mild reaction conditions, environmental
protection and other characteristics, commonly used acetyl
reagent acetyl chloride or acetic anhydride.
[0047] More preferably, the acetyl reagent is acetyl chloride,
which has the fastest reaction rate.
[0048] Further, in the step (2), the concentration of the
inorganic alkali aqueous solution is 5 to 10%, and the amount
thereof is 0.5 to 2.0 times of the weight of the organic phase.
[0049] More preferably, the aqueous alkali solution is used in
an amount of 1.0 to 2.0 times the weight of the organic phase.
[0050] Further, in the step (3), the molar ratio of the reducing
agent to the esterified product is 0.3 to 0.5.
[0051] Further, in the step (3), the reducing agent is sodium
borohydride, potassium borohydride or borane diethyl ether.
Hydrogenation of hydrogenation reagent hydrogen anion release,
strong alkaline, and has a strong nucleophilic ester products
can be ester groups reduced to hydroxyl.
[0052] More preferably, the reducing agent is sodium
borohydride, the reaction conditions are mild, cheap, more
widely used.
[0053] Further, in the step (3), the temperature is lowered by
using ethanol. Ethanol in addition to the esterified product of
the organic phase can be rapidly cooled to the desired reaction
temperature, its miscibility with organic solvents, but also
promote the dissolution of reactants to speed up the reduction
reaction rate.
[0054] Further, in the step (3), the amount of ethanol is 15-40%
by weight of the organic solvent and the amount of the water is
0.5-2.0 times by weight of the organic solvent.
[0055] More preferably, the amount of ethanol is from 20 to 40%
by weight of the organic solvent and the amount of water is from
0.5 to 1.5 times the weight of the organic solvent.
[0056] Further, in the step (4), the molar ratio of the
halogenated reagent to the reduced product is 1.2 to 1.5.
[0057] In the step (4), the halogenating reagent is thionyl
chloride, phosphorus trichloride, thionyl bromide, phosphorus
tribromide, phosphorus pentabromide, N-chlorosuccinimide, N-
Bromosuccinimide or N-iodosuccinimide. By halogenation, the
hydroxyl groups in the reduced product are replaced by halogens
to form the halogen substituted as the side chain for the
subsequent synthesis of hydroxychloroquine sulfate.
[0058] More preferably, the halogenating agent is thionyl
chloride.
[0059] Further, in the step (4), the catalyst is N,
N-dimethylformamide in an amount of 0.05 to 0.2 times the weight
of the halogenated reagent.
[0060] Further, in the step (4), the concentration of the
inorganic alkali aqueous solution is 8 to 10%, and the amount
thereof is 4.0 to 6.0 times of the weight of the organic phase.
[0061] The method for synthesizing hydroxychloroquine sulfate
using the side chain comprises the following steps:
[0062] (A) N protection reaction: 4-amino-7-chloroquinoline,
co-solvent was added to an organic solvent, warmed to 30 ~ 40 °
C, p-toluenesulfonyl chloride was added and reacted for 2 to 6
hours, , Recrystallization, drying 4-Tos
amino-7-chloroquinoline;
[0063] (B) Condensation reaction: the catalyst and 4-Tos
amino-7-chloroquinoline are added to the side chain organic
phase, the temperature is raised to 60-80 DEG C, the reaction is
completed, the temperature is lowered to 5-20 DEG C and the
mixture is separated into layers, The organic layer is
concentrated to obtain hydroxyquinoline crude, recrystallized
and dried to obtain hydroxyquinoline;
[0064] More preferably, after the reaction is completed, the
temperature is lowered to 5 to 10 ° C and the layers are
separated.
[0065] (C) Salt-forming reaction: adding the hydroxyquinoline
base to an alcoholic solvent, raising the temperature to 50-60 °
C., dissolving completely, adding sulfuric acid dropwise for 1
hour, cooling to 0-10 ° C. to obtain sulfuric acid
Hydroxychloroquine.
[0066] Further, in the steps (A) and (B), the reaction system
needs to be added to an aqueous solution of an inorganic base to
react before stratification of the reaction is completed.
[0067] In the step (A), an aqueous solution of an inorganic
alkali at 0 to 10 ° C is used. In the step (B), after the
reaction is completed, the reaction system is first cooled to
20-30 ° C and then added to an aqueous solution of inorganic
alkali at 20-40 ° C for 3 to 8 hours, preferably 30-40 ° C.
[0068] In the step (A), the molar ratio of p-toluenesulfonyl
chloride to 4-amino-7-chloroquinoline is 1.0 to 1.2.
[0069] Further, in the step (A), the organic solvent is
methylene chloride, chloroform or dichloroethane in an amount of
3 to 6 times the weight of 4-amino-7-chloroquinoline.
[0070] More preferably, the organic solvent is chloroform.
[0071] Further, in the step (A), the cosolvent is DMF, DMSO or
dioxane in an amount of 0.1-0.6 times the weight of
4-amino-7-chloroquinoline.
[0072] More preferably, the co-solvent is DMF.
[0073] More preferably, the cosolvent is used in an amount of
0.1 to 0.4 times the weight of 4-amino-7-chloroquinoline.
[0074] Further, in the step (A), the mass concentration of the
inorganic alkali aqueous solution is 5 to 10%, and the amount
thereof is 1.0 to 2.0 times the weight of the organic phase.
[0075] In the step (A), the drying temperature is 40-70 ° C.
[0076] Further, in the step (B), the molar ratio of the side
chain to 4-Tos amino-7-chloroquinoline is 1.0 to 1.5.
[0077] More preferably, the molar ratio of the side chain to
4-Tos amino-7-chloroquinoline is 1.0 to 1.2.
[0078] Further, in the step (B), the catalyst is potassium
iodide, sodium iodide, tetrabutylammonium bromide, DMAP or
pyridine in an amount of 0.02 to 0.1 times the weight of the
side chain.
[0079] More preferably, the catalyst is tetrabutylammonium
bromide.
[0080] Further, in the step (B), the concentration of the
inorganic alkali aqueous solution is 5-40%, and the amount is
1.0-3.0 times the weight of the organic phase.
[0081] More preferably, the concentration of the aqueous
inorganic base solution is 10-40%.
[0082] In the step (B), the drying temperature is 40-70 ° C.
[0083] Further, in the step (C), the molar ratio of sulfuric
acid to hydroxyquinolyl is 1.0 to 1.1.
[0084] Further, in step (C), the alcohol solvent is 95% ethanol,
methanol or absolute ethanol solution, and the dosage is 3-5
times of the weight of hydroxyquinoline.
[0085] More preferably, the solvent is 95% ethanol.
[0086] In the step (C), the crystallization time is 0.5 to 3
hours.
[0087] In the step (C), the drying temperature is 40-70 ° C.
[0088] In the above method for synthesizing the side chain and
the hydroxychloroquine sulfate, the inorganic alkali used is
sodium carbonate, potassium carbonate, sodium hydroxide,
potassium hydroxide, sodium bicarbonate or potassium
bicarbonate, and the inorganic alkali in step (1) is preferably
The inorganic base in step (2) and step (4) is preferably sodium
carbonate, and the inorganic base in step (A) and step (B) is
preferably sodium hydroxide. The inorganic base in the step (1)
is added as a catalyst to water together with
N-ethylethanolamine, a phase transfer catalyst and an organic
solvent in order to promote the condensation reaction of
N-ethylethanolamine and 5-chloro-2-pentanone Process to speed up
the reaction rate, preferably stronger alkaline potassium
hydroxide. The inorganic bases in the subsequent steps are all
present in the form of an aqueous alkali solution for
neutralizing the acid formed during the reaction and for
adjusting the pH wherein the products formed in steps (2) and
(4) are less stable, Thus, less basic sodium carbonate is used,
while the products formed in steps (A) and (B) are more stable,
preferably more basic, sodium hydroxide.
[0089] In the above method for synthesizing a side chain, the
method for drying is as follows: the organic layer is dried
under the action of a desiccant at 10 to 20 DEG C for 1 to 2
hours, the desiccant is anhydrous sodium sulfate or anhydrous
magnesium sulfate in an amount of 10 ~ 20% of organic solvent.
[0090] The reaction mechanism of the synthetic route of the
present invention is:
[0091] First, N-ethylethanolamine and 5-chloro-2-pentanone are
condensed, esterified, reduced and halogenated to obtain side
chains. The reaction process is as follows:
[0092]
[0093] Then, 4-amino-7-chloroquinoline is reacted with
p-toluenesulfonyl chloride to give 4-Tos
amino-7-chloroquinoline. Finally, 4-Tos amino-7-chloroquinoline
is condensed with the side chain to form a salt,
Hydroxychloroquine, the reaction process is as follows:
[0094]
[0095] (Where R = Cl, Br, I, preferably -Cl)
[0096] In summary, due to the adoption of the above technical
solutions, the beneficial effects of the present invention are
as follows:
[0097] 1、In the invention, a novel side chain for synthesizing
hydroxychloroquine sulfate is prepared by condensation,
esterification, reduction and halogenation reaction of
N-ethylethanolamine and 5-chloro-2-pentanone, wherein the side
chain of Synthesis of non-ammoniated process, no catalytic
hydrogenation process, the solvent used is easy to recycle,
safety and environmental protection, and easy to operate,
reducing the difficulty of industrial production;
[0098] 2、The side chain of the present invention replaces the
existing hydroxychloroquine side chain and discards the
conventional 4,7-dichloroquinoline instead of
4-amino-7-chloroquinoline with p-toluenesulfonyl chloride to
give 4-Tos amino-7- Chloroquinoline, and the new side chain can
be synthesized at low temperature hydroxychloroquine sulfate,
reducing the risk of high temperature side reaction impurities,
enhance the intrinsic quality of the product, simplifying the
production process;
[0099] 3、The low-temperature condensation process of the
invention has the advantages of low temperature and short time,
is favorable for reducing energy consumption and improving
equipment utilization;
[0100] 4.The invention has the advantages of simple synthesis
route, mild reaction conditions, safety and environmental
protection, high yield and high quality, low manufacturing cost
and suitable for industrial production of hydroxychloroquine
sulfate.
[0101] BRIEF DESCRIPTION OF THE DRAWINGS FIG
[0102] Figure 1 is a schematic view of the synthesis route of
the present invention;
[0103] Figure 2 is an HPLC chromatogram of hydroxychloroquine
sulfate sample;
[0104] Figure 3 is an HPLC chromatogram of hydroxychloroquine
sulfate reference substance.
[0105] detailed description
[0106] All of the features disclosed in this specification may
be combined in any manner other than mutually exclusive features
and / or steps.
[0107] The present invention will be described in detail below
with reference to FIGS. 1, 2 and 3.
[0108] N-ethylethanolamine, 5-chloro-2-pentanone,
4-amino-7-chloroquinoline and p-toluenesulfonyl chloride used in
the present invention, as well as the organic solvents and
alcoholic solvents used are all commercially available
Industrial raw materials, "95% ethanol" for the industrial 95
ethanol.
[0109]
Example 1
[0110] Preparation of side chains:
[0111] (1)Condensation reaction: 30 g of N-ethylethanolamine,
0.6 g of tetrabutylammonium bromide, 25 g of potassium
hydroxide, 240 g of chloroform and 120 g of water were added to
a reaction flask, and then the temperature was controlled to be
20 to 30 ° C. 38 g of 5- 2-pentanone, after the addition was
complete, the reaction was stirred for 3 hours, still
stratified, the aqueous phase was discarded, the organic layer
was added 24g anhydrous sodium sulfate, the temperature was
controlled at 10 ~ 20 ℃, stirred and dried for 1 hour, filtered,
The organic phase of the condensation product was detected. The
content of the condensation product was 50.2g. The molar yield
was 92% (based on 5-chloro-2-pentanone) and the GC purity was ≧
98.5%.
[0112] (2)Esterification reaction: the condensation product
obtained in step (1) organic phase (condensation product 50.2g)
was cooled to 0 ~ 5 ℃, 24g acetyl chloride was added dropwise,
after completion of the dropwise addition, the reaction was
incubated for 2 hours, the reaction is complete, the reaction
The solution was slowly added to an aqueous solution of sodium
carbonate (350 g, mass fraction of sodium carbonate 6%)
pre-cooled to 0-5 ° C and stirred for 30 minutes. The layers
were separated and the organic phase was washed with 200 g of
water and the layers were separated. Water and sodium sulfate at
the temperature of 10-20 DEG C, stirring and drying for 1 hour
and filtering to obtain the organic phase of the esterification
product. The content of the esterification product was 57.8g,
the molar yield was 91.9% and the GC purity was ≧ 99.0%.
[0113] (3)Reduction reaction: 40g of ethanol is added to the
organic phase (57.8g of the esterified product) of the
esterified product obtained in the step (2), the temperature is
decreased to -5 to 0 DEG C, 12.0g of sodium borohydride is
slowly added, The reaction was 2.0 hours, 180g of water was
added, stirred for 30 minutes, standing stratification, and then
washed once with 100g of water, standing layered organic layer
plus 24g anhydrous sodium sulfate, the temperature was
controlled at 10 ~ 20 ℃, stirred and dried for 1 hour, Filtered
to obtain the organic phase of the reduced product. The content
of the product was measured. The content of the reduced product
was 54.6 g, the molar yield was 93.6% and the GC purity was ≧
99.0%.
[0114] (4)Halogenation reaction: 2.0g MDF was added to the
organic phase of the reduction product (54.6g containing the
reduction product) prepared in the step (3), the temperature was
controlled at 25-40 ℃, 37.0g thionyl chloride After the addition
was completed, the reaction was allowed to proceed for 4.0
hours. The reaction system was slowly added to an aqueous
solution of sodium carbonate (800 g, 8% sodium carbonate) at 0-5
° C. The layers were separated and the organic layer was washed
with 200 g of water and left to stand The organic layer was
added with 24 g of anhydrous sodium sulphate and the temperature
was controlled at 10-20 ° C. The mixture was stirred and dried
for 1 hour and filtered to obtain a side chain organic phase
with a content of 56.8 g, a molar yield of 96% and a GC purity
of ≧ 99.0 %.
[0115] Example 2
[0116] Preparation of side chains:
[0117] (1)Condensation reaction: 30g of N-ethylethanolamine,
0.9g of tetrabutylammonium bromide, 25g of potassium hydroxide,
240g of chloroform and 120g of water were added into a reaction
flask, and then the temperature was controlled to be between 20
and 30 DEG C and 38g of 5-chloro- 2-pentanone, after the
addition was complete, the reaction was stirred for 3 hours,
still stratified, the aqueous phase was discarded, the organic
layer was added 24g anhydrous sodium sulfate, the temperature
was controlled at 10 ~ 20 ℃, stirred and dried for 1 hour,
filtered, The organic phase of the condensation product was
detected. The content of the condensation product was 50.8g, the
molar yield was 93.1% (based on 5-chloro-2-pentanone) and the GC
purity was ≧ 98.5%.
[0118] (2)Esterification reaction: the condensation product
obtained in step (1) was cooled to 0 to 5 DEG C in the organic
phase (containing the condensation product 50.8g), and 24g
acetyl chloride was added dropwise to the mixture. After the
addition was completed, the reaction was incubated for 2 hours,
The reaction mixture was slowly added to an aqueous solution of
sodium carbonate (350 g, mass fraction of sodium carbonate 6%)
pre-cooled to 0-5 ° C. and stirred for 30 minutes. The layers
were separated and the organic layer was washed with 200 g of
water. The layers were separated and the organic layer was added
with 24 g Anhydrous sodium sulfate was added. The temperature
was controlled at 10 ~ 20 ℃. The mixture was stirred and dried
for 1 hour. The mixture was filtered to obtain an organic phase
of the esterified product. The content of the esterification
product was 57.9g. The molar yield was 92.0% and the GC purity
was ≧ 99.0%.
[0119] (3)Reduction reaction: 40g of ethanol was added into the
organic phase (57.9g of the esterified product) of the
esterified product obtained in the step (2), cooled to -5 ~ 0 ℃,
12.0g of sodium borohydride was slowly added, The reaction was
carried out at 0 ° C for 2 hours and 180 g of water was added.
The mixture was stirred for 30 minutes, allowed to stand for
delamination and then washed once with 100 g of water. The
layers were separated and the organic layer was added with 24 g
of anhydrous sodium sulfate. After drying for 1 hour and
filtering, the organic phase of the reduced product was
obtained. The content of the reduced product was 53.8 g, the
molar yield 92.1% and the GC purity ≧ 99.0%.
[0120] (4)Halogenation reaction: the reduction product obtained
in step (3) is taken as organic phase (containing 53.8 g of
reduced product), 2.0 g of MDF is added, the temperature is
controlled at 25-40 ° C., 36.0 g of thionyl chloride is added
dropwise while keeping the temperature dropping, , The reaction
4.0 hours, the reaction system was slowly added to a 0 ~ 5 ° C
aqueous solution of sodium carbonate (800g, sodium carbonate
mass fraction of 8%), the layers were separated, the organic
layer was added 200g water washing, standing stratification,
organic Layer was added 24g anhydrous sodium sulfate, the
temperature was controlled at 10 ~ 20 ℃, stirred and dried for 1
hour, filtered to give a side chain organic phase, the content
was detected, side chain 56.0g, 96% molar yield, GC purity ≧
99.0%.
[0121] Example 3
[0122] Preparation of side chains:
[0123] (1)Condensation: 30 g of N-ethylethanolamine, 1.2 g of
tetrabutylammonium bromide, 25 g of potassium hydroxide, 240 g
of chloroform and 120 g of water were charged into a reaction
flask, and then the temperature was controlled at 20 to 30 ° C.
38 g of 5-chloro- 2-pentanone, after the dropwise addition, the
reaction was stirred for 3 hours, still stratified, the aqueous
phase was discarded, the organic layer was added 24g anhydrous
sodium sulfate, the temperature was controlled at 10 ~ 20 ℃,
stirred and dried for 1 hour, filtered, the filtrate is The
organic phase of the condensation product was detected. The
content of the condensation product was 51.7g, the molar yield
was 94.7% (based on 5-chloro-2-pentanone) and the GC purity was
≧ 98.5%.
[0124] (2)Esterification reaction: the condensation product
obtained in step (1) organic phase (condensation product 51.7g)
was cooled to 0 ~ 5 ℃, incubated dropwise 24g acetyl chloride,
after the addition was complete, the reaction was incubated for
2 hours, the reaction was completed and the reaction The
solution was slowly added to an aqueous solution of sodium
carbonate (350 g, mass fraction of sodium carbonate 6%)
previously cooled to 0-5 ° C and stirred for 30 minutes. The
layers were separated and the organic layer was washed with 200
g of water and the layers were separated. Water and sodium
sulfate at a controlled temperature of 10 to 20 DEG C, stirring
and drying for 1 hour and filtering to obtain an organic phase
of the esterified product. The content of the esterified product
was detected. The esterified product was 59.6g, the molar yield
was 93.2% and the GC purity was ≧ 99.0%.
[0125] (3)Reduction reaction: 40g of ethanol was added to the
organic phase (59.6g of the esterified product) of the
esterified product obtained in the step (2), the temperature was
lowered to -5 to 0 DEG C, 12.0g of sodium borohydride was slowly
added, and the reaction was incubated 2.0 hours, 180g of water
was added and stirred for 30 minutes, standing stratification,
and then washed once with 100g of water, standing
stratification, the organic layer was added 24g anhydrous sodium
sulfate, the temperature was controlled at 10 ~ 20 ℃, stirred
and dried for 1 hour, filtered , The organic phase of the
reduced product was obtained, and the content thereof was
measured. The yield of the reduced product was 55.6 g, the molar
yield was 92.4% and the GC purity was ≧ 99.0%.
[0126] (4)Halogenation reaction: The organic phase of the
reduction product (55.6g containing the reduction product)
prepared in the step (3) is added with 2.0g of MDF, the
temperature is controlled at 25-40 DEG C, 36.0g of thionyl
chloride is added dropwise while keeping the temperature
dropping, , The reaction 4.0 hours, the reaction system was
slowly added to a 0 ~ 5 ° C aqueous solution of sodium carbonate
(800g, sodium carbonate mass fraction of 8%), the layers were
separated, the organic layer was added 200g water washing,
standing stratification, organic Layer was added 24g anhydrous
sodium sulfate, the temperature was controlled at 10 ~ 20 ℃,
stirred and dried for 1 hour, filtered to give a side chain
organic phase, the content was detected, side chain 57.0g, molar
yield 94.5%, GC purity ≧ 99.0%.
[0127] Example 4
[0128] Preparation of side chains:
[0129] (1)Condensation reaction: 30 g of N-ethylethanolamine,
0.6 g of tetrabutylammonium bromide, 25 g of potassium
hydroxide, 240 g of chloroform and 120 g of water were added to
a reaction flask, and then the temperature was controlled to be
20 to 30 ° C. 38 g of 5- 2-pentanone, after completion of the
dropwise addition, the reaction was stirred for 3 hours,
standing stratification, the aqueous phase was discarded, the
organic layer was added 24g anhydrous sodium sulfate, the
temperature was controlled at 10 ~ 20 ℃, stirred and dried for 1
hour, filtered, As the condensation product of the organic
phase, the content was detected, the condensation product 50.2g,
the molar yield of 91.9% (5-chloro-2-pentanone dollars), GC
purity ≧ 98.5%.
[0130] (2)Esterification reaction: the condensation product
obtained in step (1) organic phase (condensation product 50.2g)
was cooled to 0 ~ 5 ℃, 24g acetyl chloride was added dropwise,
after completion of the dropwise addition, the reaction was
incubated for 2 hours, the reaction is complete, the reaction
The solution was slowly cooled to 0-5 ° C in an aqueous solution
of sodium carbonate (350g, mass fraction of sodium carbonate 6%)
and stirred for 30 minutes. The layers were separated and the
organic layer was washed with 200g of water. The layers were
separated and the organic layer was added with 24g of anhydrous
sulfuric acid Sodium. The temperature was controlled at 10 ~ 20
℃. The mixture was stirred and dried for 1 hour and filtered to
obtain the organic phase of the esterified product. The content
of the esterified product was determined. The esterified product
was 57.4g, the molar yield was 92.4% and the GC purity was ≧
99.0%.
[0131] (3)Reduction reaction: 40g of ethanol was added to the
organic phase (57.4g of the esterified product) of the
esterified product obtained in the step (2), the temperature was
lowered to -5 ~ 0 ℃, 12.0g of sodium borohydride was slowly
added, 2.0 hours, 180g of water was added and stirred for 30
minutes, standing stratification, and then washed once with 100g
of water, standing stratification, the organic layer was added
24g anhydrous sodium sulfate, the temperature was controlled at
10 ~ 20 ℃, stirred and dried for 1 hour, filtered , The organic
phase of the reduced product was obtained, and the content
thereof was measured. The amount of the reduced product was 54.4
g, the molar yield was 93.8% and the GC purity was ≧ 99.0%.
[0132] (4)Halogenation reaction: The organic phase of the
reduction product (54.4g containing the reduction product)
prepared in the step (3) was added 2.0gMDF, the temperature was
controlled at 25 ~ 40 ℃, 39.0g of thionyl chloride was added
dropwise while keeping the temperature dropping, , The reaction
4.0 hours, the reaction system was slowly added to a 0 ~ 5 ° C
aqueous solution of sodium carbonate (800g, sodium carbonate
mass fraction of 8%), the layers were separated, the organic
layer was added 200g water washing, standing stratification,
organic Layer was added 24g anhydrous sodium sulfate, the
temperature was controlled at 10 ~ 20 ℃, stirred and dried for 1
hour, filtered to obtain a side chain organic phase, the content
was detected, side chain 56.7g, molar yield 96.1%, GC purity ≧
99.0%.
[0133] Example 5
[0134] Preparation of hydroxychloroquine sulfate:
[0135] (A) N Protection reaction: 45 g of
4-amino-7-chloroquinoline and 5 g of DMF were added to 180 g of
chloroform, and the temperature was raised to 30 to 40 ° C. 50.0
g of p-toluenesulfonyl chloride was added and reacted for 3
hours. After the reaction was completed, The system was added to
a sodium hydroxide solution (200 g, sodium hydroxide mass
fraction 8%) at 0-10 ° C. The layers were separated and the
organic layer was further washed with 100 g of water. The layers
were separated and the organic layer was concentrated under
reduced pressure to recover the chloroform. The mixture was
refluxed at elevated temperature for 30 minutes, then cooled to
0-5 ° C to recrystallize, filtered, and dried at 50-60 ° C to
obtain 80 g of 4-Tos amino-7-chloroquinoline, 95.5% of moles and
purity of ≧ 99.5%.
[0136] (B) Condensation reaction: 78.0 g of 4-Tos
amino-7-chloroquinoline obtained in the step (A), 3.0 g of
tetrabutyl Ammonium bromide, and the temperature was raised to
65-70 ° C. After the reaction for 6.0 hours, the system was
cooled to 20-30 ° C and added to an aqueous solution of sodium
hydroxide (300 g, sodium hydroxide mass fraction 15%) at 30-40 °
C. The reaction mixture was incubated at 30-40 ° C for 6.0
hours, cooled to 10-15 ° C and allowed to stand for
delamination. The organic layer was concentrated to give a crude
product of hydroxyquinoline after recovering the chloroform by
addition of 260 g of 95% ethanol, 10 ℃, recrystallization,
filtration, dried at 50 ~ 60 ℃ hydroxyquinoline base 110.4g, the
molar yield of 96.1% (4-amino-7-chloroquinoline dollars), purity
≧ 99.5%.
[0137] (C) Salt-forming reaction: Take 70g of hydroxyquinoline
base prepared in step (B) and add 200g of 95% ethanol into a
reaction flask, increase the temperature to 50-60 ° C, dissolve,
and dropwise add 18.8g of 80% , The reaction was incubated for 1
hour after the addition was completed, cooled to 0 to 10 ° C for
2.0 hours, filtered and dried at 50-60 ° C to obtain 57.7 g
hydroxychloroquine sulfate, with a molar yield of 93.2% and a
purity of ≧ 99.8% %, The largest single impurity ≦ 0.1%, the
unknown impurity ≦ 0.1%, the ignition residue ≦ 0.2%, the water
≦ 0.3%, and the heavy metal ≦ 10 ppm.
[0138] Example 6
[0139] Preparation of hydroxychloroquine sulfate:
[0140] (A) N Protection reaction: 45 g of
4-amino-7-chloroquinoline and 5 g of DMF were added to 180 g of
chloroform, the temperature was raised to 30 to 40 ° C, 52.0 g
of p-toluenesulfonyl chloride was added and reacted for 4 hours.
After the reaction was completed, The system was added to a
sodium hydroxide solution (200 g, sodium hydroxide mass fraction
8%) at 0-10 ° C. The layers were separated and the organic layer
was further washed with 100 g of water. The layers were
separated and the organic layer was concentrated under reduced
pressure to recover the chloroform. The mixture was refluxed at
elevated temperature for 30 minutes, then cooled to 0-5 ° C to
recrystallize, filtered and dried at 50-60 ° C to obtain 81.3 g
of 4-Tos amino-7-chloroquinoline, 97.02% of molar purity and ≧
99.5% of purity.
[0141] (B) Condensation reaction: 72.0 g of 4-Tos
amino-7-chloroquinoline obtained in the step (A), 2.5 g of
tetrabutyl Ammonium bromide, and the temperature was raised to
65-70 ° C. After the reaction for 6.0 hours, the system was
cooled to 20-30 ° C and added to an aqueous solution of sodium
hydroxide (300 g, sodium hydroxide mass fraction 15%) at 30-40 °
C. The reaction was incubated at 30-40 ° C for 6.0 hours, cooled
to 10-15 ° C and allowed to stand for delamination. The organic
layer was concentrated and recovered to give a crude product of
hydroxyquinoline based on the recovery of chloroform, followed
by addition of 260 g of 95% ethanol. The mixture was warmed to 0
~ 10 ℃, recrystallization, filtration, drying at 50 ~ 60 ℃
hydroxyquinoline 101.9g, the molar yield of 95.3%
(4-amino-7-chloroquinoline dollars), purity ≧ 99.5%.
[0142] (C) Salt-forming reaction: Take 70g of hydroxyquinoline
base prepared in step (B) and add 200g of 95% ethanol into a
reaction flask, increase the temperature to 50-60 ° C, dissolve,
and dropwise add 18.8g of 80% , The reaction was incubated for 1
hour after the addition was completed, cooled to 0 to 10 ° C for
2.0 hours, filtered and dried at 50-60 ° C to obtain 58.1 g of
hydroxychloroquine sulfate with a molar yield of 93.8%, purity
of ≧ 99.8% and total impurity of ≦ 0.2 %, The largest single
impurity ≦ 0.1%, the unknown impurity ≦ 0.1%, the ignition
residue ≦ 0.2%, the water ≦ 0.3%, and the heavy metal ≦ 10 ppm.
[0143] Example 7
[0144] Preparation of hydroxychloroquine sulfate:
[0145] (A) N Protection reaction: 45 g of
4-amino-7-chloroquinoline and 5 g of DMF were added to 180 g of
chloroform, the temperature was raised to 30 to 40 ° C, 52.0 g
of p-toluenesulfonyl chloride was added and reacted for 4 hours.
After the reaction was completed, The system was added to a
sodium hydroxide solution (200 g, sodium hydroxide mass fraction
8%) at 0-10 ° C. The layers were separated and the organic layer
was further washed with 100 g of water. The layers were
separated and the organic layer was concentrated under reduced
pressure to recover the chloroform. The mixture was refluxed at
elevated temperature for 30 minutes, then cooled to 0-5 ° C to
recrystallize, filtered and dried at 50-60 ° C to obtain 80.6 g
of 4-Tos amino-7-chloroquinoline, 96.19% of moles and purity of
≧ 99.5%.
[0146] (B) Condensation reaction: 72.0 g of 4-Tos
amino-7-chloroquinoline obtained in the step (A), 2.5 g of
tetrabutyl Ammonium bromide, and the temperature was raised to
65-70 ° C. After the reaction for 6.0 hours, the system was
cooled to 20-30 ° C and added to an aqueous solution of sodium
hydroxide (300 g, sodium hydroxide mass fraction 15%) at 30-40 °
C. The reaction was incubated at 30-40 ° C for 6.0 hours, cooled
to 10-15 ° C and allowed to stand for delamination. The organic
layer was concentrated and recovered to give a crude product of
hydroxyquinoline based on the recovery of chloroform, followed
by addition of 260 g of 95% ethanol. The mixture was warmed to 0
Recrystallization at -10 ° C, filtering and drying at 50-60 ° C
to obtain 100.7g of hydroxyquinolyl group with a molar yield of
95.0% (based on 4-amino-7-chloroquinoline) with a purity of ≧
99.5%.
[0147] (C) Salt-forming reaction: Take 70g of hydroxyquinoline
base prepared in step (B) and add 200g of 95% ethanol into a
reaction flask, increase the temperature to 50-60 ° C, dissolve,
and dropwise add 18.8g of 80% , The reaction was incubated for 1
hour after the addition was completed, cooled to 0 to 10 ° C for
2.0 hours, filtered and dried at 50-60 ° C to obtain 58.7 g of
hydroxychloroquine sulfate with a molar yield of 94.8% and a
purity of ≧ 99.8% %, The largest single impurity ≦ 0.1%, the
unknown impurity ≦ 0.1%, the ignition residue ≦ 0.2%, the water
≦ 0.3%, and the heavy metal ≦ 10 ppm.
[0148] Example 8
[0149] Preparation of hydroxychloroquine sulfate:
[0150] (A) N Protection reaction: 45 g of
4-amino-7-chloroquinoline and 5 g of DMF were added to 180 g of
chloroform, the temperature was raised to 30 to 40 ° C, 52.0 g
of p-toluenesulfonyl chloride was added and reacted for 4 hours.
After the reaction was completed, The system was added sodium
hydroxide aqueous solution (200g, sodium hydroxide mass fraction
8%) at 0-10 ° C. The layers were separated and the organic layer
was further washed with 100g of water and the layers were
separated. The organic layer was concentrated under reduced
pressure to recover the chloroform, Methanol, and heated to
reflux for 30 minutes to dissolve, cooled to 0 ~ 5 ℃
recrystallization, filtered, dried at 50 ~ 60 ℃ to obtain 80.9g
4-Tos amino-7-chloroquinoline, 96.50% molar purity ≧ 99.5%.
[0151] (B) Condensation reaction: 75.0 g of 4-Tos
amino-7-chloroquinoline obtained in the step (A), 3.0 g of
tetrabutyl Ammonium bromide, and the temperature was raised to
60-65 ° C. After the reaction was completed for 6.0 hours, the
system was cooled to 20-30 ° C and added to an aqueous solution
of sodium hydroxide (300 g, sodium hydroxide mass fraction 15%)
at 30-40 ° C. The reaction was incubated at 30-40 ° C for 6.0
hours, cooled to 10-15 ° C and allowed to stand for
delamination. The organic layer was concentrated and recovered
to give a crude product of hydroxyquinoline based on the
recovery of chloroform, followed by addition of 260 g of 95%
ethanol. The mixture was warmed to 0 ~ 10 ℃ recrystallization,
filtration, dried at 50 ~ 60 ℃ hydroxyquinoline 103.4g, the
molar yield of 93.6% (4-amino-7-chloroquinoline dollars), purity
≧ 99.5%.
[0152] (C) Salt-forming reaction: Take 70g of hydroxyquinoline
base prepared in step (B) and add 200g of 95% ethanol into a
reaction flask, increase the temperature to 50-60 ° C, dissolve,
and dropwise add 18.8g of 80% , The reaction was incubated for 1
hour after the addition was completed, cooled to 0 to 10 ° C for
2.0 hours, filtered and dried at 50-60 ° C to obtain 57.8 g of
hydroxychloroquine sulfate with a molar yield of 93.6% and a
purity of ≧ 99.8% %, The largest single impurity ≦ 0.1%, the
unknown impurity ≦ 0.1%, the ignition residue ≦ 0.2%, the water
≦ 0.3%, and the heavy metal ≦ 10 ppm.
[0153] Example 9
[0154] High performance liquid chromatography (HPLC), using
liquid as the mobile phase, using a high-pressure infusion
system, a single solvent with different polarity or different
proportions of mixed solvents, such as mobile phase buffer was
pumped into the stationary phase of the column, After the
components are separated in the column, enter the detector for
testing, in order to achieve the analysis of the sample. The
HPLC chromatogram of the hydroxychloroquine sulfate sample
prepared in Example 5 is shown in FIG. 2, and the HPLC
chromatogram of the hydroxychloroquine sulfate reference
standard is shown in FIG. 3.
[0155] As can be clearly seen from the comparison of FIG. 2 and
FIG. 3, the hydroxychloroquine sulfate prepared by the present
invention has less impurity types, higher total purity and lower
maximum single impurity purity than the hydroxychloroquine
sulfate reference standard, and is superior in quality In the
reference.
[0156] As described above, this is an embodiment of the present
invention. The present invention is not limited to the above
embodiments. Anyone should understand that structural changes
made under the inspiration of the present invention, and any
technical solutions that have the same or similarities with the
present invention fall into the protection scope of the present
invention.
CN107894474A
Method for simultaneous detection of hydroxychloroquine
side chains, raw materials and intermediates by gas
chromatography
[ PDF ]
Abstract
The invention belongs to the technical field of drug
analysis and particularly relates to a method for simultaneous
detection of hydroxychloroquine side chains, raw materials and
intermediates by gaschromatography. The method can
simultaneously determine the hydroxyl side chains, ethylamine,
xylene, ethylamine ethanol, chloropentanone, ethylamine
diethanolamine, amino pentanone and ethanol, and the
specificity, linearity, range, precision, detection line, and
accuracy are in line with the requirements of the verification
guiding principles for quality standard analysis methods of
traditionalChinese medicines in Chinese Pharmacopoeia 2015
Edition Volume IV. The method aims to provide a technical basis
for the detection and monitoring of the synthesis process of the
hydroxychloroquine sidechains.
[0001]
Technical field
[0002] The invention relates to the technical field of drug
analysis, in particular to a method for simultaneous detection
of hydroxychloroquine side chains and their raw materials and
intermediates by gas chromatography.
[0003]
Background technique
[0004] Hydroxychloroquine (formula I), chemically named
7-chloro-4-[5-(N-ethyl-N-2-hydroxyethyl-2-pentyl]
aminoquinoline, is a 4-aminoquinoline Drugs, originally used
clinically for the treatment of anti-Plasmodium, are now widely
used in the treatment of discoid lupus erythematosus and
systemic lupus erythematosus, and are also the first choice for
the treatment of rheumatoid arthritis. In addition, they have
immunosuppressive and anti-inflammatory reactions. Other aspects
also have applications.
[0005]
[0006] Hydroxychloroquine is synthesized from
4,7-dichloroquinoline and
5-(N-ethyl-N-2-hydroxyethylamine)-2-pentylamine in a
cost-synthetic reaction, among which 5-(N-ethyl)
-N-2-hydroxyethylamine)-2-pentylamine (Formula II), also known
as hydroxychloroquine side chain, is a key intermediate for the
synthesis of hydroxychloroquine. There are seven kinds of raw
materials and intermediates involved in the synthesis route of a
hydroxychloroquine side chain (Formula III) disclosed in Chinese
Patent (Published: CN 104803859 A), which are ethylamine
(Formula 1) and xylene (Formula 1). 5) Ethylamine Ethanol
(Formula 2), Chloropentene (Formula 4), Ethylamine
Diethanolamine (Formula 3), and Amino Pentoxone (Formula 6).
Residues of intermediates with incomplete raw materials and
reactions in the reaction The high purity results in low purity
of the target product and will affect the yield of
hydroxychloroquine synthesized with 4,7-dichloroquinoline in the
later period, thereby reducing the quality and clinical efficacy
of hydroxychloroquine. Therefore, it is particularly necessary
to carry out quality control during the synthesis of
hydroxychloroquine side chains.
[0007]
[0008] From the structural formula of the hydroxychloroquine
side chain, it is known that there is no conjugation effect and
significant ultraviolet absorption, and it is generally
difficult to analyze it by liquid chromatography, which is
simple, convenient, and cost-effective. In addition, the raw
materials and intermediates of the hydroxychloroquine side chain
are all liquid and have the characteristics of small molecular
weight and good thermal stability. Therefore, gas chromatography
is suitable for analysis. Gas chromatography (GC) technology has
the characteristics of high efficiency, convenience, and
accurate separation. It has become an important research field
for instrument analysis and provides an indispensable important
analysis basis for the disciplines of physics, chemistry, and
medicine. Today, GC is a very mature technology and its
application will continue to deepen and expand.
[0009]
Summary of the Invention
[0010] The object of the present invention is to provide a
rapid, convenient, accurate, and sensitive method for the
simultaneous detection of hydroxychloroquine side chains and the
seven starting materials and intermediates involved in the
process by gas chromatography.
[0011] In the present invention, by using direct injection gas
chromatography, the simultaneous determination of seven kinds of
raw materials involved in the hydroxychlorochloroquine side
chain and its technological process was established through the
selection and optimization of different stationary phases,
temperature-programmed time and sample preparation solvent. The
new method of the intermediates and the scientificity, accuracy
and feasibility of the analytical method of the invention have
been confirmed through verification, aiming to provide a
technical basis for the detection and monitoring of the
synthesis process of hydroxychloroquine side chains.
[0012] In order to achieve the above object of the present
invention, the following technical solutions are adopted.
[0013] A gas chromatographic method for the detection of
hydroxychloroquine side chains and their starting materials and
intermediates. The method for the simultaneous detection of
hydroxychloroquine side chains, ethylamine, ethylamine ethanol,
ethylamine diethanolamine, chloropentanone, xylene,
amino-pentane Ketone and ethanol; includes the following steps:
[0014] (1)Chromatographic conditions
[0015] The chromatographic column is a cross-linked capillary
column, which is heated by a program; the inlet temperature is
250-310°C; the carrier gas is nitrogen; the detector is a
hydrogen flame ionization detector FID, the detector temperature
is 260-315°C; the hydroxychloroquine side chain Ethylamine,
ethylamine, ethylamine ethanol, ethylamine diethanolamine,
chloropentanone, xylene, aminopentanone, and ethanol have a
resolution of greater than 1.5;
[0016] (2)Preparation of mixed control solution
[0017] The hydroxychloroquine side chain, ethylamine ethanol,
xylene, chloropentanone, ethylamine diethanolamine,
aminopentanone, ethylamine and ethanol were accurately weighed
and placed in the same volumetric flask and diluted with a
solvent to make a mixture. Reference solution; every 1 mL of the
mixed reference solution, the hydroxychloroquine side chain is
0.01 to 0.09 g, ethylamine ethanol, xylene, chloropentanone,
ethylamine diethanolamine, aminopentanone, and ethanol are
independently 0.001 to 0.009. g, ethylamine 0.011 ~ 0.019g;
[0018] (3)Preparation of the test solution
[0019] Take hydroxychloroquine side chain, accurately weighed,
solubilized and diluted to make a uniform solution containing
0.19 ~ 0.30g of this product per 1mL as the test solution;
[0020] (4)Determination
[0021] The precise volume of the mixed reference solution and
the test solution were measured and injected separately into the
gas chromatograph for determination.
[0022] In the present invention, in step (1), the cross-linked
capillary column is selected from any of DB-1, HP-1, HP-5 or
DB-624 cross-linked capillary columns.
[0023] In the present invention, in step (1), the initial
temperature of the program temperature increase is 80 to 120° C.
for 1 to 8 minutes, and the temperature is increased to 180 to
240° C. at a rate of 12 to 17° C./min and stored for 3 to 15
minutes.
[0024] In the present invention, in step (1), the flow rate of
nitrogen is 1.5 to 3.5 mL/min, and the split ratio is 25:1 to
35:1.
[0025] In the present invention, in step (2) and step (3), the
solvent is DMF, DMSO, or N-methylpyrrolidone.
[0026] In the present invention, in step (2), the
hydroxychloroquine side chain is 0.04 to 0.06 g, ethylamine
ethanol, xylene, chloropentanone, ethylamine diethanolamine,
amino pentanone and ethanol per 1 mL of the mixed standard
solution. Independent from 0.004 to 0.006g and ethylamine 0.014
to 0.016g.
[0027] In the present invention, in step (3), a uniform solution
containing 0.22 to 0.26 g of the product is used as a test
solution per 1 mL.
[0028] In the present invention, in the step (4), the volume of
the mixed reference solution and the test solution is 0.6 to 1
μL.
[0029] Compared with the prior art, the beneficial effects of
the present invention are:
[0030] The present invention discloses the simultaneous
determination of seven kinds of raw materials and intermediates
including hydroxychloroquine side chain and ethanol, ethylamine
ethanol, xylene, chloropentanone, ethylamine diethanolamine,
amino pentane and ethylamine by gas chromatography. method.
[0031] Validated by methodology, its specificity and system
adaptability, linearity, range, detection limit, precision, and
accuracy meet the requirements of the Guiding Principles for
Validation of Methods for the Analysis of Drug Quality Standards
in the Appendix of the 2015 edition of the Chinese
Pharmacopoeia.
[0032] This method provides a technical basis for the detection
and monitoring of hydroxychloroquine side chain synthesis
processes.
[0033] Description of the drawings
[0034] Figure 1 shows the chromatogram of the reference
solution. 1. Ethylamine, 2. Ethylamine ethanol, 3. Ethylamine
diethanolamine, 4. Chloropentanone, 5. Xylene, 6.
Aminopentanone, 7. Etanol, II. Hydroxychloroquine side chain. 8.
NMP.
[0035] Figure 2 blank solution assay chromatograms.
[0036] detailed description
[0037] The technical scheme of the present invention will be
described in detail below with reference to the accompanying
drawings and embodiments.
[0038] Example 1
[0039] (1)Chromatographic condition and system suitability test
The column was a DB-624 cross-linked capillary column
(30m×0.53mm.id, 3.0μm); the initial temperature of the program
temperature was kept at 100°C for 2 minutes, and then the
temperature was raised to 200°C at a rate of 15°C. Store for 10
min; injector temperature is 300°C; carrier gas is nitrogen;
detector is hydrogen flame ionization detector (FID), detector
temperature is 310°C; flow rate is 3.0 mL/min, split ratio is
30:1; The degree of separation of chloroquine side chain,
ethylamine, ethylamine ethanol, ethylamine diethanolamine,
chloropentanone, xylene, aminopentanone, and ethanol should be
greater than 1.5;
[0040] (2)Preparation of Mixed Reference Solution Take
ethylamine ethanol, xylene, chloropentanone, ethylamine
diethanolamine, aminopentanone, ethylamine, hydroxychloroquine
side chain (pure product, lot number: Y023-150101, from Shanghai
Zhongxi three-dimensional drug Industry Co., Ltd.) The
appropriate amount, respectively, accurately weighed, placed in
the same bottle, add N-methylpyrrolidone dissolved and diluted
to produce about 1mL each containing ethylamine ethanol, xylene,
chloropentanone, ethylamine diethanolamine, A standard solution
of 0.004 g of amino pentane, 0.016 g of ethylamine, and 0.05 g
of a hydroxychloroquine side chain was used as a control
solution.
[0041] (3)The test solution was prepared by taking the
appropriate amount of hydroxychloroquine side chain (pure
product, lot number: Y023-150101, supplied by Shanghai Zhongxi
3D Pharmaceutical Co., Ltd.), accurately weighed, and dissolved
and diluted with N-methylpyrrolidone to make 1 mL each. About
0.25g of this product as a homogeneous solution for the test
solution;
[0042] (4)Measure the precise amount of each of the mixed
reference solution and the test solution by 1 μL. The direct
injection method is injected into the gas chromatograph to
determine the value.
[0043] Application example: Simultaneous determination of
hydroxychloroquine side chains and their raw materials and
intermediates by gas chromatography
[0044] Hydroxychloroquine is a 4-aminoquinoline drug. It was
first used clinically for the treatment of anti-parasites. It is
now widely used in the treatment of discoid lupus erythematosus
and systemic lupus erythematosus. It is also the first choice
for the treatment of rheumatoid arthritis. . In addition, there
are also applications in immunosuppressive and anti-inflammatory
reactions. The hydroxychloroquine side chain is a key
intermediate for the synthesis of hydroxychloroquine. There are
seven kinds of raw materials and intermediates involved in the
synthesis of hydroxychloroquine side chain lines. The excessive
amount of raw materials and incomplete reaction intermediates in
the reaction will lead to the purity of the target product is
not high, and the byproduct of the reaction is cyclopropyl. The
ketonic ketone is difficult to remove in the reaction of the
late hydroxychloroquine side chain and 4,7-dichloroquinoline to
synthesize hydroxychloroquine, thereby reducing the quality and
clinical efficacy of hydroxychloroquine. Therefore, it is
particularly necessary to carry out quality control during the
synthesis of hydroxychloroquine side chains. After the
experiment and research, the simultaneous determination of
hydroxychloroquine side chain, its synthetic raw materials and
the intermediates of ethylamine, ethylamine ethanol, ethylamine
diethanolamine, chloropentanone, xylene, amino pentane and
ethanol content were established. law.
[0045] The methodological review is as follows:
[0046] (1)Specificity and System Adaptability
[0047] Separately take the appropriate amount of
hydroxychloroquine side chain, ethylamine, ethylamine ethanol,
ethylamine diethanolamine, chloropentanone, xylene,
aminopentanone, and ethanol to prepare a solution by dissolving
N-methylpyrrolidone and carry out the headspace as described
above. Samples were taken and assayed. The results showed (see
Figure 1) that the retention times were 15.869 min for the
hydroxychloroquine side chain, 2.531 min for ethylamine, 5.904
min for ethylamine ethanol, 11.613 min for ethylamine
diethanolamine, 7.691 min for chloropentanone, Xylene 6.399,
6.497, 6.841 min, aminopentanone 16.646 min, ethanol 2.662 min.
[0048] (2)Linear
[0049] The appropriate amount of hydroxychloroquine side chain
was taken and diluted with N-methylpyrrolidone to form a series
of standard solutions containing hydroxychloroquine side chains
of 1.0600, 3.2580, 7.6986, 19.246, 28.870, 72.174, 96.232,
120.29 mg/mL, respectively. Determine the chromatographic
conditions and determine the peak area (Y) for the linear
regression of the concentration of the corresponding solvent (X,
mg/mL). The linear relationship of the hydroxychloroquine side
chain in the concentration range of 1.06 to 120.29mg/mL is good,
and the regression equation is:
[0050] Hydroxychloroquine side chain Y=304609X-887401 R2=0.9992
[0051] (3)Precision
[0052] Precisely take 2 mL of the test solution and dilute to 5
mL with solvent to obtain a solution containing 100 mg of
hydroxychloroquine side chains per mL. Prepare 6 parts,
according to the proposed chromatographic conditions, into the
gas chromatograph, record the peak area. The relative standard
deviation RSD was calculated to be 1.52%, in line with the
requirements of the 2015 edition of the Chinese Pharmacopoeia.
[0053] (4)Minimum detection limit
[0054] The detection limit of the hydroxychloroquine side chain
with S/N=3 was 0.2379 μg/mL.
[0055] Accuracy
[0056] Take 2mL of the test solution and dilute to 5mL with
solvent to obtain a solution containing 100mg of
hydroxychloroquine side chains per mL. Six parts were prepared
and injected into the gas chromatograph according to the above
chromatographic conditions. Area normalization method was used
to calculate the average content of 6 parts was 99.42%. Another
precision weighing hydroxychloroquine side chain 0.60g plus
appropriate amount of glacial acetic acid dissolved. Six parts
were prepared and potentiometrically titrated with a 0.1%
perchloric acid titrant to calculate the content, and the
average content was calculated to be 98.97%. The
hydroxychloroquine side chain stock solution was taken and
diluted with N-methylpyrrolidone in three concentration
gradients of 80%, 100%, and 120%. Each concentration was
prepared in 3 portions for a total of 9 parts. According to the
above chromatographic conditions, the sample was injected into
the gas phase. Chromatograph. The area normalization method
calculates an average content of 99.38%. The three methods have
an RSD of 0.25%
[0057] The results show that the product has good accuracy.
WO2019165337
HIGH-YIELDING CONTINUOUS FLOW SYNTHESIS OF ANTIMALARIAL
DRUG HYDROXYCHLOROQUINE
[ PDF ]
Abstract
Cost effective, semi-continuous flow methods and systems for
synthesizing the antimalarial drug hydroxychloroquine (HCQ) in
high yield are provided. The synthesis method that uses simple,
inexpensive reagents to obtain the crucial intermediate
5-(ethyl(2-hydroxyethyl)- amino)pentan-2-one,
vertical-integration of the starting material 5-iodopentan-2-one
and the integration of continuous stirred tank reactors.
001] HIGH-YIELDING CONTINUOUS FLOW SYNTHESIS OF ANTIMALARIAL
DRUG HYDROXYCHLOROQUINE
[0003] STATEMENT OF FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0004] This invention was made with government support under
contract W91 INF- 16-2-0023 awarded by the Defense Advanced
Research Projects Agency (DARPA). The United States government
has certain rights in the invention.
[0005]
BACKGROUND OF THE INVENTION
[0006] Field of the Invention
[0007] The invention generally relates to improved, cost
effective, semi-continuous flow systems and methods for
synthesizing hydroxychloroquine (HCQ). In particular, the
invention provides a synthesis method that uses simple,
inexpensive reagents to obtain the crucial intermediate
5-(ethyl(2-hydroxyethyl)amino)pentan-2-one, vertical-integration
of the starting material 5-iodopentan-2-one, and the integration
of continuous stirred tank reactors (CSTRs).
[0008] Description of Related Art
[0009] In 2016, an estimated 212 million cases of malaria,
including 429,000 fatalities, were reported worldwide, with the
majority of these cases occurring in sub-Saharan Africa and
Southern Asia. The malaria epidemic is particularly difficult to
control due to the multi-drug resistant nature of the malaria
parasite Plasmodium falciparum.
[0010] Hydroxychloroquine (Figure 1A, HCQ) is an anti-malarial
drug developed for both treatment and prevention of the disease
in response to the widespread malaria resistance to chloroquine,
(Figure IB, CQ). The World Health Organization has identified
HCQ as an essential anti-malarial medication for a basic
healthcare system. Additionally,
[0011] hydroxychloroquine (HCQ) is an effective non-steroidal
anti-inflammatory drug in the treatment of various autoimmune
diseases such as rheumatoid arthritis (e.g. in cardiovascular
patients), lupus, and childhood arthritis (or juvenile
idiopathic arthritis) among others.
[0012] Unfortunately, global access to HCQ has been hindered by
high manufacturing costs. Thus, the development of cost
effective synthetic strategies to increase global access to this
important global health drug is of great importance. The current
HCQ commercial synthesis employs the key intermediate
5-(ethyl(2-hydroxyethyl) amino)pentan-2-one, 6, and its
production is a major cost driver (see Figure 2A). An
alternative route (Figure 2B) by Li and co-workers (2015)
eliminates the protection-deprotection steps, but its use of a
complex multi transition metal catalyst system to achieve direct
SN 2 substitution of the chlorine on 3 by the amine 7, is
sub-optimal.
[0013] There is a pressing need to develop new methods of
synthesizing HCQ that are cost effective while producing the
drug in high yield.
[0014]
SUMMARY OF THE INVENTION
[0015] Other features and advantages of the present invention
will be set forth in the description of invention that follows,
and in part will be apparent from the description or may be
learned by practice of the invention. The invention will be
realized and attained by the compositions and methods
particularly pointed out in the written description and claims
hereof.
[0016] Provided herein is a cost effective semi-continuous flow
method for the synthesis of the antimalarial drug HCQ. The
synthesis involves the reaction of simple, inexpensive reagents
to obtain crucial intermediates for the reaction, and overall
employs a reduced number of synthesis steps while achieving a
high, multi gram yield of the product. The synthetic strategy
involves vertical-integration of the starting material
5-iodopentan-2-one and the integration of continuous stirred
tank reactors for key steps of the method.
[0017] It is an object of this invention to provide a method for
synthesizing
[0018] hydroxychloroquine (HCQ), comprising: in a flow reactor,
i) reacting 5-iodopentan-2-one with 2-(ethylamino)ethan-l-ol to
form 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one; and ii)
converting 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one to
[0019] (E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime; and
in a first continuous stirred tank reactor (CSTR) iii)
contacting (E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime
with a catalyst to form
5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane; and in a second
CSTR. iv) reacting the
5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane with
4,7,-dichloroquinoline in the presence of a base to form HCQ. In
some aspects, steps i), ii) and iii) are conducted in a solvent
that is the same for each step. In additional aspects, the
solvent is tetrahydrofuran (THF). In other aspects, reacting
step iv) is performed in an alcohol. In further aspects, the
alcohol is ethanol. In yet further aspects, the base is
K^CCL/EtsN. In other aspects, reacting step iv) proceeds for 6
hours. In additional aspects, the 5-iodopentan-2-one is formed
by a) reacting a-acetyl butyrolactone with an iodine donor in an
aqueous solvent. In yet further aspects, the method further
comprises a step of b) extracting the 5-iodopentan-2-one from
the aqueous solvent with an organic solvent. In additional
aspects, the steps of a) reacting and b) extracting are
performed in line in a first flow reactor. In other aspects, the
first flow reactor is in line with the flow reactor of claim 1.
In further aspects, the iodine donor is hydroiodic (HI) acid. In
yet further aspects, the a-acetyl butyrolactone is neat. In
additional aspects, the step of extracting is performed using a
hydrophobic, membrane-based separator. In further aspects, the
catalyst is a Raney nickel catalyst.
[0020] The disclosure also provides a system for synthesizing
hydroxychloroquine (HCQ), comprising a first heated reactor coil
configured to receive 5-iodopentan-2-one and
[0021] 2-(ethylamino)ethan-l-ol and output
5-(ethyl(2-hydroxyethyl)amino)pentan-2-one; a first packed bed
reactor comprising a neutralizing agent and configured to
receive
[0022] 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one from the first
heated reactor and output neutralized
5-(ethyl(2-hydroxyethyl)amino)pentan-2-one; a second heated
reactor coil configured to receive neutralized
5-(ethyl(2-hydroxyethyl)amino)pentan-2-one from the first packed
bed reactor, receive hydroxylamine, and output
(E)-5-(ethyl(2-hydroxyethyl) amino)pentan-2-one oxime; a second
packed bed reactor comprising a neutralizing agent and
configured to receive 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one
oxime from the second heated reactor coil, and output
neutralized (E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one
oxime; a first continuous stirred tank reactor (CSTR) configured
to contain a catalyst, receive neutralized
(E)-5-(ethyl(2-hydroxyethyl)amino) pentan-2-one oxime from the
second packed bed reactor, and output
5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane; and a second CSTR
configured to receive
5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane from the first
CSTR, receive 4,7,-dichloroquinoline, and output HCQ. In certain
aspects, the system further comprises a heated reaction coil
configured to receive a-acetyl butyrolactone and receive an
iodine donor, and output 5-iodopentan-2-one, a reaction coil
configured to receive
[0023] 5-iodopentan-2-one from the heated reaction coil, and
receive a base and a hydrophobic, membrane-based separator
configured to receive 5-iodopentan-2-one from the unheated
reaction coil extract 5-iodopentan-2-one from the aqueous
solvent with an organic solvent, and output 5-iodopentan-2-one
in an organic phase. In additional aspects, the first heated
reactor coil receives the 5-iodopentan-2-one in an organic phase
from the hydrophobic, membrane-based separator. In yet further
aspects, the catalyst is a Raney nickel catalyst. BRIEF
DESCRIPTION OF THE DRAWINGS
[0024] Figure 1A and B. Commercially available antimalarial
drugs. A, hydroxychloroquine (HCQ); B, chloroquine (CQ).
[0025] Figure 2A and B. Batch Syntheses of
5-(ethyl(2-hydroxyethyl) amino)pentan-2-one. A, prior art
method; B, prior art method of Li (2015).
[0026] Figure 3. Retrosynthetic strategy to hydroxychloroquine.
[0027] Figure 4. Flow process for synthesis of
5-iodopentan-2-one (10).
[0028] Figure 5. Schematic representation for continuous in-line
extraction of 10.
[0029] Figure 6. Schematic representation of continuous
telescoped process to synthesize 11.
[0030] Figure 7. Schematic representation of reductive amination
of 12.
[0031] Figure 8. Optimization of the flow process for synthesis
of 12.
[0032] Figure 9. Schematic representation of a flow system.
[0033] Figure 10. 'H NMR Spectra of compound (10).
[0034] Figure 11.I3 C NMR Spectra of compound (10).
[0035]
DETAILED DESCRIPTION
[0036] Provided herein is a highly efficient method for the
semi-continuous synthesis of the antimalarial drug
hydroxychloroquine (HCQ). The method is“semi-continuous” because
some steps of the method are conducted using continuous flow but
others are conducted using continuous stirred tank reactors
(CSTR) which are vertically integrated into the process. The
method results in an overall yield improvement of about 52% over
the current commercial HCQ production process, even though the
methods use reactants that are simpler and less expensive than
those employed in current commercial processes. A key feature in
the new process is the elimination of protecting groups without
invoking the use of expensive catalysts as required by Li
(2015). The present high-yielding, multigram-scale
semi-continuous synthesis thus provides an opportunity to
achieve increased affordable global access to hydroxychloroquine
for the prevention and treatment of malaria and various
autoimmune diseases.
[0037] The reactions of the continuous flow method are
preferably carried out using the same solvent for several steps;
however, this is not necessarily always the case. Those of skill
in the art may choose to separate one or more of the optimized
steps of the method and/or to use a different solvent or
multiple solvents (e.g. rinsing the lines with the appropriate
solvent prior to use), to make HCQ. Alternatively, one or more
of the optimized reactions, either individually or in groups of
several reactions, may be used for purposes other than making
HCQ. For example, the starting materials and intermediates
described herein are useful chemicals for a variety of purposes,
and may be of interest in and of themselves, without further
conversion. All such methods of making each chemical entity
disclosed herein are encompassed.
[0038]
DEFINITIONS
[0039] Raney nickel catalyst: Raney nickel is a fine-grained
solid composed mostly of nickel derived from a nickel-aluminum
alloy. Several grades are known, but most are gray solids. Some
are pyrophoric, most are used as air-stable slurries. The
original form, Raney®-Nickel is a registered trademark of W. R.
Grace and Company, but other generic forms are known and are
also referred to generically as“Raney nickel” or as e.g.
"skeletal catalyst" or
[0040] "sponge-metal catalyst". These catalysts have properties
similar to those of Raney®-Nickel. The catalyst may be a binary
Ni-Al alloy and/or may comprise small amounts of a third metal
(a "promoter") such as zinc or chromium, forming a ternary
alloy. The third metal enhances the activity of the catalyst.
All forms of this catalyst may be used in the methods described
herein. Continuous stirred-tank reactors (CSTR), also known as
vat- or backmix reactors, or continuous-flow stirred-tank
reactors (CFSTR), are known in the art. CSTRs facilitate rapid
dilution rates which make them resistant to both high pH and low
pH fluctuations. It is sometimes economically beneficial to
operate several CSTRs in series, e.g. for the same reaction, and
this strategy may be implemented in the present methods. This
allows, for example, the first CSTR to operate at a higher
reagent concentration and therefore a higher reaction rate. In
these cases, the sizes of the reactors may be varied in order to
minimize the total capital investment required to implement the
process.
[0041] Room temperature generally refers to a temperature of
from about 15 - 25 °C, and is generally about 20-22 °C.
[0042]
REACTIONS
[0043] Synthesis of starting material (10)
[0044] In the present synthesis, 5-iodopentan-2-one (10)
replaces the traditional chlorinated starting material (3 in
Figure 2). This iodinated starting material is made using
a-acetyl butyrolactone 8 (used neat) via a decarboxylative
ring-opening reaction, generally via reaction with an aqueous
solution of an iodine donor (e.g. see Figure 4). Iodine donors
that may be used include but are not limited to e.g. HI, FI,
Nal, KI, Lil, etc. In some aspects, the iodine donor is HI in an
aqueous solution. The amount of iodine donor (e.g. Hl) is
typically at least about 20 to about 60%, and is generally at
least about 40%, and is preferably at least about 50%, such as
about 55%. The temperature of the reaction is generally at least
about 40 °C or above, e.g. about 40, 45, 50, 55, 60, 65, 70, 75,
80, 85 or 90 °C, with about 80 °C being a preferred temperature.
The reaction optimally proceeds for about 2.5 to about 15
minutes, e.g. about 2.5, 5.0, 10.0, or 15.0 minutes or longer,
with about 5-10 minutes being the preferred range, e.g. about 5,
6, 7, 8, 9, or 10 minutes. The reaction pressure is generally
from about 1.5 to 5.0 bar, e.g. about 1.5, 2.0, 3.0, 3.5, 4.0,
4.5 or 5.0 bar, with about 3 bar being preferred.
[0045] The reaction can optionally be monitored, e.g. by GC-MS,
'H NMR, etc. No intermediates are produced and the starting
material is completely consumed during the reaction.
[0046] In preferred aspects, extraction and neutralization are
accomplished in-line as part of a flow-based method as shown in
Figure 5. An amphoteric compound which functions as a base (such
as saturated sodium bicarbonate (NaHC03 ) or Na3 C03 , (sodium
carbonate), potassium carbonate (K2 CO3 ), etc.,) and one or
more suitable organic solvents (e.g. hexanes and/or methyl tert-
butyl ether, methylene chloride (DCM), ethyl acetate, etc.) are
introduced in-line and are reacted with 5-iodopentan-2-one (10)
in a reactor coil maintained at room temperature (e.g. about 25
°C). One or more hydrophobic, membrane-based separators receive
the input from the reactor coil and it is used to produce an
aqueous waste stream (comprising excess HI) and an organic
stream comprising 10. Examples of suitable hydrophobic,
[0047] membrane-based separators include but are not limited to:
Zaiput, Versapore®, Zefluor™, polytetrafluoroethylene (PTFE),
polycarbonate membrane, etc. When a membrane-based separator is
used, there is a loss of product to the water layer (e.g.
generally 10% or less) but this is tolerated in order to avoid
the need for complete batch workup steps.
[0048] In some aspects, 10 is then transferred (integrated)
directly into a flow method, e.g. as the input to the next
reactor coil, depicted in Figure 6. Alternatively, the reaction
and separation may be done in batch in which crude 10 is
extracted (generally at room
[0049] temperature) e.g. with one or more hydrophobic solvents
(as listed above), and neutralized e.g. to about pH = 7 using a
base (as listed above). The combined organic phases are dried
(e.g. using anhydrous sodium sulfate) and evaporated in vacuo to
dryness to yield 10 for use in the first step of the
semi-continuous synthesis method described in detail below.
[0050]
STEPS OF THE REACTION TO FORM HCQ
[0051] Synthesis of 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one
(6):
[0052] 5-iodopentan-2-one (10) formed as described above is used
to synthesize
[0053] 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (6) as
follows:
[0054] Compound 6 is synthesized from 10 in a flow reactor unit,
preferably using a solvent system that is compatible with
subsequent flow reactions of the method. In some aspects, the
solvent is tetrahydrofuran (THF). However, other solvents such
as 1,4-dioxane, 2-methyl THF (tetrahydrofuran), MTBE (methyl
tert-butyl ether), DCM (dichloromethane or methylene chloride),
etc., may also be employed. Those of skill in the art will
recognize the advantages of rinsing the flow reactor with dry
solvent and/or flushing the system with an inert gas (e.g. N2 )
prior to use.
[0055] To perform the reaction, 10 is combined with
2-(ethylamino)ethan-l-ol (7) in a suitable solvent, e.g. THF at
about room temperature and streamed into a reactor coil, as
depicted in Figure 6. The temperature in the coil is in the
range of from about 70 to 90 °C, e.g. about 70, 95, 80, 85 or 90
°C, and the flow rate typically ranges from about 0.1 to about
1.0 ml/min, e.g. about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,
0.9 or 1.0 ml/min or higher, for larger coils.
[0056] The reaction is then quenched by passing the reaction
mixture e.g. through a packed bed reactor containing e.g.
potassium carbonate, sodium carbonate, lithium carbonate,
lithium hydroxide, sodium bicarbonate, or other suitable
material. The temperature in the packed bed reactor is generally
about 85 - 100 °C, such as about 85, 90, 95 or 100 °C. This
yields product 6, which is transferred directly to the next
in-line step.
[0057] Alternatively, the output of the reaction between 10 and
7 is collected and quenched, extracted with one or more organic
solvents (e.g. DCM) and the combined organic layers are dried
over sodium sulfate, and evaporated to give 6, which can be used
in further reactions. Synthesis of
(E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime (11)
[0058] Compound 6 is ultimately converted to
5-(ethyl(2-hydroxyethyl)amino)-2- aminopentane 12 via
intermediate oxime 11. Briefly, a simple conversion of the
ketone group of 6 yields oxime 11, which is then reduced to give
12.
[0059] A. Synthesis of oxime 11
[0060] The conversion of 6 to oxime 1 1 is preferably done
in-line as part of a continuous flow synthesis method, as shown
in Figure 6. 6 is combined with an agent such as NfTOFl (e.g.
about 0.5, 1.0 or 1.5 M). This reaction is generally performed
in a reactor coil (e.g. at about 0.5, 1.0 or 1.5 mF/min, such as
about 1.0 mF/min) at a temperature of from about 80 to 100 °C,
e.g. about 80, 85, 90, 95 or 100 °C, and with a tR of about
15-30 minutes, e.g. about 15,
[0061] 20, 25, or 30 minutes such as about 20 min. The reaction
is quenched e.g. by passage through a packed bed reactor
comprising a compound such as potassium carbonate, sodium
carbonate, lithium carbonate, lithium hydroxide, sodium
bicarbonate, etc. The temperature in the packed bed reactor is
generally about 85 - 100 °C, such as about 85, 90, 95 or 100 °C.
This yields oxime 11. If needed, 11 is e.g. concentrated, taken
up in a solvent such as DCM, etc. prior to the next reaction.
However, further purification is generally not needed and 11 may
pass directly to the next step.
[0062] Synthesis of
5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane (12)
[0063] The next to last step of the production of HCQ is the
conversion of oxime 11 to
5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane (12). Accordingly,
product 11 is passed to the next reaction, which takes place in
a continuous stirred tank reactor (CSTR). 11 is efficiently
reduced to 12 in a CSTR using a suitable solvent (e.g. THF,
diglyme, 1,4-dioxane, methanol, ethanol, 2-methyl THF, IPA
(2-propanol)), etc. Significantly, the reaction proceeds in the
presence of a Raney Nickel catalyst, which is retained or
sequestered in the CSTR. The reaction mixture comprises compound
11 at a concentration ranging from about 0.05-2.0 M (such as
about 0.05. 0.1. 0.2. 0.3. 0.4. 0.5. 0.6, 0.7. 0.8. 0.9, 1.0.
1.1 , 1.2. 1.3. 1.4. 1.5. 1.6. 1.7, 1 .8. 1.9. or 2.0. in a
suitable solvent. The solvent is preferably the same as that
which is used in the prev ious How steps, such as THF or
diglyme, 1 ,4-dioxane, methanol, ethanol, 2-methyl THF, IPA.
etc. However, this is not strictly necessary and methods w hich
use other solvents for one or more steps of the method are also
encompassed. The reaction mixture is generally introduced into
the reaction vessel at a set Ho rate of e.g. 0.6-2.5 mL min1
such as about 0.6, 1 .0, 1.5, 2.0 or 2.5 mL min1 . The reaction
pressure is typically set to about 5- 15 bar. such as about 10
bar with an inert gas such as hydrogen supplied at a suitable
How rate (e.g. 0.1 to 1 .0 mL min 1 , such as about 0.5 mL min1
). The reaction takes place at a temperature in the range of
from about 70 to about 90 °C. e.g. about 70, 75. 80, 85 or 90
°C. such as about 80 C. The reaction generally proceeds w ith
agitation e.g. stirring (e.g. at about 500 to 100 rpm. such as
about 750 rpm) to provide proper mixing. The reaction volume may
be monitored and hen suitable (e.g. hen a difference between two
thermocouples is detected, such as about a 1. 2, 3. 4. or 5 °C
difference, such as a 3°C difference) a level control opens
allow ing products to exit the reactor. Conversely, when the
temperature difference between the two thermocouples is greater
than e.g. about 1. 2. 3. 4, or 5 °C. such as 3°C. reactants
enter the tank. Product is collected e.g. when a steady-state is
reached. The reaction mixture is
[0064] (optionally) filtered and/or dried, extracted , etc.,
prior to being used in the next (and last) step of the reaction.
[0065] Synthesis of hydroxychloroquine (1)
[0066] The final step in the synthesis of HCQ involves the
reaction of 12 with 4,7,-dichloroquinoline, 13. This step is
also performed in a CSTR, and the reactions take place in an
alcohol solvent, preferably ethanol. However, in some aspects,
other alcohols such as methanol, n-butanol, isopropanol, etc.
may be employed. The reactants are 12 plus a suitable base, e.g.
NaOH, KOH, K2 CO3 , ET3 N, D1PEA (N,N-Diisopropylethylamine), or
combinations thereof, especially combinations with ET3 N such as
NaOH/ETiN, DIPEA/ET3 N or K2 CO3 /ET3 N. In preferred aspects,
K2 C03 /Et3 N is used. This step is advantageously accelerated
(compared to conventional methods) by employing K2 CC>3 /Et3
N. As a result, a high yield of HCQ is obtained, e.g. in less
than about 6 hours of reaction time.
[0067] Reactants, 13 and 12 are combined in approximately a 1/1
molar ratio (e.g. about 1/1.2 molar ratio, respectively) with
equal equivalents of Et3N and K2 CO3 . The amount of each of Et3
N and K2 C03 is generally about half that that of reactant 13,
mole/mole. The reactants are combined in sufficient solvent e.g.
ethanol to allow thorough mixing. The reaction is allowed to
proceed in an inert atmosphere (e.g. under N2 ) at a temperature
of about 100 to 150 °C, e.g. at about 100, 105, 1 10, 1 15, 120,
125, 130, 135, 140, 145 or 150 °C, such as about 125 °C, and
requires about 6 hours for completion.
[0068] Following completion of the reaction, ethanol is removed
(e.g. via distillation) and the product is recovered e.g. by
extraction, separation, drying, etc. as needed to afford the
final product.
[0069] SYSTEMS
[0070] Also provided are systems for synthesizing
hydroxychloroquine (HCQ) . The systems are semi-continuous flow
systems and comprise elements/components that are in-line, flow
components and also CSTRs. For example, the systems generally
comprise a plurality of reaction coils (also referred to herein
as“reactor coils”), e.g. generally 3 or 4, which may or may not
be heated, depending on the reaction(s) that take place within a
coil. The systems also generally comprise a plurality of packed
bed reactors. In addition, various lines, valves, connectors,
separators, reservoirs (e.g. to serve as sources of a reactant),
etc. are included in the system, and the system components are
advantageously operably linked in-line. That is to say,
generally a product, such as a reactant, that is produced in one
component of the system is transferred directly to a component
in which it undergoes a further reaction, without intervening
steps of purification (other than e.g. steps of phase
separation, neutralization, etc. which can also be done
in-line).
[0071] In some aspects, the systems comprise a first heated
reactor coil that is configured to (i.e. comprises a least one
inlet to) receive 5-iodopentan-2-one and
2-(ethylamino)ethan-l-ol, and an outlet to output
5-(ethyl(2-hydroxyethyl)amino)pentan-2-one, usually directly
into a first packed bed reactor. The first packed bed reactor
typically comprises a neutralizing agent and is configured to
include an inlet to receive input from first heated reactor
coil, typically 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one. The
5-(ethyl(2-hydroxyethyl)amino) pentan-2-one flows through the
first packed bed reactor, is neutralized, and is then passed
directly to a second heated reactor coil configured to (having
at least one inlet to) receive neutralized
5-(ethyl(2-hydroxyethyl)amino)pentan-2-one from the first packed
bed reactor. The second heated coil is also configured to
receive hydroxylamine, and a reaction takes place in the second
heated coil to form
(E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime.
[0072] The oxime is output from the second heated reaction coil
to a second packed bed reactor, which like the first packed bed
reactor, comprises a neutralizing agent. The neutralizing agents
in the first and second packed bed reactors may be the same or
different. The second packed bed reactor comprises an inlet to
receive 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime from
the second heated reactor coil and and outlet to output
neutralized
[0073] (E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime.
[0074] The systems disclosed herein also comprise one or more
continuous stirred tank reactors (CSTRs) which comprise a
stirring mechanism. For example, a first CSTR is generally
configured to contain a Raney nickel catalyst, receive
neutralized
[0075] (E)-5-(ethyl(2-hydroxyethyl)amino) pentan-2-one oxime
from the second packed bed reactor, and output
5-(ethyI(2-hydroxyethyl)amino)-2- aminopentane. This CSTR
generally also comprises an inlet for a gas, e.g. an iert gas
such as FT. Typically the output of the first CSTR is received
by a second CSTR. The second CSTR receives both
[0076] 5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane (from the
first CSTR) and
[0077] 4,7,-dichloroquinoline (from a source of
4,7,-dichloroquinoline). The reaction between these two
chemicals within the second CSTR produces HCQ, which can
subsequently be output from the second CSTR for further
processing, if needed (e.g. via extraction, purification,
concentration, drying, etc. Further processing generally also
includes forming the HCQ into dosage forms, e.g. tablets, liquid
dosage forms, etc.
[0078] Is some aspects, the 5-iodopentan-2-one that is input
into the first reaction coil is transferred from another in-line
flow system, which may be integrated directly into the system
described above, or may be a stand-alone system. This second
system comprises at least a heated reaction coil configured to
receive a-acetyl butyrolactone and an iodine donor. The reaction
that takes place in the heated reaction coil produces
5-iodopentan-2-one, which is then output to a reaction coil
configured to receive the 5-iodopentan-2-one from the heated
reaction coil, and also to receive a base. The reaction coil may
or may not be heated because the reaction takes place, e.g. at
room temperature (rt). However, in some aspects, heating may be
required to maintain the reaction coil at a consistent
temperature, e.g. at or near rt. This segment of the overall
system further comprises at least one hydrophobic,
membrane-based separator with an inlet to receive
5-iodopentan-2-one from the rt reaction coil. The hydrophobic,
membrane-based separator extracts 5-iodopentan-2-one into an
organic solvent, and outputs the 5-iodopentan-2-one in an
organic phase via a suitable outlet. In some aspects, the
5-iodopentan-2-one is transferred directly in-line into the
first heated reactor coil described above, e.g. without
intervening steps of collection, purification, etc. In other
aspects, the 5-iodopentan-2-one is collected and processed as
needed, before being provided as the starting material in the
semi-continuous system described above, e.g. before being input
into the first reaction coil.
[0079] A schematic, non-limiting representation of an exemplary
semi-continuous flow system is shown in Figure 9. Depicted are
multiple reaction coils 110, 111, 112 and 113; multiple
reservoirs (120, 121, 122, 123 and 124) for containing/storing
reactants which are supplied to other components via connecting
lines (170), valves (not depicted), etc., a hydrophobic membrane
separator 130 from which waste passes through waste line 135 to
waste container 136, multiple bed reactors 140 and 141, two
CSTRs 150 and 151, and a gas storage tank 160. In the exemplary
system that is shown:
[0080] reactants a-acetyl butyrolactone (8) and an iodine donor
flow from reservoirs 120 and 121, respectively;
[0081] starting material 5-iodopentan-2-one (10) is produced in
reaction coil 110 and flows to reaction coil 111 as do e.g.
hexane/MTBE and NaHC03 (from reservoirs 122 and 123,
respectively);
[0082] 5-iodopentan-2-one (10) and the reaction milieu enter
hydrophobic membrane separator 130; 5-iodopentan-2-one (10) in
an organic phase flows from membrane separator 130 to reaction
coil 12 while aqueous waste flows to waste container 136 via
waste line 135;
[0083] 2-(ethylamino)ethan-l-ol (7) is introduced to reaction
coil 112 from reservoir 124;
[0084] 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (6) is
produced in reaction coil 112 and enters packed bed reactor 140,
where the reaction is quenched;
[0085] 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (6) enters
reaction coil 113 together with a base from reservoir 125;
[0086] (E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime (11)
is produced in reaction coil 113 and then passes through packed
bed reactor 141 and then to CSTR 150;
[0087] 5-(ethyl(2-hydroxyethyl)amino)-2-aminopentane (12) is
synthesized in CSTR 150 (e.g.
[0088] containing Raney nickel catalyst 80 and under FF gas from
gas storage tank 160) and passes to CSTR 151; and
4,7,-dichloroquinoline, 13 enters CSTR from reservoir 126, and
the final product, HCQ is synthesized in CSTR 116.
[0089] The arrow leaving CSTR 151 illustrates removal of HCQ.
[0090] It is to be understood that this invention is not limited
to particular embodiments described herein above and below, and
as such may, of course, vary. It is also to be understood that
the terminology used herein is for the purpose of describing
particular embodiments only, and is not intended to be limiting.
[0091] Where a range of values is provided, it is understood
that each intervening value between the upper and lower limit of
that range (to a tenth of the unit of the lower limit) is
included in the range and encompassed within the invention,
unless the context or description clearly dictates otherwise. In
addition, smaller ranges between any two values in the range are
encompassed, unless the context or description clearly indicates
otherwise.
[0092] Unless defined otherwise, all technical and scientific
terms used herein have the same meaning as commonly understood
by one of ordinary skill in the art to which this invention
belongs. Representative illustrative methods and materials are
herein described; methods and materials similar or equivalent to
those described herein can also be used in the practice or
testing of the present invention.
[0093] All publications and patents cited in this specification
are herein incorporated by reference as if each individual
publication or patent were specifically and individually
indicated to be incorporated by reference, and are incorporated
herein by reference to disclose and describe the methods and/or
materials in connection with which the publications are cited.
The citation of any publication is for its disclosure prior to
the filing date and should not be construed as an admission that
the present invention is not entitled to antedate such
publication by virtue of prior invention. Further, the dates of
publication provided may be different from the actual dates of
public availability and may need to be independently confirmed.
[0094] It is noted that, as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise. It is
further noted that the claims may be drafted to exclude any
optional element. As such, this statement is intended to serve
as support for the recitation in the claims of such exclusive
terminology as "solely," "only" and the like in connection with
the recitation of claim elements, or use of a "negative"
limitations, such as "wherein [a particular feature or element]
is absent", or "except for [a particular feature or element]",
or "wherein [a particular feature or element] is not present
(included, etc.)...".
[0095] As will be apparent to those of skill in the art upon
reading this disclosure, each of the individual embodiments
described and illustrated herein has discrete components and
features which may be readily separated from or combined with
the features of any of the other several embodiments without
departing from the scope or spirit of the present invention. Any
recited method can be carried out in the order of events recited
or in any other order which is logically possible.
[0096] EXAMPLE
[0097] The continuous synthesis described herein involves a
retrosynthetic process (Figure 3) in which 10, an iodo analogue
to starting material 3, is generated in a single step via a
decarboxylative ring-opening of a-acetyl butyrolactone 8. The
iodo-analogue, 10, is then used without isolation to prepare
compound 6.
[0098] A direct one-step reductive animation of 6 to give 12 can
be accomplished by simple heterogeneous reduction with H2
/Raney-Nickel. However, THF is employed in all of the prior flow
steps and is a poor choice as a solvent for the reductive
amination step due to limited solubility of ammonia in THF.
H2/Raney-Nickel reductions are often carried out in alcoholic
media where much higher concentrations of ammonia are achievable
but would require a solvent exchange. There are many reports of
continuous flow chemistry methods for reductive amination of
ketones [25-31]; however, such processes typically require
soluble reductants such as diisobutylaluminium hydride
(DIBAL-H), superhydrides, or supported borohydride species
[32-36] Although these approaches are effective, they are
significantly more costly than using simple heterogeneous
reduction with H2/Raney-Nickel. Therefore, we explored an
alternate strategy: first, simple conversion of the ketone group
of 6 to oxime 11, which is then followed by reduction with H2
/Raney-Nickel to give 5-(ethyl(2-hydroxyethyl)amino)-
2-aminopentane 12. This efficiently reduces 11 to 12 with THF as
the solvent in a continuous stirred tank reactor (CSTR).
[0099] The last step of HCQ synthesis requires reaction of 12
with 4,7,-dichloroquinoline, 13, which when used neat takes
24-48 hours at 120-140°C to give 75-80% yield of HCQ, 1 [37]. We
have found that this step can be accelerated by employing K2
C03/ triethylamine, to facilitate the formation of HCQ, 1,
resulting in a comparable yield in less than 6 hours. Thus, we
have integrated the continuous preparation of reaction with a
new efficient continuous flow synthesis of 12 with the final
step by using a CSTR to accommodate the longer reaction time
required to produce HCQ. Initial optimization efforts to prepare
6 revealed poor reactivity of starting material 3, so we pursued
the iodo-analogue of 3, 5-iodopentan-2-one (10) as an
alternative. By optimizing the reaction concentration, we have
also shown that 10 reacts rapidly and cleanly with 7 under flow
conditions to give 6 in high-yield (>80%). Furthermore, we
have developed and optimized a continuous synthesis of 10 (Table
1, (Figure 4), wherein hydroiodic acid is reacted with neat
3-acetyldihydrofuran-2(3H)-one, 8, to provide a rapid route to
10 which is significantly higher in yield than previously
reported syntheses [38-39] Initial results using diluted
hydroiodic acid (20-40%) provided only modest conversion to
product over a range of temperatures (Table 1, entries 1-5);
however, use of 55% hydroiodic acid (Table 1, entries 6-8) was
found to give near quantitative conversion. The reaction profile
was monitored using GC-MS and 'H NMR - no intermediates were
observed under these conditions. Optimization of the flow rate
with 55% hydroiodic acid (Table 1, entries 6-8) revealed that a
flow rate of 1.0 ml min1 (/«= 5 min) gave an isolated yield of
89%.
[0100] Table 1. Optimization of the Flow Process for Synthesis
of 10
[0101] Entry HI Temp (°C) tR =min Pressure Conv ^ (%)
[0102] [Aqueous%] (bar)
[0103] 1 20 r.t. 5 1.5 5
[0104] 2 20 40 5 2.0 31
[0105] 3 20 80 5 2.0 34
[0106] 4 40 80 5 2.0 43
[0107] 5 40 80 5 2.5 46
[0108] 6 55 80 5 3.0 98 (89%)b
[0109] 7 55 80 2.5 3.0 91
[0110] 8 55 80 10 3.0 92
[0111] [a] conversion determined by GC-MS and Ή NMR [b] Isolated
yield
[0112] Due to the need to use an excess of hydroiodic acid it is
important to remove its excess from the eluting reaction stream
before telescoping into the next step in flow. The product
stream containing crude 10 was mixed in-line with
methyl-tertbutylether (MTBE) and saturated NaHCC>3 before
phase separation using a hydrophobic, membrane-based separator
(Zaiput) [40] (Scheme 3) to afford purified 10 in the organic
phase. A loss of 5-10% of product to the water layer was
observed, however this was deemed adequate as it prevented the
need for a complete workup step in batch.
[0113] In the next step, 6 was reacted with hydroxylamine, which
was facilitated by passing through a packed-bed of K2 CO3 to
give oxime 11 (Table 2). As was seen with the reaction to
produce 6 (Table 1) reactant concentrations also had a dramatic
effect on oxime formation. A series of experiments were
conducted to optimize the continuous formation of 11. Reaction
yields were modest at lower reactant concentrations across
several temperatures and residence times (Table 2). Conversion
to 11 increased when reactant concentrations were increased (9%
at 0.1 M to 72% at 1 M) (Table 2, entries 1-6). Optimization of
the flow rate with 1 M concentrations of each reactant (Table 2,
entries 6-8) showed that a flow rate of 1.0 ml min1 (/«= 20 min)
was optimal, giving an isolated yield of 78% (Table 2, entry 7).
[0114] Table 2. Optimization of conversion of 6 to oxime 11
[0115] Entry Concentration^ Temp (°C) tR =min Conv of l l
[0116] o/„]
[0117] 1 0.1 M 100 10 9
[0118] 2 0.2 M 100 10 16
[0119] 3 0.4 M 100 10 34
[0120] 4 0.6 M 100 10 37
[0121] 5 0.8 M 100 10 62
[0122] 6 1.0 M 100 10 72 7 1.0 M 100 20 85 (78)tc]
[0123] 8 1.0 M 100 40 76 [a] Concentration of 10, 7 and
hydroxylamine; [b] conversion determined by GC-MS and 'H NMR;
[c] Isolated yield
[0124] The reductive amination of 11 performed in the first
generation batch process was carried out using Raney Nickel at
80 °C, 10 bar hydrogen pressure for 4-6h [21-24]. In order to
perform this step in a continuous fashion, a continuous stirred
tank reactor [25, 41] was employed (Table 3). Materials were
delivered to the CSTR vessel through an HPLC pump and reacted
under hydrogen pressure with mechanical stirring. The dip tube
in the CSTR was outfitted with a fritted metal filter, allowing
for retention of the heterogeneous catalyst within the CSTR
vessel. Optimization of this CSTR-based flow process (Table 3)
showed near quantitative yields of 12 over a broad range of
oxime 11 reactant concentrations. An optimum residence time was
determined to be hours.
[0125] Table 3. Optimization of synthesis of 12
[0126] Entry Oxime Temp (°C) Pressure tR = hours Conv of l2
[0127] [Concentration] (bar) (%)[a]
[0128] 1 0.05 M 80 10 4 94%
[0129]
[0130] [a] conversion determined by GC-MS and H NMR [b] Isolated
yield
[0131] After optimizing the individual steps up to compound 12
the entire reaction was telescoped into a continuous reaction
process that converts 10 and 6 into 12 (Figure 8) with an
overall isolated yield of 68% for compound 12.
[0132] With an optimized continuous process for producing the
key intermediate 12, in-hand, reaction conditions for the
conversion of 12 to HCQ were examined. In the commercial process
this step is carried in batch under neat reactant conditions and
requires a relatively long reaction time of 24-48h [42-44] In
order to convert this step to a flow chemistry method, we
employed a CSTR (Table 4). This final step, transforming 12 and
13 into 1, was first investigated in batch to optimize the
conditions when implemented in an CSTR.
[0133] Table 4: Optimization of hydroxychloroquine 1
[0134]
[0135] Entry Base Solvent Temp Conv. to 1
[0136] (°C) (%)[a]
[0137] 1 NaOH EtOH 125 30
[0138] 2 KOH EtOH 125 35
[0139] 3 K2 C03 EtOH 125 82
[0140] 4 Et3 N EtOH 125 61
[0141] 5 DIPEA EtOH 125 55
[0142] 6 K2 C03 /Et3 N EtOH 125 88 (78)b
[0143] Reaction condition: 4,7-Dichloroquine 13 (1.0 equiv.),
base (1.0 equiv.), amine 12 (1.2 equiv) [a] conversion
determined by HPLC and 'H NMR [b] Isolated yield
[0144] Process optimization for the final step began by
screening the effect of solvent and base(s) on HCQ yield.
Screening of different polar-protic and non-protic solvents (see
Table S-2 in SI) [45] demonstrated that ethanol is most
effective for this transformation. During the screening of
bases, the pKa of the amine and alcohol groups present in
compound 12 were given careful consideration in order to
minimize C-0 bond formation (Table 4). NaOH or KOH in ethanol
gave low (<40%) conversion, whereas using K2 C03 in ethanol
gave 82% conversion to HCQ (Table 4, Entry 3). Attempts with
organic bases (Entries 5-6) resulted in only moderate
conversions to the desired product; however, using a 1 :1
mixture of K2 C03 /Et3 N (1/1) in ethanol resulted in 88%
conversion (Table 4, Entry 6) to 1, with corresponds to an
isolated yield of 78%.
[0145] Conclusion
[0146] In summary, we have developed a high-yielding continuous
flow process for the synthesis of hydroxychloroquine (HCQ) by
optimizing continuous flow methods for the synthesis of key
intermediates 6 and 12. Additionally we have developed and
optimized flow chemistry conditions for performing reductive
animation of 1 1 using Raney-Nickel as catalyst in a continuous
stirring tank reactor (CSTR) for the synthesis of compound 12,
and have incorporated it into a fully continuous telescoped
process for synthesis of 12 from lactone 8 and aminoethanol 7.
Feeding the output stream containing 12 from the above CSTR into
a second CSTR in which 12 is converted to HCQ provides a
completely continuous flow process from producing HCQ from
readily available starting materials. This efficient process has
the potential to increase global access to this strategically
important antimalarial drug. Optimization Reactions
[0147] All reactions for the preparation of substrates performed
in standard, dry glassware under an inert atmosphere of nitrogen
or argon unless otherwise described. All starting materials and
reagents purchased from commercial sources and used as received
unless otherwise noted.! H and13 C NMR spectra recorded using
600 MHz spectrometers. Chemical shifts (d) values given in ppm,
and coupling constants (J) given in Hz. The 7.26 resonance of
residual CHCft (or 0 ppm of TMS) for proton spectra and the
77.23 ppm resonance of CDCI3 for carbon spectra were used as
internal references. Continuous flow experiments were carried
out using the E-series flow reactor instrument purchased from
Vapourtec Ltd. PFA tubing (1/16 OD x 1 mm ID) was used for all
reactor coils in flow experiments. Most of the reagents and
starting materials were purchased from commercial sources and
used as received. All HPLC chromatograms recorded on Agilent
Technologies 1260 Infinity instrument with a Poroshell 120
EC-C18 column (4.6 x 50 mm, 2.7 micron). Continuous flow
hydrogenation was performed using FlowCAT instrument. Synthesis
of 5-iodopentan-2-one (10):
[0148] Two solutions, 2-Acetylbutyrolactone (8) (1.176 mL, 10.35
mmol, 1.0 equiv) and Hydroiodic acid (55% aqueous sol) were
pumped at 1.0
mLmin1 using peristaltic pumps through a 10 mL coil (residence
time, tR = 5 mins) at 80 °C. The completion of the reaction was
monitored using GC-MS. Complete consumption of starting material
was observed. The reaction mixture was cooled to room
temperature and sodium bicarbonate was added until neutralized
at pH = 7. The crude mixture was extracted with hexanes/MTBE and
the combined organic phases were dried over anhydrous sodium
sulfate and evaporated in vacuo to dryness yielding the desired
product as a light brown liquid (14.72 g, 89%).
[0149] ‘H NMR (600 MHz, CDC13 ): d 3.22 (t, J= 6.9 Hz, 2H), 2.59
(t, J= 6.9 Hz, 2H), 2.17 (s, 3H), 2.06 (quin, J = 7.0 Hz, 2H);,
3 C NMR (125 MHz, CDC13 ): d 207.4, 44.0, 30.3, 27.2, 6.7;
Spectra were obtained in accordance with those previously
reported [3]; see Figure 10 and Figure 1 1.
[0150] Synthesis of 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one
(6):
[0151] Telescope of compound 6: Prior to the start of the
experiment, the flow reactor unit was rinsed with dry THF and
flushed with nitrogen gas. At room temperature, the stock
solutions of 5-iodopentan-2-one
[0152] (10) (1.0 M) and 2-(ethylamino)ethan-l-ol (7) in THF
solution (1.0 M) were streamed in at 0.5 mLmin1 via a T-piece
into a 10 mL reactor coil (tR =10 min) and passed through a
packed bed reactor of potassium carbonate at 100 °C. The output
solution was collected and quenched with a saturated solution of
ammonium chloride. The aqueous phase was extracted by DCM (3 x
50 mL) and the organic layers were combined, dried over sodium
sulfate, and evaporated in vacuo to give a light brown liquid
(14.05 g, 86%);
[0153] 'H NMR (600 MHz, CDC13 ): d 3.53 (t, J= 5.2 Hz, 2H), 2.58
(m, 3H), 2.53 (m, 2H), 2.45 (t, J= 6.7 Hz, 4H), 2.59 (t, J= 6.9
Hz, 2H), 2.17 (s, 3H), 2.07 (quin, J= 7.0 Hz, 2H);13 C NMR (125
MHz, CDCI3): d 208.9, 58.6, 55.0, 52.4, 47.2, 41.3, 30.0, 21.2,
1 1.7;
[0154] Spectra were obtained in accordance with those previously
reported [38,39]
[0155] Synthesis of
(E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime (11):
[0156] Flow: Prior to the start of the experiment, the flow
reactor unit was rinsed with dry THF and flushed with nitrogen
gas. At room temperature, the stock solutions of
5-iodopentan-2-one (10) (1.0 M)
[0157] and 2-(ethylamino)ethan-l-ol (7) in THF solution (1.0 M)
were streamed in at 0.5 mLmin1 via a T-piece into a 10 mL
reactor coil (tR =10 min) and passed through a packed bed
reactor of potassium carbonate. The output solution was
streamlined with hydroxylamine (1.0 M) at 1.0 mLmin1 via a
T-piece into a 10 mL reactor coil (tR =10 min) and passed
through a packed bed reactor of potassium carbonate at 100 °C.
The reaction mixture was then concentrated in vacuo, taken up in
dichloromethane (3x20 mL) and concentrated under reduced
pressure to yield 11 as light brown liquid. The crude product
was used in the next step without further purification.
[0158] Synthesis of 2-((4-aminopentyl)(ethyl)amino)ethan-l-ol
(12):
[0159] Flow: The synthesis of compound 12 was performed in a HEL
continuous stirred tank reactor (CSTR) with a reaction volume of
150
mL. The reaction vessel was first charged with Raney Nickel ( I
.Og). The Raney Nickel catalyst was retained in the CSTR by the
2 pm metal filter frit on the diptube of the exit stream. The
reaction mixture, consisting of compound 11 (0.05-2.0 M) in THF,
was pumped by an HPLC pump set at a flow rate of 0.6-2.5 mLmin1
into the reaction vessel. The reaction pressure was set to 10
bar of hydrogen supplied by hydrogen gas (ultra high purity) at
a flow rate of 0.5 mLmin1 . The reaction temperature was set to
SO which was controlled by a thermocouple positioned in the
reaction mixture. The reaction was stirred with mechanical
stirring (750 rpm) to provide proper mixing. Two thermocouples
were used to control the reaction volume in the reactor by
setting a level control of -3°C. The lower thermocouple
constantly measured and controlled the reaction temperature and
the upper thermocouple measured the temperature at approximately
150 mL reactor volume. When the two thermocouples were w ithin
3°C, the level control Opened" the exit stream diptube to allow
products to exit the reactor, or closed' the exit stream diptube
to allow the reactor to fill when the temperature difference
between the two thermocouples was greater than 3°C. Product was
collected after a full reaction volume of material ( 150 mL) had
passed through the CSTR indicating that steady-state was
reached. The reaction was monitored by liquid chromatography and
'H NMR. The reaction mixture was filtered through a celite pad
and dried under reduced pressure. The solution was extracted
with water (10 mL) and dichloromethane (3 x 20 mL). The organic
layers were combined, washed with brine and dried over sodium
sulfate and evaporated in vacuo. The resulting oil was
fractionally distilled to give a colorless liquid (16.83 g,
84%). *H NMR (600 MHz, CDC13 ): d 3.53 (t, J =5.3 Hz, 2H), 2.89
(sx, 7 = 6.4 Hz, 1H), 2.57 (t, J= 5.5 Hz, 2H), 2.55 (t, J = 7.0
Hz, 2H), 2.45 (t, 7 = 7.0 Hz, 2H), 1.55-1.44 (m, 2H), 1.36-1.27
(m, 2H), 1.22 (t, 7= 7.1 Hz, 2H), 1.07 (d, 7 = 7.1 Hz, 2H), 1.00
(t, 7 = 7.1 Hz, 2H);l 3 C NMR (125 MHz, CDC13 ): d 58.2, 54.9,
53.2, 46.9, 46.7, 36.6, 23.8, 22.4, 10.6; Spectra were obtained
in accordance with those previously reported [38,39]
[0160] Synthesis of
2-((4-((7-chloroquinoIm-4-yI)amino)pentyl)(ethyl)amino)ethan-l-oI
(1):
[0161] Batch: In a CSTR reactor, 4,7-Dichloroquinoline (200 mg,
1.0 mmol), compound (12) (208 mg, 1.2 mmol), triethylamine
(0.069 mL, 0.5 mmol, 0.5 equiv) and potassium carbonate (69 mg,
0.5 mmol, 0.5 equiv) were combined and to this mixture was added
ethanol (1.0 mL). The ethanol was distilled off from the
reaction
mixture and kept under nitrogen atmosphere (15 psi). The
reaction was left at 125 °C in the nitrogen atmosphere for 6h.
After cooling, the mixture was transferred into a separatory
funnel using 1 M aqueous sodium hydroxide (5 mL) and
dichloromethane (2x20mL). The organic phases were separated and
the aqueous phase was re-extracted with dichloromethane (2x10
mL). The organic layers were combined and dried over sodium
sulfate and evaporated in vacuo. The crude material was purified
using flash chromatography with DCM:Et3 N:MeOH ( 95:3:2) to give
a white solid (0.263 g, 78%). 'H NMR (600 MHz, CDC13 ): S 8.48
(d, =5.4 Hz, 1H), 7.93 (d, J =5.4 Hz, 1H), 7.70 (d, J =
[0162] 9.2 Hz, 1H), 7.34 (dd, J= 8.8, 7.3 Hz, 1 H), 6.39 (d,
J=5.4 Hz, 1H), 4.96 (d, .7=7.5 Hz, 1H), 3.70 (sx, J = 6.8 Hz,
1H), 3.55 (m, 2H), 2.57 (m, 5H), 2.49 (m, 2H), 1.74-1.62 (m,
1H), 1.65-1.53 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H), 1.24 (d, J =
7.2 Hz, 2H);13 C NMR (125 MHz, CDCI3 ): d 152.2, 149.5, 149.2,
135.0, 129.0, 125.4, 121.2, 1 17.4, 99.4, 58.6, 54.9, 53.18,
48.5, 47.9, 34.5, 24.1, 20.6, 1 1.9;
[0163] Spectra were obtained in accordance with those previously
reported [38,39].
[0164] While the invention has been described in terms of its
several exemplary
[0165] embodiments, those skilled in the art will recognize that
the invention can be practiced with modification within the
spirit and scope of the appended claims. Accordingly, the
present invention should not be limited to the embodiments as
described above, but should further include all modifications
and equivalents thereof within the spirit and scope of the
description provided herein.
CN105693606A
Asymmetric synthesis method of optically pure
(R)/(S)-hydroxychloroquine
[ PDF ]
Abstract
The invention discloses an asymmetric synthesis method of
optically pure (R)/(S)-hydroxychloroquine.
4-amino-7-chloroquinoline and 5- ethyl(2-hydroxyethyl)
amine-2-pentanone are taken as starting raw materials and are
subjected to an asymmetric reductive ammoniation reaction under
the catalysis of chiral acid, optically pure hydroxychloroquine
is obtained, and the spatial configuration of a product is
controlled through spatial configuration of the chiral acid. The
method adopts simple steps, the raw materials are easy to
obtain, the yield is higher, the stereoselectivity is good, the
operation is simple, the chiral construction cost is relatively
lower, and the method is suitable for large-scale production.
[0001] Technical field
[0002] The invention belongs to the field of drug synthesis and
organic synthesis, and relates to an asymmetric synthesis method
of optically pure (R)/(S)-hydroxychloroquine.
[0003] Background technique
[0004] Hydroxychloroquine, chemical name
2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]-ethanol,
has a chiral carbon center with (-)- (R)-Hydroxychloroquine and
(+)-(S)-hydroxychloroquine are two optical isomers belonging to
4-aminoquinoline. The clinical use is (R)/(S) two optical
isomers. The mixture is mixed in equal proportions, that is, the
racemic compound is administered. It was first used in the
treatment of antimalarial, hydroxychloroquine phosphate and
sulfate are now widely used in the clinical treatment of discoid
lupus erythematosus and systemic lupus erythematosus; in
addition, hydroxychloroquine also has applications in
immunosuppression and anti-inflammatory reactions. .
[0005] Recent studies have shown that hydroxychloroquine is also
expected to develop into a new class of anti-diabetic drugs. In
a clinical trial, 32 healthy subjects, in a double-blind,
randomized trial of up to 14 weeks, showed that
hydroxychloroquine can effectively increase insulin sensitivity,
increase beta-cell viability, and regulate sugar Metabolism,
which in turn lowers the level of HbA1c, is expected to be
developed as a drug for diabetes prevention.
[0006] At the same time, studies on hydroxychloroquine
metabolism in humans showed significant differences in the
absorption, distribution, metabolism and excretion of
(-)-(R)-hydroxychloroquine and (+)-(S)-hydroxychloroquine. The
plasma protein binding rate of (-)-(R)-hydroxychloroquine was
37%, and the plasma protein binding rate of
(+)-(S)-hydroxychloroquine was 64%; when the racemic compound
was administered, (-) The blood concentration of
-(R)-hydroxychloroquine is always higher than
(+)-(S)-hydroxychloroquine, and the ratio is different in
animals and humans. In addition, the metabolic constants of the
optical isomers have different half-life, peak time, and
drug-time curve area. More critically, the renal clearance rate
of (-)-(R)-hydroxychloroquine was only about 40% of
(+)-(S)-hydroxychloroquine. The enormous physiological and
biochemical properties of the two isomers in the human body
prompted a deeper study of the differences between
(R)/(S)-hydroxychloroquine; at the same time, according to the
national new drug declaration requirements, different optical
isomers should be Treat according to different chemical
entities. Therefore, the development of a new optical pure
hydroxychloroquine synthesis method has a positive significance
for the application of this class of drugs in new fields.
[0007] The chemical synthesis of hydroxychloroquine has been
studied earlier and the route is mature, but it is limited to
the synthesis of racemates, and there are few synthetic methods
for (R) or (S)-hydroxychloroquine. Using
5-(N-ethyl-N-2-hydroxyethylamine)-2-pentylamine as starting
material, multiple resolution and recrystallization of
(+)-(S)-mandelic acid can be obtained. (R) and
(S)-5-(N-ethyl-N-2-hydroxyethylamine)-2-pentylamine in 55%
yield; then reacted with 4,7-dichloroquinoline to give hydroxy
Chloroquine. The synthetic method has a complicated route and
complicated operation. Therefore, the synthesis and synthesis of
new optically pure hydroxychloroquine is not only a requirement
of medicinal chemistry, but also a requirement of organic
chemistry.
[0008] Summary of the invention
[0009] It is an object of the present invention to provide an
asymmetric synthesis of optically pure
(R)/(S)-hydroxychloroquine.
[0010] In order to achieve the above object, the present
invention adopts the following technical solutions:
[0011] 1)The borane reducing agent and the chiral acid are added
to the organic solvent, and then uniformly stirred at room
temperature (10 to 30 minutes, the solution is clarified or
uniformly suspended) to obtain a mixture A, and 4-amino-7- is
added to the mixture A. Chloroquinoline and
5-ethyl(2-hydroxyethyl)amine-2-pentanone (known chemical CAS:
74509-79-8) are reacted at room temperature for 1-2 h, then
warmed to reflux and kept at 12~ 48h, after the reflux is
completed, it is naturally cooled to room temperature to obtain
a mixed solution B; the borane-based reducing agent is used in
an amount of 1 to 2 times that of 4-amino-7-chloroquinoline, the
chiral acid, based on the amount of the substance. The amount of
use is 0.1 to 0.3 times that of 4-amino-7-chloroquinoline, and
the amount of the 5-ethyl(2-hydroxyethyl)amine-2-pentanone is 1
to 4 of 4-amino-7-chloroquinoline. 2 times; the chiral acid is
chiral carbonic acid, phosphoric acid or sulfonic acid;
[0012] 2)Saturated brine was added to the mixture B, extracted
with ethyl acetate, and then purified by column chromatography.
[0013] The borane reducing agent is selected from the group
consisting of an alkali metal borohydride, a cyano or triacetoxy
substituent of the alkali metal borohydride, a borane, a borane
trimethylamine complex or a tetrabutylcyano boron. Ammonium
alkylate.
[0014] The alkali metal borohydride is selected from the group
consisting of lithium borohydride, sodium borohydride or
potassium borohydride.
[0015] The chiral acid is selected from (D) or (L)-mandelic
acid, (D) or (L)-tartaric acid, (D) or
(L)-di-p-methylbenzoyltartaric acid, (D) or ( L)-malic acid, (D)
or (L)-camphorsulfonic acid or (+) or (-)-binaphthol phosphate.
[0016] The organic solvent is selected from the group consisting
of dichloromethane, tetrahydrofuran, toluene, dioxane,
dimethylformamide or dimethyl sulfoxide.
[0017] The organic solvent is used in an amount such that the
concentration of 4-amino-7-chloroquinoline reaches 0.1 to 1
mol/L (the concentration of the reactant has a certain influence
on the yield and the optical purity, and the concentration range
is a summary of the experimental results).
[0018] In the column chromatography, the packing of the
chromatography column is silica gel, and the amount of the
silica gel in the chromatography column is 5-20 times the mass
of 4-amino-7-chloroquinoline.
[0019] The column chromatography was performed with isocratic
elution. The eluent was a mixture of dichloromethane, methanol
and triethylamine, and the volume ratio of
dichloromethane:methanol:triethylamine=95:3:2.
[0020] The product is (-)-(R)-hydroxychloroquine and
(+)-(S)-hydroxychloroquine.
[0021] The beneficial effects of the present invention are
embodied in:
[0022] Compared with the prior art, the present invention uses
4-amino-7-chloroquinoline and
5-ethyl(2-hydroxyethyl)amine-2-pentanone as raw materials, and
borane compound as reducing agent, chiral acid. Providing an
asymmetric catalytic environment, the optically pure
hydroxychloroquine is synthesized in one step by asymmetric
reductive amination reaction. The stereo configuration of the
chiral acid controls the stereo configuration of the product,
avoiding the resolution of the racemic compound, and has a short
synthetic route. The ratio and selectivity are high, the
operation is simple, the chiral secondary amine construction
cost is relatively low, and the environment is friendly, which
is suitable for the technical advantage of large-scale
synthesis.
[0023] The reducing agent used in the present invention is a
borane compound, and the reducing ability is moderate and the
price is low, so that the asymmetric reduction reaction has
higher yield and is suitable for industrial synthesis.
[0024] Detailed ways
[0025] The invention will now be described in detail in
connection with the embodiments.
[0026] Hydroxychloroquine contains a chiral carbon center, and
its different optical isomers have different pharmacological and
pharmacological properties. According to the national new drug
declaration requirements, different optical isomers should be
treated according to different chemical entities. Therefore, The
construction of a chiral center is very important for the
application of this class of compounds in the field of new
drugs.
[0027]
Example 1
[0028] Reaction process: Add 500 mL of dioxane, 3.3 g (0.15 mol)
of lithium borohydride (reducing agent) and 3.5 g (0.015 mol) of
(D)-camphor to a 500 mL three-necked flask equipped with a
constant pressure funnel and a reflux condenser. The sulfonic
acid (chiral reagent) was stirred at room temperature for 10 min
to obtain a mixture. To a constant pressure funnel was added
17.8 g (0.1 mol) of 4-amino-7-chloroquinoline and 15.7 g (0.12
mol) of 5-ethyl (2- Hydroxyethyl)amine-2-pentanone and 100 mL of
dioxane (solvent), and slowly drip the mixture into the mixture
(about 30 min) from a constant pressure funnel. After the
completion of the dropwise addition, the reaction was continued
at room temperature for 2 h, and then the temperature was raised
to reflux. 110 ° C), and maintained for 12 h (TLC detection
reaction). After the reaction was completed, it was naturally
cooled to room temperature, 400 mL of saturated brine was added
to the reaction system, and then extracted with ethyl acetate,
150 mL each time, and extracted three times. The extracted
organic phase was dried over anhydrous sodium sulfate, dried and
then sp. The solvent was removed by evaporation (vacuum degree
10 KPa, operating temperature 50 ° C), and then added to a
silica gel column containing 150 g of silica gel (200-300 mesh)
to eluent (dichloromethane:methanol:triethylamine volume
ratio=95 :3:2) Isocratic elution, TLC detection, after combining
the same effluent, the solvent was removed by rotary evaporation
(vacuum degree 10 KPa, operating temperature 50 ° C) to obtain
pale yellow liquid (+)-(S)-hydroxychloroquine (Formula 1) ,
product) 18.5 g, yield 55%.
[0029]
[0030] Product treatment: a small amount of product is dissolved
in acetone, adding 2 times the amount of phosphoric acid,
overnight reaction, suction filtration, acetone washing, drying
to obtain hydroxychloroquine phosphate (phosphate is more
stable, easy to operate; phosphate optical rotation parameters
and other parameters have been There are reports in the
literature, which is convenient for comparison).
[0031] The hydroxychloroquine phosphate was enantioselectively
analyzed by chiral HPLC, ee% = 78%, [α] 20D = +79.1 °
(phosphate, c = 0.96, H2O). ESI-MS: 336 (M+H), 1H NMR (CDCl3 300
MHz) δ ppm: 0.97-0.99 (3H, t); 1.26-1.29 (3H, d); 1.44-1.80 (4H,
m); 2.33-2.73 (6H, m); 3.40-3.91 (3H, m); 5.15 (1H, brs); 6.35
(1H, d); 7.26 (1H, dd); 7.73 (1H, d); 7.93 (1H, d); 8.49 (1H) ,
d). 13 C NMR (CDCl 375 MHz) δ ppm: 11.4; 20.2; 23.7; 34.2; 47.4;
48.1; 53.1; 54.8; 58.4; 99.1; 117.3; 121.2; 124.9; 128.5; 134.6;
149.0; Consistent with the literature report.
[0032] Example 2
[0033] The reaction process and product treatment were similar
to those in Example 1, except that the solvent, reducing agent
and chiral reagent were: 250 mL of toluene (150 mL in a
three-necked flask, 100 mL in a constant pressure funnel), and
11 g (0.14 mol) of cyanide. Potassium borohydride and 1.89 g
(0.014 mol) of (D)-malic acid. 4-Amino-7-chloroquinoline and
5-ethyl(2-hydroxyethyl)amine-2-pentanone were slowly dropped
from a constant pressure funnel into a mixture of a reducing
agent and a chiral reagent, and then allowed to react at room
temperature for 1 h. The temperature in the reflux was 130 ° C
and was maintained for 24 h.
[0034] The product was (+)-(S)-hydroxychloroquine 15.1 g, yield
45%; enantioselective chiral HPLC analysis, ee%=70%,
[α]20D=+74.3° (phosphate, c= 0.94, H2O).
[0035]
Example 3
[0036] The reaction process and product treatment were similar
to those in Example 1, except that the solvent, reducing agent
and chiral reagent were: 280 mL of dimethyl sulfoxide (180 mL in
a three-necked flask, 100 mL of a constant pressure funnel), and
34 g (0.16 mol). Sodium triacetoxyborohydride and 2.4 g (0.016
mol) of (D)-mandelic acid. The temperature in the reflux was 160
° C and held for 12 h.
[0037] The product was (+)-(S)-hydroxychloroquine 13.5 g in 40%
yield. Enantioselective chiral HPLC analysis, ee% = 69%, [α] 20D
= +74 ° (phosphate, c = 1.0, H 2 O).
[0038] Example 4
[0039] The reaction process and product treatment were similar
to those in Example 1, except that the solvent, reducing agent
and chiral reagent were: 200 mL of tetrahydrofuran (100 mL in a
three-necked flask, 100 mL in a constant pressure funnel), and
140 mL of borane (0.14 mol). A tetrahydrofuran solution (1.0 M,
the solvent may also be diethyl ether or dimethyl sulfide) and
4.2 g (0.028 mol) of (D)-tartaric acid. The temperature in the
reflux was 80 ° C and was maintained for 48 h.
[0040] The product was (1)-(S)-hydroxychloroquine 13.9 g, yield
43%. Enantioselective chiral HPLC analysis, ee% = 88%, [α] 20D =
+95.7 ° (phosphate, c = 1.02, H2O).
[0041]
Example 5
[0042] The reaction process and product treatment were similar
to those in Example 1, except that the solvent, reducing agent
and chiral reagent were: 240 mL of dichloromethane (140 mL in a
three-necked flask, 100 mL in a constant pressure funnel), and
10.2 g (0.14). Mol) borane trimethylamine complex and 2.1 g
(0.014 mol) of (L)-mandelic acid. The temperature in the reflux
was 75 ° C and held for 40 h.
[0043] The product was a pale brown solid,
(-)-(R)-hydroxychloroquine (formula 2) 16.8 g, yield 50%.
[0044]
[0045] Enantioselective chiral HPLC analysis, ee% = 80%, [α] 20D
= -82.8 ° (phosphate, c = 1.06, H2O).
[0046]
Example 6
[0047] The reaction process and product treatment were similar
to those in Example 1, except that the solvent, reducing agent
and chiral reagent were: 160 mL of dimethylformamide (100 mL in
a three-necked flask, 60 mL in a constant pressure funnel), 45.1
g. (0.16 mol) tetrabutylcyanoborohydride ammonium and 5.97 g
(0.02 mol) of (+)-binaphthol phosphate. The temperature in the
reflux was 150 ° C and maintained for 18 h.
[0048] The product was (+)-(S)-hydroxychloroquine 13.1 g in 39%
yield. Enantioselective chiral HPLC analysis, ee% = 66%, [α] 20D
= +70.1 ° (phosphate, c = 0.98, H2O).
CN103772277
Hydroxychloroquine linolenate and synthesis method
thereof
[ PDF ]
Abstract
The invention discloses a structural formula of
hydroxychloroquine linolenate and also provides a method for
preparing hydroxychloroquine linolenate. The method comprises
the following steps: preparing hydroxychloroquine from
hydroxychloroquine sulfate and a sodium hydroxide liquid, and
purifying by adding ethyl acetate; adding an organic solvent, a
catalyst and a dewatering agent in linolenic acid, then adding
the prepared hydroxychloroquine to carry out
constant-temperature reaction for 12-24 hours, wherein the mole
equivalence ratio of linolenic acid to hydroxychloroquine is
(1:1)-(1:1.5); and finally, carrying out column chromatography
separation to obtain high-purity hydroxychloroquine linolenate.
After lots of hydroxychloroquine linolenate is absorbed by tumor
cells, hydroxychloroquine linolenate is metabolized to form
hydroxychloroquine, thereby increasing the concentration of
focus medicine and reducing medicine dose.
[0001] Technical field
[0002] The present invention relates to hydroxychloroquinelinone
and a process for the preparation thereof.
[0003] Background technique
[0004] Hydroxychloroquine is a 4-aminoquinoline derivative which
is commonly used clinically. Hydroxychloroquine is a traditional
antimalarial drug used to control the clinical symptoms of
malaria and the preventive prevention of malaria, rheumatoid
arthritis, juvenile chronic arthritis, discoid and systemic
lupus erythematosus, and skin lesions caused or exacerbated by
sunlight. . Studies in recent years have shown that
hydroxychloroquine has a good inhibitory effect on a variety of
malignant tumors. Hydroxychloroquine inhibits the growth of
human breast cancer cells MCF-7 and MDA-MB-231 and regulates the
protein acetylation process of tumor cell MCF-7.
Hydroxychloroquine also inhibits the activity of chronic
lymphocytic leukemia cells by inducing apoptosis in cells by
activating caspase-3 and regulating the ratio of BCL-2 to Bax.
Hydroxychloroquine also increases lysosomal and mitochondrial
permeability, thereby inducing apoptosis. As an autophagy
inhibitor, hydroxychloroquine inhibits the growth of tumor cells
by inhibiting the autophagy of tumor cells, destroying the
metabolism of tumor cells.
[0005] The amount of polyunsaturated fatty acids in tumor cells
is much higher than that in normal cells. As an unsaturated
fatty acid, alpha linolenic acid can be efficiently taken up by
tumor tissues. Comprehensive application of the principle of
tumor targeting prodrug design and the principle of structural
splicing, designing and synthesizing prodrugs is a method for
the synthesis of new drugs. The present invention synthesizes a
prodrug of hydroxychloroquine (hydroxyl) by structural
modification of hydroxychloroquine. Chloroquine linoleate),
which utilizes the property of linolenic acid to be efficiently
taken up by tumor cells, is loaded with an antitumor drug such
as hydroxychloroquine to increase the drug concentration of the
target site of the drug molecule, thereby achieving the purpose
of improving the antitumor efficiency of the drug.
[0006] In order to solve the above-mentioned deficiencies in the
prior art, the present invention proposes a new solution.
[0007] Summary of the invention
[0008] It is an object of the present invention to provide a
tumor-targeted prodrug: hydroxychloroquinolinate which, after in
vivo metabolism, can be a drug which reduces the amount of a
drug, reduces toxicity, and enhances antitumor activity.
[0009] At the same time, the present invention also provides a
process for preparing hydroxychloroquine linolenate.
[0010] In order to achieve the above object, the technical
solution adopted by the present invention is:
[0011] The invention has the structure of the
hydroxychloroquinolinate prepared by using hydroxychloroquine
sulfate and linolenic acid as raw materials, and the structural
formula is as follows:
[0012]
[0013] The synthetic route is:
[0014]
[0015] The preparation process includes:
[0016] 1、Hydroxychloroquine is prepared by using
hydroxychloroquine sulfate and sodium hydroxide solution,
wherein the molar ratio of hydroxychloroquine sulfate to sodium
hydroxide solution is 1:3, and then ethyl acetate is added for
purification;
[0017] 2、The linolenic acid is mixed with an organic solvent, a
catalyst and a dehydrating agent, and stirred under nitrogen for
5 minutes to 1 hour, and then heated to normal temperature; then
the prepared hydroxychloroquine is added, and the reaction is
carried out at room temperature for 12~. 24 hours, wherein the
molar equivalent ratio of linolenic acid and hydroxychloroquine
is 1:1 to 1:1.5;
[0018] 3、After the reaction is stopped, the organic solvent is
added, and the solution is heated to 50 ° C, and washed with a
hydrochloric acid solution, a saturated sodium chloride solution
and water, and the organic phase is washed with anhydrous sodium
sulfate and concentrated to give a brownish oil.
[0019] The oil is dissolved in methyl tert-butyl ether, and the
solution is washed with hydrochloric acid solution. The oil
phase is separated and dissolved in methanol. The activated
carbon is decolorized and concentrated to give a yellow oil. The
yellow oil is separated by column chromatography. After elution
separation, it was concentrated again and dried to give
hydroxychloroquinoline linoleate.
[0020] Linolenic acid requires the addition of an organic
solvent, a catalyst and a dehydrating agent before it is reacted
with hydroxychloroquine. Wherein the organic solvent is selected
from the group consisting of chloroform, dichloromethane or
ethyl acetate; the catalyst is selected from the group
consisting of 4-dimethylaminopyridine, 4-methylmorpholine,
triethylamine, pyridine or 1-hydroxybenzotriazole; the
dehydrating agent is selected from Dicyclohexylcarbodiimide,
N,N'-diisopropylcarbodiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
[0021] In the preparation of hydroxychloroquinelinone, when the
mixture is subjected to column chromatography, it is necessary
to select a suitable stationary phase and eluent. According to
the physicochemical properties and experimental demonstration of
hydroxychloroquinolinone, the stationary phase selected by the
present invention is silica gel, wherein the silica gel column
chromatography with 200-300 mesh has good effect, and the silica
gel with 200 mesh is optimized. The eluent for column
chromatography is chloroform-methanol or
dichloromethane-methanol, and dichloromethane-methanol is
optimally selected.
[0022] The hydroxychloroquinolinone prepared by the present
invention is a novel compound which can be used to prepare an
antitumor drug according to the principle of a prodrug.
[0023] In summary, the present invention has the following
advantages:
[0024] Hydroxychloroquinelinone is a conjugate of
hydroxychloroquine and linolenic acid through an ester bond. As
a prodrug, hydroxychloroquinolinone in the body can be more
effectively concentrated in the tumor site under the action of
linolenic acid. Increase the concentration of hydroxychloroquine
at the tumor site, reduce the accumulation of hydroxychloroquine
in non-target tissues, and reduce the toxic side effects of the
drug;
[0025] The esterification reaction synthesis method adopted by
the invention has the advantages of simple operation, mature
technology, simple post-treatment, good application prospect,
and high purity chlorochloroquinolinate obtained by column
chromatography.
[0026] Detailed ways
[0027] The improved hydroxychloroquinolinate of the present
invention has the structural formula of Formula I and has the
chemical formula C 36 H 54 O 2 N 3 Cl.
[0028] Hydroxychloroquinelinone is a new compound, which has not
been reported in the literature. Its structure was confirmed by
mass spectrometry MS and nuclear magnetic resonance HNMR. The
data are as follows:
[0029] MS, m/z (%): 543 (M+, 5.56), 438 (M+-C6H4NO, 5.05), 333
(M+-2C6H4NO, 2.40), 106 (C6H4NO+, 100.00), 78 (C5H4N+, 48.64)
[0030] 1HNMR (CDCl3, 300MHz): δ (ppm)
[0031] 0.86(t, J = 7.5 Hz, 3H, CH3), 0.97 (t, J = 7.5 Hz, 3H,
CH3), 1.26-1.44 (m, 19H), 2.03-2.12 (m, 5H), 2.34 (t, J = 7.5
Hz, 2H, COCH 2), 2.80 (t, J = 5.4 Hz, 3H), 3.16 (bs, 3H), 3.29
(bs, 2H), 3.29 (s, 2H), 3.93 (bs, 1H), 4.50 (s, 2H), 5.35-5.37
(m, 6H, CH=CH), 6.57 (bs, 1H, NH), 7.44 (s, 1H), 8.19 (s, 1H),
9.19 (bs, 2H).
[0032]
Example 1
[0033] 21.7 g of 50 ml of hydroxychloroquine sulfate was weighed
and placed in a 500 mL three-neck round bottom flask. Under ice
bath conditions, 150 mL of water was added and stirred to
dissolve. 150 mmol of 50 mL of 12% aqueous sodium hydroxide
solution was slowly added dropwise, and a white oil was formed
during the dropwise addition, and 50 mL of ethyl acetate was
added at this time. After slowly warming to room temperature,
100 mL of ethyl acetate was added, and the organic phase was
separated; the aqueous phase was extracted twice with ethyl
acetate, and the organic phase was combined. The organic phase
was washed with a saturated aqueous solution of sodium chloride
and water, dried over anhydrous sodium sulfate, filtered, and
evaporated to give hydroxy chloroquine 16.5 g of 48.8 mmol of
colorless transparent oil.
[0034] Under cooling with nitrogen and ice bath, add 32.5 mmol
of a-linolenic acid 12.9 g and 220 mL of dichloromethane with a
purity of 70% to a 500 mL three-neck round bottom flask, and
then add an appropriate amount of 4-methylmorpholine, 4
-Dimethylaminopyridine and
1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, the
reaction was allowed to warm to room temperature after stirring
for 30 min. Wherein dichloromethane can be replaced by
chloroform, the catalyst can be replaced by triethylamine,
pyridine or 1-hydroxybenzotriazole; the dehydrating agent can
use dicyclohexylcarbodiimide, N, N'-diisopropylcarbamate The
imine or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride is substituted.
[0035] 48.5 mmol of hydroxychloroquine 16.5 g was added to
linolenic acid, and the reaction was stirred for 12 hours. To
the flask, 100 mL of methylene chloride was added, and the
mixture was heated to a temperature of about 50 ° C. The mixture
was washed with a hydrochloric acid solution, a saturated
aqueous sodium chloride solution and purified water. Add 300 mL
of methyl tert-butyl ether to the brownish yellow oil and
transfer to a separatory funnel. The solution is washed with 200
mL of hydrochloric acid solution. The separatory funnel is
divided into three phases, and the upper layer is methyl
tert-butyl ether phase. The middle layer is oily and the lower
layer is water phase. The oil was separated and dissolved in 200
mL of methanol. EtOAc was evaporated. The column chromatography
was carried out using a silica gel having a stationary phase of
200 mesh. The eluent was dichloromethane/methanol, wherein the
volume ratio of dichloromethane to methanol was gradually
increased from 50:1 to 15:1, and the eluate was concentrated and
dried to obtain 18.9 mmol of hydroxychloroquinolinone 11.3 g,
the yield was 52.5%.
[0036]
Example 2
[0037] 8.7 g of hydroxychloroquine 20 mmol was weighed and
placed in a 250 mL one-neck round bottom flask, and 60 mL of
water was added thereto, followed by stirring at room
temperature. A 20 mL portion of a 20% aqueous sodium hydroxide
solution was slowly added dropwise, and a large amount of a
white oil was obtained. A white oil was dissolved in ethyl
acetate (40 mL), and the organic phase was separated. The
aqueous phase was extracted twice with ethyl acetate. The
organic phase was washed with 50 mL of saturated sodium chloride
aqueous layer and dried over anhydrous sodium sulfate.
[0038] Under nitrogen protection and ice bath cooling, 19.2 mmol
of a-linolenic acid 7.6 g and 100 mL of dichloromethane with a
purity of 70% were added to a 250 mL three-neck round bottom
flask, and an appropriate amount of 4-dimethylaminopyridine and
bicyclo was sequentially added. The hexylcarbodiimide was
stirred for 60 minutes, and the reaction system was heated to
normal temperature. An appropriate amount of triethanolamine and
hydroxychloroquine 6.5 g of 19.2 mmol was added, and the
reaction was stirred for 24 hours. 50 mL of methylene chloride
was added to the flask, and the reaction solution was filtered.
The filtrate was placed in an ice box, and after standing for a
while, the reaction solution was filtered, and the process was
carried out 5 times. The dried filtrate was concentrated to give
a brown oil. The oil was dissolved in 80 mL of ethyl acetate and
transferred to a separatory funnel. The solution was washed with
a solution of hydrochloric acid (80 mL). The mixture was
separated into three phases, the upper layer was methyl t-butyl
ether phase, the middle layer was oily, and the lower layer was
The aqueous phase was separated, and the oil was separated and
dissolved in 100 mL of methanol. Decolorization was carried out
by adding activated carbon. After decolorization, column
chromatography was carried out using a silica gel having a
stationary phase of 300 mesh. The eluent was
dichloromethane/methanol, and the volume ratio of
dichloromethane to methanol was determined. Increasingly from
50:1 to 15:1, after elution, it was concentrated to give
hydroxychloroquinolinate 5.8 g of 9.7 mmol in a yield of 50.5%.
CN110283121
Hydroxychloroquine synthetic method
[ PDF ]
Abstract
The invention provides a hydroxychloroquine synthetic method,
including the steps of mixing 4,7-dichloroquinoline,
2-[(4-aminopentyl)(ethyl)amino]ethanol and
N,N-diisopropylethylamine, reacting under protective gas, and
after the reaction, performing extraction, concentration and
purification to obtain the hydroxychloroquine. By using the
synthetic method provided by the invention,
N,N-diisopropylethylamine is used as both an acid-binding and a
solvent to promote smooth reaction, the amount is small (only
theoretical amount), and the consumption is low; the reaction
time is short, alkalization is not needed after treatment, the
hydroxychloroquine can be obtained by just the operations of
extraction and recrystallization, and the operation is simple;
the extraction solvent and the recrystallization solvent may be
the same solvent, which is beneficial to the recovery and
utilization of the solvent, and the production cost is reduced;
the total recovery is increased from 45.9% to 74.7%, the product
quality is increased from 99.0% to 99.8% or above (HPLC purity),
and single impurity being less than or equal to 0.1%.
[0001] Technical field
[0002] The present invention relates to the field of medicinal
chemistry, and in particular to the preparation of
hydroxychloroquine for use in the treatment of malaria,
rheumatoid arthritis and systemic lupus erythematosus.
[0003] Background technique
[0004] Hydroxychloroquine (1) is a 4-aminoquinolone compound,
chemical name
2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]-ethanol,
chemical structure as follows:
[0005]
[0006] 1951In the year, hydroxychloroquine was successfully
developed by Winthrop. It was originally used for malaria
treatment. It was used to treat systemic lupus erythematosus in
1955. It was first introduced in the United States in 1956, and
then successively in Japan, France, Denmark, Finland, Germany,
etc. National and regional listings. In 1998, the US FDA
approved hydroxychloroquine for the treatment of rheumatoid
arthritis and lupus erythematosus. Compared with other similar
drugs, it has an advantage in safety, not only can improve the
symptoms of arthritis in patients, but also anti-oxidation and
anti-lipid, avoid platelet aggregation, reduce the blood sugar
level of patients, and accelerate the rate of insulin secretion.
In addition, to improve the overall sensitivity of insulin, in
the treatment of dermatomyositis, lichen planus, AIDS, etc. also
have a positive effect.
[0007] US 2,546,658 discloses a process for the synthesis of
hydroxychloroquine, the process of which is as follows:
[0008] Using 4,7-dichloroquinoline (2) and
5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (3) as raw
materials, using phenol as solvent and sodium iodide as catalyst
After stirring at 125-130 ° C for 18 h, the reaction solution
was cooled, methanol was added, then filtered with charcoal, the
filtrate was added with phosphoric acid, the wall was rubbed
with a glass rod, allowed to stand for 2 days, suction filtered,
and the filter cake was rinsed with methanol. After drying,
hydroxychloroquine diphosphate was obtained in a yield of 41.9%
(in terms of 2). The obtained hydroxychloroquine phosphate was
dissolved in water, dissociated with ammonium hydroxide,
extracted with chloroform, and the chloroform was evaporated
under reduced pressure. The residue was crystallised from
diethyl ether to afford hydroxy chloroquine (1), yield: 44.
Diphosphate meter). The specific route is as follows:
[0009]
[0010] The method mainly has the following disadvantages: i) the
reaction uses phenol as a solvent, the phenol is highly toxic
and corrosive, and is extremely harmful to people and the
environment, and is converted into an aqueous solution of sodium
phenolate to form harmful phenol-containing wastewater in the
post-treatment process. Increased the difficulty of the three
waste treatment; ii) the condensation reaction time is 18h, the
long-term reaction will not only increase the production cost,
but also lead to the increase of the content and quantity of
impurities, especially the long-term high temperature reaction,
which will increase the deethylated impurities. Produced, and
this impurity is difficult to remove; iii) use of phosphoric
acid to remove impurities during the reaction, resulting in the
production of a large amount of phosphorus-containing
wastewater, further increasing environmental pressure; iv)
extraction solvent chloroform is a type of solvent,
carcinogenic, environmentally unfriendly; v) Recrystallization
solvent Ether is flammable and explosive, and has a high safety
hazard; vi) The procedure is long, the operation is cumbersome,
and the total yield is very low, only 18.6%.
[0011] CA2561987A1 discloses a method for synthesizing
hydroxychloroquine sulfate, and the reaction process of the
method is as follows:
[0012]
[0013] The method has the advantages of long steps, complicated
operation and high cost; the condensation reaction time is as
long as 20-24 hours, which leads to an increase in the content
and quantity of impurities, resulting in lower product quality.
[0014] WO2005062723A2 discloses a method for synthesizing
hydroxychloroquine sulfate, the reaction process of which is as
follows:
[0015]
[0016] The reaction time is too long (45-50h), and the energy
consumption is large, which not only increases the production
cost, but also increases the generation of impurities, which is
not conducive to industrial production; in the post-treatment
process, the product is firstly made into phosphate and then
alkalized with ammonium hydroxide. The product is freed,
extracted with dichloromethane, the operation is cumbersome, and
a large amount of phosphorus-containing wastewater is generated,
which increases the pressure of “waste water” treatment; in
particular, the final product is obtained by column
chromatography, the operation is complicated, the cost is high,
and it is not suitable for industrial large-scale production. .
[0017] US 5,314,894 discloses a method for synthesizing
hydroxychloroquine sulfate, the reaction process of which is as
follows:
[0018]
[0019] A large amount of high-boiling N-ethyldiisopropylamine is
used as a reaction solvent in the method, which is difficult to
recover, easily leads to solvent residue affecting product
purification, and increases environmental protection cost;
condensation reaction time is too long (48h), energy consumption
is very large And increase the production of impurities;
post-treatment requires alkalization, re-extraction, drying,
concentration, column, fractionation, etc. to obtain the
product, many steps, complicated operation, low yield (only
45.9%); the final product passed Column chromatography and
fractional distillation are two steps, the operation is
cumbersome, the cost is high, and it is not suitable for
industrial large-scale production.
[0020] CN107266323A discloses a method for synthesizing
hydroxychloroquine sulfate, and the reaction process of the
method is as follows:
[0021]
[0022] The method uses carcinogenic chloroform as a solvent, and
the amount is large, which is extremely harmful to people and
the environment; the use of high-boiling N,N-dimethylformamide
as a solvent is difficult to recycle, and the wastewater is
greatly affected. The environmental protection pressure; the
route is long and complicated, the operation is cumbersome; the
raw materials are expensive and the cost is high.
[0023] Each of the above routes has shortcomings such as long
reaction time, large reagent toxicity, cumbersome operation,
environmental pollution, high production cost, and poor product
quality. It is difficult to achieve safe and environmentally
friendly green production requirements, lack market
competitiveness, and is not suitable for industrial production.
Especially with the increase of production capacity, the
environmental protection cost has risen sharply. Therefore, it
is urgent to study a green synthetic route suitable for
industrial production, with the aim of solving the problems of
low greening, low yield and low product purity in the current
process.
[0024] Summary of the invention
[0025] The object of the present invention is to overcome the
deficiencies in the prior art and to provide a method for
synthesizing hydroxychloroquine suitable for green synthesis in
industrial production.
[0026] In order to achieve the above object, the present
invention provides a method for synthesizing hydroxychloroquine,
which comprises the steps of:
[0027] Mixing 4,7-dichloroquinoline,
5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine with
N,N-diisopropylethylamine, and reacting under protective gas
After the reaction is completed, extraction, concentration, and
purification are carried out to obtain hydroxychloroquine.
[0028] Preferably, the method of synthesis comprises an
extraction step to extract hydroxychloroquine.
[0029] Preferably, the extraction solvent used in the extraction
step is a single solvent or a mixed solvent of isopropyl
acetate, ethyl acetate, dichloromethane, methyl tert-butyl
ether, toluene or methyl isobutyl ketone. Isopropyl acetate is
preferred.
[0030] Preferably, in the synthesis method, after the reaction
is completed, alkalization is not required, direct extraction,
concentration, and cooling and crystallization are carried out
to obtain crude hydroxychloroquine.
[0031] Preferably, the method of synthesis comprises a
recrystallization step of crude hydroxychloroquine to refine
hydroxychloroquine.
[0032] Preferably, the recrystallization solvent used in the
recrystallization step is a single solvent or a mixed solvent of
isopropyl acetate, ethyl acetate, acetone, methyl tert-butyl
ether, toluene or methyl isobutyl ketone. Isopropyl acetate is
preferred.
[0033] Preferably, the shielding gas is nitrogen, argon, or
helium.
[0034] Preferably, the reaction time is 4 to 15 h, preferably 8
to 10 h; the reaction temperature is 90 to 160 ° C, preferably
125 to 135 ° C, and the reaction temperature is preferably
gradually increased.
[0035] Preferably, the molar ratio of 4,7-dichloroquinoline to
5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine is 1:2.5 to
1:0.8, preferably 1:1.2. ~1:1.6.
[0036] Preferably, the molar ratio of 4,7-dichloroquinoline to
N,N-diisopropylethylamine is from 1:1.5 to 1:0.8, preferably
1:1.
[0037] The advantages of the method for synthesizing
hydroxychloroquine and its sulfate provided by the present
invention are as follows:
[0038] 1)Avoid the use of corrosive and carcinogenic phenol as a
reaction solvent, and avoid the use of carcinogenic
dichloroethane and chloroform as extraction solvents or
recrystallization solvents.
[0039] 2)The extracting agent and the recrystallization solvent
can use the same solvent such as isopropyl acetate, which is
advantageous for recycling and reducing the production cost.
[0040] 3)The use of shielding gas effectively controls the
generation of various types of oxidizing impurities; the short
reaction time greatly reduces the generation of impurities such
as deethylated impurities.
[0041] 4)The total yield increased from 45.9% to 74.7%, and the
product quality increased from 99.0% to 99.8% (HPLC purity), and
the single impurity was ≤0.1%, which greatly improved the market
competitiveness of the product.
[0042] 5)The theoretical amount of N,N-diisopropylethylamine is
used as an acid anhydride and as a reaction solvent to promote
the smooth progress of the reaction, while the amount is small,
the loss is low, and the cost is lowered;
[0043] 6)The post-treatment does not require alkalization, and
high-quality hydroxychloroquine can be obtained in a high yield
only by operations such as extraction and recrystallization,
thereby avoiding complicated operations such as column and
fractionation, greatly simplifying the process and reducing the
cost;
[0044] 7)The reaction conditions are mild, the operation is
simple, the equipment requirements are low, and it is suitable
for industrial production.
[0045] 8)The process has completed four batches of pilot-scale
amplification experiments, and the pilot test is stable.
[0046] detailed description
[0047] For a better understanding of the contents of the present
invention, further description will be made below in conjunction
with the specific embodiments. This embodiment is implemented on
the premise of the technical solution of the present invention,
and detailed implementation manners and specific operation
procedures are given, but the scope of protection of the present
invention is not limited to the following embodiments.
[0048] The present invention provides a specific
hydroxychloroquine reaction route as follows:
[0049]
[0050] Melting point, mass spectrum and NMR result of
hydroxychloroquine: melting point: 90.9-91.9 ° C; ESI-MS (m/z):
336.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm: 8.51 (d, J=5.5 Hz,
1H), 7.95 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.37
(dd, J = 9.0, 2.2 Hz, 1H), 6.4 (d, J = 5.5 Hz, 1H), 5.05 (d, J =
7.5 Hz, 1H), 3.72 (p, J = 6.5 Hz, 1H), 3.6 (t, J = 5.1 Hz, 2H),
2.63 (m, 4H), 2.6 ( m,1H), 2.56 (t, J = 6.4 Hz, 2H), 1.80 - 1.59
(m, 4H), 1.33 (d, J = 6.4 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H)
[0051] Example:
[0052] 4,7-dichloroquinoline (500 g, 2.5 mol),
5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine
(5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine) was added to a
3000 mL three-necked flask equipped with a reflux condenser.
668g, 3.8mol) and N,N-diisopropylethylamine (323g, 2.5mol), pass
nitrogen protection, start mechanical stirring, slowly warm to
125 ~ 135 ° C reflux reaction for 8h; cool the reaction
solution, to be concentrated The liquid was cooled to below 50 °
C, and 1500 mL of water was added; after stirring for 15
minutes, the reaction liquid was cooled to below 40 ° C,
extracted with isopropyl acetate (3000 mL * 3), and the organic
phase was washed with water (3000 mL * 2), and washed with
saturated brine ( 3000mL*1), 2/3 isopropyl acetate was recovered
under reduced pressure, then slowly reduced to 0～5°C for 1h;
filtered with Buchner funnel to obtain 801g (wet weight) of
off-white solid, and then isopropyl acetate Crystallization gave
a wet weight of 710 g of a white powdery solid, which was dried
under vacuum at 40 ° C for 6 h to afford 627 g (HPLC: 99.83%) as
a white solid.
CN109456266
Novel preparation method of hydroxychloroquine sulfate
[ PDF ]
Abstract
The invention discloses a preparation method of
hydroxychloroquine sulfate. The preparation method is
characterized in that a parent core 4,7-dichloroquinoline used
as a starting material and a hydroxychloroquine side chain
5-(N-ethyl-N-2- ethanolamine)-2-amylamine undergo condensation
reaction in the presence of a catalyst to obtain a
hydroxychloroquine free base, and then the
hydroxychloroquinefree base undergoes salt formation with
sulfuric acid to obtain the hydroxychloroquine sulfate. The
preparation method overcomes the disadvantages in the prior art,
and has the advantages that the useamount of the side chain is
reduced; the total yield is more than or equal to 90 percent;
the yield of the hydroxychloroquine sulfate is more than or
equal to 96 percent; the total yield is more thanor equal to 86
percent; the purity of the hydroxychloroquine sulfate is more
than 99. 7 percent; and the single impurity is less than 0.1
percent. The preparation method meets the pharmacopoeia
requirements and is short in reaction time, easy and convenient
to operate, low in pollution, low in cost and suitable for
industrial production.
[0001] Technical field
[0002] The invention belongs to the field of medicine and
chemical technology, and specifically designs a medicine for
treating discoid lupus erythematosus and systemic lupus
erythematosus - hydroxychloroquine sulfate.
[0003] Background technique
[0004] Hydroxychloroquine Sulfate (HCQ) is chemically known as
2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]-ethanol
sulfate, CAS No. 747-36- 4. The chemical structure is as
follows:
[0005]
[0006] Hydroxychloroquine sulfate was successfully developed by
Winthrop and first listed in the United States in 1956. It was
later listed in France, Denmark, Japan, Germany, Finland and
other countries and regions. On May 29, 1998, the US FDA
approved hydroxychloroquine sulfate tablets for the treatment of
lupus erythematosus and rheumatoid arthritis.
[0007] US 2,546,658 discloses a process for the synthesis of
hydroxychloroquine sulfate, the process of which is as follows:
[0008]
[0009] The patent was published in 1951, the process is
relatively backward, the use of phenol as a solvent, phenol
pollution is large, phenol-containing wastewater is a kind of
pollution in industrial wastewater, and phenol is solid at room
temperature, must be heated into liquid to produce, The
operation is cumbersome, the recovery is difficult, the
post-processing difficulty is increased, the yield is low, less
than 20%, and the product is difficult to handle, and is not
suitable for industrial production.
[0010] CA2561987 discloses a process for preparing
hydroxychloroquine sulfate, the reaction process of which is as
follows:
[0011]
[0012] The method comprises the steps of sequentially adding
isopropanol, hydroxychloroquine side chain,
4,7-dichloroquinoline, stirring, slowly heating, slowly
distilling off isopropanol, stirring at 120-130 ° C for 20-24 h,
then cooling to 70-80 Add water and methyl isobutyl ketone,
adjust the pH to above 10, separate the liquid, add acetic
anhydride at room temperature and stir overnight, then add
lithium hydroxide monohydrate, water and methanol, stir again at
room temperature overnight, and wash the organic phase again
with water. Once, methanol and sulfuric acid are added to the
organic phase, and the mixture is filtered with salt to obtain
crude hydroxychloroquine sulfate. The crude product is added to
water and methyl isobutyl ketone, stirred and dissolved, and the
pH is adjusted to 10-11 by adding sodium hydroxide. The liquid
phase is separated, and the organic phase is washed with brine,
decolorized by adding activated carbon, filtered, and the
filtrate is evaporated to obtain hydroxychloroquine free base,
and salt is formed with concentrated sulfuric acid in an
anhydrous alcohol to obtain a hydroxychloroquine sulfate
product. The purification process of the method is cumbersome,
the route is long, the waste water and the waste solid amount
are large, and it takes two steps to form salt, which takes a
long time and is not suitable for process production.
[0013] WO2010027150 discloses a method for synthesizing
hydroxychloroquine sulfate, the reaction route of which is as
follows:
[0014]
[0015] The method comprises adding 4,7-dichloroquinoline, a
hydroxychloroquine side chain to an autoclave, pressurizing with
nitrogen or argon to 5-20 bar, and reacting at 100-120 ° C for
4-6 hours. After the reaction was completed, hydrochloric acid
was added to adjust the acidity, and impurities were extracted
by chloroform extraction. The aqueous phase was adjusted with
alkali and then extracted with chloroform. The chloroform was
evaporated, crystallised from dichloroethane, and concentrated
sulfuric acid was added under anhydrous ethanol to obtain
hydroxychloroquine sulfate. The reaction involves high pressure,
and there are certain safety hazards. The alkalization loss is
large after acidification first, and chloroform is a second type
solvent. Dichloroethane is a kind of solvent and should be
controlled.
[0016] CN103724261A discloses an industrial process for the
production of hydroxychloroquine sulfate:
[0017]
[0018] The method comprises: under nitrogen protection,
4,7-dichloroquinoline is directly condensed with a
hydroxychloroquine side chain at a high temperature for 13-24
hours, then acidification and impurity removal, alkalization
extraction, crystallization to obtain hydroxychloroquine free
base, and then Hydrolysis with concentrated sulfuric acid in an
alcohol solution gives hydroxychloroquine sulfate. The method is
directly mixed and heated by a solvent-free method, and
impurities of side chain dehydration polymerization are easily
generated during the reaction, and 4,7-dichloroquinoline is
easily sublimed at a high temperature, and heating for a long
time causes 4,7-dichloroquinoline from the reaction system.
Sublimation in the middle, affecting the yield, after the end of
the reaction, it is necessary to first adjust the acid, then
alkalized, the operation is cumbersome, the waste water and
waste solid amount are large, and the operation is cumbersome,
and is not suitable for industrial production.
[0019] CN102050781 discloses a process for preparing
hydroxychloroquine sulfate. Similar to CA2561987, it is
necessary to slowly distill off the reaction solvent, and it is
necessary to control the distillation temperature and time, the
reaction requires a large amount of solvent, and the temperature
control process and the solvent are precisely controlled in
industrial production. The steaming process is more difficult.
[0020] CN104230803 discloses an industrial preparation method of
hydroxychloroquine sulfate. The condensation reaction of
4,7-dichloroquinoline with hydroxychloroquine side chain is
carried out by distilling off the solvent under the catalysis of
sodium alkoxide. Under high temperature conditions, sodium
alkoxide will undergo nucleophilic substitution with
4,7-dichloroquinoline to form an ether product, which is
difficult to remove, affecting the purification of
hydroxychloroquine free base, and the alcoholic hydroxyl group
on the side chain is in sodium alkoxide. In the presence of
hydroxy anion, 4,7-dichloroquinoline produces by-products, which
makes purification difficult, and the reaction should control
the temperature rising process and solvent evaporation rate, and
the operation is difficult.
[0021] In the preparation method of the above-disclosed
hydroxychloroquine sulfate, there are disadvantages, so it is
necessary to find an industrial preparation method which is
simple in operation, high in efficiency, high in yield and high
in quality, and environmentally friendly.
[0022] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a high
performance liquid chromatogram of hydroxychloroquine sulfate.
[0023] Summary of the invention
[0024] The invention relates to a novel preparation method of
hydroxychloroquine sulfate, which is prepared by dissolving
4,7-dichloroquinoline and hydroxychloroquine side chain under
the protection of an inert gas in a substituted benzene or other
strong polar solvent and heating and condensing under heating.
After crystallization, hydroxychloroquine free base is obtained,
and then salt is formed with sulfuric acid to obtain
hydroxychloroquine sulfate. The reaction route is as follows:
[0025]
[0026] 1.The shielding gas may be nitrogen, argon or helium,
preferably nitrogen.
[0027] 2.The mass ratio of 4,7-dichloroquinoline to the side
chain is 1:1-1.2.
[0028] 3.The catalyst is a self-made alumina-supported fluoride
salt: wherein the fluorine salt may be an organic fluoride salt
or an inorganic fluoride salt, and is selected from the group
consisting of sodium fluoride, potassium fluoride, cesium
fluoride, etc., and potassium fluoride is preferred.
[0029] 4.The reaction solvent may be a substituted benzene such
as toluene, chlorobenzene or xylene, or an aprotic strong polar
solvent such as dimethyl sulfoxide or N,N-dimethylformamide. The
solvent is used in an amount of from 3 times to 5 times the
amount of 4,7-dichloroquinoline. The reaction temperature is
100-150 degrees and the reaction time is 4-12 hours.
[0030] 5.The hydroxychloroquine free base can be purified by
crystallization using an acetate, and may be selected from ethyl
acetate, isopropyl acetate, n-butyl acetate, and preferably
ethyl acetate.
[0031] 6.Hydroxychloroquine free base is salted with sulfuric
acid in an aqueous alcohol solution to obtain hydroxychloroquine
sulfate. The alcohol may be selected from the group consisting
of methanol, ethanol, and propanol. The alcohol concentration
may be 60% to 75%, and the salt formation temperature may be
0-20. Degree, the reaction time can be 8~12h.
[0032] The advantages of the invention are as follows:
[0033] 1. The amount and type of organic solvent used in the
reaction are reduced, the cost is reduced, and environmental
friendliness is improved.
[0034] 2. Avoid the use of toxic catalysts, atmospheric
reactions, and shorten the reaction time
[0035] 3. High yield, simple post-treatment, simple operation
steps, suitable for industrial production
[0036] 4. The salt formation process uses controlled
crystallization to avoid inclusion of impurities.
[0037] 5. The hydroxychloroquine yield obtained by the invention
is ≥90%, the liquid phase purity is ≥99.7%, the
hydroxychloroquine sulfate yield is ≥96%, the total yield is
≥86%, the hydroxychloroquine sulfate purity is greater than
99.7%, the single impurity is less than 0.1%, the melting point
It is 239 ° C ~ 240 ° C. Both yield and purity are high, which
in turn reduces production costs and pollution control costs.
[0038] The industrial preparation method of hydroxychloroquine
sulfate of the present invention is further illustrated and
explained below by way of examples without limiting the scope of
the invention.
[0039] Example 1: Preparation of Alumina Supported Potassium
Fluoride
[0040] 10 g of anhydrous potassium fluoride, 30 g of 200-mesh
alumina powder was dissolved in 100 ml of water, ultrasonically
stirred at 50 Hz for 45 min, and dried under reduced pressure at
55 ° C to obtain a solid powder, which was vacuum dried at 120 °
C for 8 hours, and then ground to a powder. Thereafter, 40 g of
a catalyst was obtained.
[0041] Example 2: Preparation of Alumina Supported
Tetrabutylammonium Fluoride
[0042] 40 g of tetrabutylammonium fluoride, 40 g of 200-mesh
alumina powder was dissolved in 100 ml of water, ultrasonically
stirred at 50 Hz for 45 min, and the water was evaporated to
dryness under reduced pressure at 55 ° C to obtain a solid
powder, which was vacuum dried at 130 ° C for 8 hours, and then
ground into Powder, 80 g of catalyst was obtained.
[0043] Example 3: Preparation of alumina supported cesium
fluoride
[0044] 10 g of cesium fluoride, 20 g of 200-mesh alumina powder,
dissolved in 100 ml of water, ultrasonically stirred at 50 Hz
for 1 hour, and dried under reduced pressure at 55 degrees to
obtain a solid powder, dried under vacuum at 100 degrees for 4
hours, and then ground to a powder. , 30 g of catalyst was
obtained.
[0045] Example 4: Preparation of hydroxychloroquine free base
[0046] 1 kg of 4,7-dichloroquinoline, 1 kg of hydroxychloroquine
side chain, 1.8 kg of potassium fluoride supported by alumina,
dissolved in 5 kg of toluene, heated to 110-120 ° C, reacted for
12 h, completely detected by TLC, cooled, evaporated to dryness
Toluene, 5 kg of ethyl acetate was added, and the mixture was
heated to reflux. The mixture was filtered while stirring, and
the filtrate was stirred and cooled for 3 hr. and filtered, and
the filter cake was washed twice with ethyl acetate and dried to
give 1.6 g of hydroxychloroquine free base, yield 94%. The
purity is 99.7%, and the melting point is 89-90 °C.
[0047] Example 5: Preparation of hydroxychloroquine free base
[0048] 1 kg of 4,7-dichloroquinoline was dissolved in 3 kg of
dimethyl sulfoxide, 3.5 kg of alumina-supported cesium fluoride
was added, heated to 125 degrees, stirred for 4 hours, cooled to
50-60 ° C, and hydroxychloroquine was added. 1.2kg side chain,
raised to 125 ° C, heated for 8 hours, cooled to room
temperature, suction filtration, 15kg water was added to the
filtrate, extracted with 3kg of dichloromethane three times,
evaporated to dryness, added with 3kg of isopropyl acetate and
stirred to obtain hydroxychloroquine free The base is 1.55 kg,
the yield is 91.39%, the purity is 99.5%, and the melting point
is 87-89 °C.
[0049] Example 6: Preparation of hydroxychloroquine free base
[0050] 1 kg of 4,7-dichloroquinoline, 1 kg of hydroxychloroquine
side chain, dissolved in 5 kg of chlorobenzene, 3.96 kg of
alumina-supported tetrabutylammonium fluoride, heated under
reflux for 12 hours, completely detected by TLC, cooled, steamed
Dry chlorobenzene, adding 5 kg of ethyl acetate, heating under
reflux, hot suction filtration, the filtrate was stirred and
cooled to 30 °C, stirring was continued for 3 hours, suction
filtration, the filter cake was washed twice with ethyl acetate,
and dried to give hydroxychloroquine free base 1.59 kg, yield
93.75%, purity 99.6%, melting point 87-90 ° C.
[0051] Example 7: Preparation of hydroxychloroquine sulfate
[0052] 1 kg of hydroxychloroquine free base was dissolved in 5 L
of 70% ethanol, cooled to 0-5 ° C, and 0.32 kg of concentrated
sulfuric acid was added dropwise. After the completion of the
dropwise addition, stirring was continued for 1 hour, and the
mixture was stirred at room temperature for 12 hours. The
crystals were slowly precipitated and suction filtered. The
filter cake was washed once with 70% ice ethanol and dried to
give 1.24 kg of white crystals.
[0053] Example 8: Preparation of hydroxychloroquine sulfate
[0054] 1 kg of hydroxychloroquine free base was dissolved in 5 L
of 75% methanol, cooled to 0-5 degrees, and 0.32 kg of
concentrated sulfuric acid was added dropwise. After the
completion of the dropwise addition, stirring was continued for
1 hour, and the mixture was stirred at room temperature for 10
hours. The crystals were slowly precipitated and suction
filtered. The filter cake was washed once with 75% ice methanol
and dried to give 1.25 kg of white crystals.
[0055] Example 9: Preparation of hydroxychloroquine sulfate
[0056] 1 kg of hydroxychloroquine was dissolved in 5 L of 60%
isopropanol, cooled to 0-5 degrees, and 0.32 kg of concentrated
sulfuric acid was added dropwise. After the completion of the
dropwise addition, stirring was continued for 1 hour, and the
mixture was stirred at room temperature for 12 hours. The
crystals were slowly precipitated and suction filtered. The
filter cake was washed once with 60% ice isopropanol and dried
to give 1.23 kg of white crystals.
WO2010027150
NEW PREPARATION OF HYDROXYCHLOROQUINE
[ PDF ]
Abstract
The present invention provides a process for the preparation
of hydroxychloroquine by the reaction of 4,7-dichloroquinoline
with N'-ethyl-N'-ß-hydroxyethyl-1,4-pentadiamine under high
pressure.
Hydroxychloroquine, which is
2-[[4-[7-chloro-4-quinolinyl]amino]pentyl]-ethylamino]ethanol
and has a structure of the following formula (1), was first
disclosed in US Patent No. 2,546,658. This US patent teaches a
process for preparing hydroxychloroquine diphosphate, which
involves reacting 4,7-dichloroquinoline of the following formula
2 with N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine of the
following formula 3 in the presence of potassium iodide (KI) and
phenol at a temperature of 125 to 130℃ for 18 hours or more to
thereby prepare crude hydroxychloroquine to which diphosphate is
then attached to obtain hydroxychloroquine diphosphate with a
yield of 35% (see Reaction Scheme 1 below).
[Reaction Scheme 1]
US Patent No. 5,314,894 discloses a process for preparing
(S)-(+)-hydroxychloroquine wherein 4,7-dichloroquinoline and
(S)-N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine with
N,N-diisopropylethylamine (b.p 127℃ were heated at reflux for 48
hours to obtain (S)-(+)-hydroxychloroquine with a yield of 46%.
Further, CA Patent No. 2,561,987 teaches a process for preparing
hydroxychloroquine, which involves reacting
4,7-dichloroquinoline (2) with
N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine (3) at a temperature
of 120 to 130℃ for 20 to 24 hours, and introducing a protective
group, as illustrated below, to the reaction product so as to
facilitate the removal of impurities, followed by hydrolysis of
the protective group to obtain a desired product
hydroxychloroquine.
In formulae A, B, C, each PG represents a protective group.
However, with currently known methods of preparing
hydroxychloroquine and its acid addition salts, there is a
difficulty in elimination of undesirable byproducts upon the
preparation of acid addition salts, due to using a toxic solvent
such as phenol or a reagent such as N,N-diisopropylethylamine,
which has a high boiling point and a structure similar to that
of the final product. Particularly, a long reaction time at high
temperatures may result in increased production costs and
buildup of byproducts, for which a higher-efficiency synthesis
method of hydroxychloroquine and disulfate is required in
related industrial fields.
To this end, there is a need for the development of a novel
method of synthesizing hydroxychloroquine, which is capable of
overcoming a variety of problems and disadvantages as discussed
above and is capable of providing a desired product with higher
purity and yield.
The present invention is intended to provide a novel method for
preparing hydroxychloroquine, which is capable of inhibiting the
formation of byproducts and decreasing production costs by
significantly decreasing a reaction temperature and a reaction
time using a certain pressure, without a catalyst and a reaction
solvent.
The present invention provides a novel method for preparing
hydroxychloroquine using a pressure, which comprises reacting
4,7-dichloroquinoline with
N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine under high pressure
to obtain hydroxychloroquine of the formula:
That is, the method of the present invention provides the
preparation of hydroxychloroquine by the reaction of
4,7-dichloroquinoline with
N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine without use of a
catalyst and a solvent.
As used herein, the term "high pressure" refers to a more
greater pressure than atmospheric pressure(1 atm, about 1 bar),
which is preferably in the range of 5 to 30 bars and more
preferably 10 to 20 bars.
In the context of the present invention, the high pressure is
exerted by an inert gas such as nitrogen (N 2 ) or argon (Ar)
gas or by moisture-free air.
The reaction time is preferably within 10 hours and more
preferably 6 hours.
The reaction temperature is preferably in the range of 100 to
120℃, although it may vary.
A reaction molar ratio of 4,7-dichloroquinoline and
N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine is preferably in the
range of 1:1.05 to 1.5 and more preferably 1:1.05 to 1.1,
although it may vary.
Further, the present invention provides a process for preparing
hydroxychloroquine sulfate, comprising:
(a) reacting 4,7-dichloroquinoline with
N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine under high pressure
to obtain hydroxychloroquine of the formula:
; and
(b) reacting the hydroxychloroquine of Step (a) with sulfuric
acid (H 2 SO 4 ) to obtain hydroxychloroquine sulfate.
Here, reaction conditions for Step (a) are as defined above.
The preparation process of hydroxychloroquine according to the
present invention will be described in greater detail
hereinafter.
The process is carried out as follows. First,
4,7-dichloroquinoline and
N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine in a molar ratio of
1:1.1 were placed into a high pressure reactor. Internal
pressure of the reactor is then adjusted to the range of 5 to 20
bars and preferably 10 to 15 bars by nitrogen pressure. The
reactor is stirred at 80℃ for 30 min until 4,7-dichloroquinoline
is completely dissolved, followed by further stirring at a
temperature of 100 to 120℃ for 4 to 6 hours.
The present invention enables the production of
hydroxychloroquine with high purity and high yield while
providing various advantages in that the formation of byproducts
is inhibited by decreasing a reaction temperature and
significantly decreasing a reaction time using a pressure
without use of a catalyst and a reaction solvent, and production
costs are reduced.
Now, the present invention will be described in more detail with
reference to the following Examples. These examples are provided
only for illustrating the present invention and should not be
construed as limiting the scope and spirit of the present
invention.
Reagents used in following examples are directly available from
Dae He Chemical Co., Ltd. (Korea) or otherwise is purchased from
Aldrich. All solvents are commercially available from Samsung
Fine Chemical Co., Ltd. (Korea).
Example 1: Preparation of hydroxychloroquine using pressure of
20 bars
10 kg of 4,7-dichloroquinoline and 11.4 kg (1.0 eq) of
N'-ethyl-N'-β -hydroxyethyl-1,4-pentadiamine were introduced
into a high pressure reactor which was then filled with nitrogen
gas to a pressure of 20 bars and stirred at 80℃ for 30 min,
followed by further stirring at 100 to 110℃ for 4 hours. The
reactor was cooled to a temperature of about 70 to 80℃. And then
30 kg of a 3N HCl aqueous solution and 20 kg of chloroform were
added thereto, and the mixture was cooled to room temperature,
stirred for 1 hour, and allowed to stand such that a desired
product was transferred to the aqueous layer while the remaining
byproducts were transferred to the chloroform layer(This
procedure was repeated three times). The aqueous layer
containing a desired compound was collected. The thus-collected
aqueous layer was extracted again with 40 kg of a 2N NaOH
aqueous solution and chloroform to remove the aqueous layer, and
5 kg of activated carbon and 5 kg of alumina was added thereto,
followed by stirring at 40℃ for 6 hours and filtration. The
filtrate was concentrated under reduced pressure and 60 kg of
ethylene dichloride (EDC) was added thereto to result in
crystallization. The resulting residue was were filtered and
dried under vacuum at 40℃ to afford 14 kg (yield: 78.2%) of the
title compound.
1 H NMR (500 MHz): δ(CDCl 3 ) 7.47(d), 7.92(d), 7.72(d),
7.33(dd), 6.38(d), 5.09(d), 3.50-3.80(m), 2.40-2.70(m),
1.50-1.80(m), 1.30(d), 1.00(t)
Example 2: Preparation of hydroxychloroquine (formula 1) using
pressure of 10 bars
10 kg of 4,7-dichloroquinoline and 11.4 kg (1.0 eq) of
N'-ethyl-N'-β-hydroxyethyl-1,4-pentadiamine were introduced into
a high pressure reactor which was then filled with nitrogen gas
to a pressure of 10 bars, and stirred at 80℃ for 30 min,
followed by further stirring at 100 to 110℃ for 6 hours. The
reactor was cooled to a temperature of about 70 to 80℃. And then
30 kg of a 3N HCl aqueous solution and 20 kg of chloroform were
added thereto, and the mixture was cooled to room temperature,
stirred, and allowed to stand such that a desired product was
transferred to the aqueous layer while the remaining byproducts
were transferred to the chloroform layer(This procedure was
repeated three times). The aqueous layer containing a desired
compound was collected. The thus-collected aqueous layer was
extracted again with 40 kg of a 2N NaOH aqueous solution and 20
kg of chloroform to remove the aqueous layer, and 5 kg of
activated carbon and 5 kg of alumina was added thereto, followed
by stirring at 40℃ for 6 hours and filtration. The filtrate was
concentrated under reduced pressure and 60 kg of EDC was added
thereto to result in crystallization. The resulting residue was
filtered and dried under vacuum at 40℃ to afford 14.5 g (yield:
75.5%) of the title compound.
1 H NMR (500 MHz) values of the obtained compound were identical
with those as in Example 1.
Example 3: Preparation of hydroxychloroquine sulfate
10 kg of hydroxychloroquine prepared in Example 1 was dissolved
in 100 kg of ethanol, and the solution was cooled to 10℃. A
solution of concentrated sulfuric acid (1.58 kg, 1.0 eq) in 50
kg of ethanol was slowly added thereto with stirring for 12
hours. The reaction solution was filtered to afford 11.0 kg
(85.2%) of the title compound as a white material.
1 H NMR (300 MHz): δ(D 2 O) 8.08(d), 7.95(d), 7.53(d), 7.35(dd)
6.64(d), 3.94(d), 3.60-3.70(m), 2.90-3.30(m), 1.50-1.80(m),
1.23(d), 1.09(t)
Example 4: Preparation of hydroxychloroquine sulfate
10 kg of hydroxychloroquine prepared in Example 1 was dissolved
in 100 kg of ethyl acetate, and a solution of concentrated
sulfuric acid (1.58 kg, 1.0 eq) in 50 kg of ethyl acetate was
slowly added thereto with stirring at 30℃. Thereafter, the
reaction solution was stirred at 0℃ for 12 hours and filtered to
afford 10.0 kg (77.5%) of the title compound as a white
material.
1 H NMR (500 MHz) values of the obtained compound were identical
with those as in Example 3.
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[ PDF ]
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[ PDF ]
Abstract
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method, 7-chloro-4-hydroxyquinoline is used as a raw material
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generate the 4,7-dichloroquinoline. The synthetic method
provided by the invention can effectively avoidthe use of
chlorinating agents unfriendly to the environment, such as
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pollution to the environment and the corrosion to equipment, and
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[ PDF ]
Abstract
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decarboxylation to produce 4-hydroxyl-7-chloroquinoline; and
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phosphorus oxychloride to obtain 4,7-dichloroquinoline crude
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