rexresearch1
Anaesthetics Syntheses
https://www.sciencedirect.com/topics/chemistry/lidocaine
Lidocaine
2-diethylamino-2′,6′-dimethylacetanilide
Lidocaine is a widely used local anesthetic that stabilizes cell membranes, blocks sodium channels, and is suitable for various clinical procedures such as dental operations and obstetrics.
Mechanism of Toxicity
The potency of lidocaine depends on various factors including age of the subject, weight, physique including obesity, vascularity of the site, and indication for use, as this would determine the absorption and excretion rate. Physiologically, lidocaine blocks neuronal transmission by interfering with the flow of sodium across excitable membranes. A single lidocaine molecule binds to a single voltage-gated sodium channel impeding the movement of sodium ions across neuronal membranes. Consequently repolarization is prevented and further depolarization is not possible. Toxicity is dose related and results from excessive quantities of lidocaine.
Lidocaine is a prototype of antiarrhythmic drugs of subgroup IB, and is widely used for treating and preventing ventricular ectopic activity during myocardial infarction.
Like procainamide, lidocaine is an amide with local anesthetizing action. Lidocaine is usually administered intravenously for short-term therapy of ventricular extrasystole, tachycardia, especially in the severe phase of myocardial infarction, arrhythmia of natural cause, and for arrhythmia that can originate in the heart during surgical manipulations. Synonyms of this drug are lidopen, xylocaine, xylocard, and others.
Toxicokinetics
Lidocaine is absorbed from the gastrointestinal tract but undergoes significant first-pass metabolism (60–70%). Absorption from local sites is dependent on the dose and vascularity of the site. It is well absorbed from mucosa. Lidocaine is widely distributed to tissues. The volume of distribution is ∼1 l kg−1. Protein binding is 60–80%. Lidocaine is dealkylated by hepatic CYP3A4 to the active metabolite monoethylglycinexylide, which is then inactivated to glycine xylidide. These metabolites and ∼5% of unchanged lidocaine are renally excreted. The elimination half-life is 1–2 h.
Lidocaine, 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide (2.2.2), is synthesized from 2,6-dimethylaniline upon reaction with chloroacetic acid chloride, which gives α-chloro-2,6-dimethylacetanilide (2.1.1), and its subsequent reaction with diethylamine [11].
Lidocaine is the most widely used local anesthetic. Its excellent therapeutic activity is fast-acting and lasts sufficiently long to make it suitable for practically any clinical use. It stabilizes cell membranes, blocks sodium channels, facilitates the secretion of potassium ions out of the cell, and speeds up the repolarization process in the cell membrane. It is used for terminal infiltration, block, epidural, and spinal anesthesia during operational interventions in dentistry, otolaryngology, obstetrics, and gynecology. It is also used for premature ventricular extrasystole and tachycardia, especially in the acute phase of cardiac infarction. Synonyms for this drug are xylocaine, neflurane, and many others.
Exposure Routes and Pathways
Local anesthetics, particularly benzocaine and lidocaine, are found in a number of topical mixtures for treatment of minor superficial pain. These may be found in both prescription and over-the-counter formulations. An adhesive patch that contains 5% lidocaine is available by prescription. This has been successfully used for treatment of focal tactile hyperalgesia, such as that seen in post-herpetic neuralgia. A eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) provides anesthesia for superficial procedures including venipuncture and some skin graft harvesting, but requires placement of an occlusive dressing and ∼60 min to reach full efficacy. Local anesthetics are commonly administered by focal infiltration to provide temporary loss of sensation for minor invasive procedures such as closure of a laceration with sutures. Mepivacaine is not effective for topical or infiltration anesthesia. If anesthesia is desired in a larger region, local anesthetics can be injected directly adjacent to major nerves or nerve roots such as is often performed for dental procedures and minor surgical procedures, especially on extremities, producing a nerve block. In addition, regional anesthesia in the lower leg and foot or lower arm and hand can be performed by administering intravenous lidocaine or prilocaine in a region that has been isolated from the general circulation by compressive exsanguination and application of a tourniquet. This is commonly known as a Bier's block. Injections into the spinal space, either epidurally or intrathecally are often used for peri- and post-operative pain, in addition to neuropathic pain states. With chronic pain states, delivery of local anesthetics with or without the addition of opiates via an implanted permanent intrathecal catheter and subcutaneous pump can provide a high degree of pain relief in selected patients. Low dose, intravenous lidocaine infusions have also been effective in treating some neuropathic pain states. Lidocaine can be used in the treatment of ventricular tachycardia or fibrillation. As will be discussed below, cardiovascular effects are an important toxicological consideration of lidocaine.
https://scholars.lmu.edu/en/publications/the-preparation-of-lidocaine
Journal of Chemical Education, Vol 76, Issue 11, November 1, 1999
The Preparation of Lidocaine
Thomas J. Reilly
In this experiment, which is intended for the introductory organic laboratory, the widely used local anesthetic Lidocaine is synthesized in two steps from 2,6-dimethylaniline. In the first step, the amine is acylated with chloroacetyl chloride. In the second step, the amide is subjected to nucleophilic substitution by diethylamine to give the final product with an overall yield of 71% based on 2,6-dimethylaniline. I have used this experiment in my organic class for several years with excellent results. Average students can isolate the crude product in less than three hours.
https://www.diva-portal.org/smash/get/diva2:1375278/FULLTEXT01.pdf
Synthesis of Lidocaine Revisited
Philip Josephson, et al.
...The “greenification” of the Lidocaine synthesis by the three students led to several green improvements of the standard procedure, for example, (1) decreased reaction temperature, (2) solvent replacement, (3) fewer equivalents of the starting material (diethylamine) by the use of an inorganic bulk base, (4) use of catalytic amounts of potassium iodide to promote the Finkelstein reaction, and (5) a two-step one-pot procedure. Furthermore, one of the developed procedures was successfully implemented in a full-scale organic chemistry laboratory course.
https://people.chem.umass.edu/mcdaniel/CHEM-267/Experiments/Lidocaine.pdf
The 2-Step Synthesis of Lidocaine
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https://home.sandiego.edu/~khuong/chem302L/Handouts/Lidocaine_handout_Su07.pdf
The Synthesis of Lidocaine
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https://pubs.acs.org/doi/10.1021/acs.jchemed.2c00143
Multicomponent Synthesis of Lidocaine at Room Temperature
Michelle Lee, et al.
A new undergraduate organic laboratory experiment has been developed and implemented for the Ugi three-component synthesis of the topical anesthetic lidocaine with excellent atom economy. Paraformaldehyde, diethylamine, and 2,6-dimethylphenyl isocyanide were combined and conveniently stirred at room temperature for a week in methanol with acetic acid. Students successfully collected their product by precipitation and filtration and then characterized it by NMR spectroscopy (1H, 13C, COSY, DEPT, HSQC), IR spectroscopy, mass spectrometry, and melting point analysis. Students also evaluated multiple lidocaine synthesis procedures using green chemistry principles and explored the reaction mechanisms of both traditional (N-acylation followed by N-alkylation) and multicomponent lidocaine syntheses. Results from both in-person and remote instruction versions of the experiment are included.
https://www.youtube.com/watch?v=9kteY5zUIhk
Synthesis of Lidocaine Lab
https://core.ac.uk/download/pdf/72732223.pdf
Research in the Teaching Laboratory: Improving the Synthesis of Lidocaine
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https://thesmartshoponline.com/product/lidocaine-hydrochloride-reagent-purity-99-9-25-grams/?gad_source=1&gclid=Cj0KCQjwyL24BhCtARIsALo0fSBQLXEhpCr5bvFot0hvYkc_PkPaLCfyc2KDxUCJlqhoq1ZJ4yWamMsaAtkUEALw_wcB
Lidocaine powder – Lidocaine HCl, reagent, purity 99.9%, 25 grams
https://www.youtube.com/watch?v=vuzqIsWFn3o
Lidocaine Preparation: Tips and Tricks for Preparing and Injecting a Local Block!
CN102060840
Preparation method of articaine hydrochloride
[ PDF ] [ PDF Translation ]
The invention discloses a preparation method of articaine hydrochloride. The method comprises the following steps: carrying out amidation reaction on 4-methyl-3-aminothiophene-2-methyl formate utilized as a raw material and 2-chloro propionyl chloride; then carrying out the ammoniation reaction with propylamine; and carrying out salification reaction with concentrated hydrochloric acid, thus obtaining the articaine hydrochloride. The invention has the following advantages: the process route of the preparation method is suitable for industrial production, the rigorous reaction conditions are avoided, raw materials are easy to obtain, the operation is simple, and the yield coefficient is high.
CN112521298A
Synthesis method of lidocaine
[ PDF ] [ PDF Translation ]
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and provides a method for synthesizing lidocaine, which comprises the steps of reacting 2, 6-dimethylaniline serving as a raw material with a 2- (diethylamino) -N, N-dialkyl acetamide compound III under acid catalysis, and carrying out acid dissolution and alkali precipitation and other treatments to obtain the lidocaine; the method has the advantages of simple reaction conditions, high utilization rate of raw materials, high product yield, high purity, and little environmental pollution, and is suitable for industrial production.
CN105294477A
Preparation method of lidocaine hydrochloride
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The invention provides a method for preparing lidocaine hydrochloride, and belongs to the technical field of anesthetic synthesis. The method comprises the following steps: by taking 2,6-xylenol as a raw material, Pd/C as a main catalyst and 2,6-dimethylcyclohexanone as a promoter, performing liquid phase amination with ammonia water at high temperature, thereby obtaining a midbody 2,6-dimethylaniline; enabling sodium methylate, 2,6-dimethylaniline and N,N-lignocaine methyl acetate as raw materials to react at 90-95 DEGC, distilling while reaction is performed to remove methanol till no methanol can be evaporated out, continuously reacting for 30 minutes, cooling to the room temperature, adding dichloroethane, washing with water, and leaving to stand to layer, thereby obtaining an organic layer, namely, a lidocaine based dichloroethane solution; further adding hydrochloric acid into the lidocaine based dichloroethane solution, adjusting the pH value to be 3.5-4 by using hydrogen chloride, adding activated carbon to reflux for 20-40 minutes, filtering, concentrating the filtrate, cooling, crystallizing, and dying, thereby obtaining lidocaine hydrochloride. The lidocaine hydrochloride prepared by using the method is simple in synthesis process and high
CN102070483B
Method for preparing lidocaine
[ PDF ] [ PDF Translation ]
Abstract
The invention provides a method for preparing lidocaine. The method comprises the following steps: using 2,6-dimethylaniline and chloroacetic chloride as raw materials to prepare an intermediate, namely acetyl chloride-2,6-dimethylaniline, and using the prepared intermediate and diethylamine to react and obtain lidocaine, wherein acetone is used as solvent and carbonate is used as catalyst in the reaction process. The method of the invention has simple synthetic technology and does not require the complicated step that the intermediate is washed with acid firstly and washed with base secondly in the post-treatment, thus avoiding unnecessary loss. Therefore, the yields of the intermediate and lidocaine prepared by the method are higher; and the prepared lidocaine has high purity which is more than 99%, and good industrial application prospect. In addition, the method of the invention uses acetone as solvent, thus the solvent is non-toxic basically and environmentally friendly, has no stimulation and can be recycled.
https://pubchem.ncbi.nlm.nih.gov/compound/Articaine-hydrochloride
Articaine Hydrochloride
Articaine Hydrochloride is the hydrochloride salt form of articaine, an amide-type local anesthetic. Articaine hydrochloride reversibly blocks nerve impulse conduction by binding to specific membrane sodium ion channels thereby interfering with the electrical excitation in the nerve, slowing the propagation of the nerve impulse and reducing the rate of rise of the action potential. This results in a loss of sensation at the injection site. Articaine hydrochloride is used for relief of pain in minor operations, usually in combination with the vasoconstrictor epinephrine.
A thiophene-containing local anesthetic pharmacologically similar to MEPIVACAINE.
CN102060840B
Preparation method of articaine hydrochloride
Abstract
[ PDF ] [ PDF Translation ]
The invention discloses a preparation method of articaine hydrochloride. The method comprises the following steps: carrying out amidation reaction on 4-methyl-3-aminothiophene-2-methyl formate utilized as a raw material and 2-chloro propionyl chloride; then carrying out the ammoniation reaction with propylamine; and carrying out salification reaction with concentrated hydrochloric acid, thus obtaining the articaine hydrochloride. The invention has the following advantages: the process route of the preparation method is suitable for industrial production, the rigorous reaction conditions are avoided, raw materials are easy to obtain, the operation is simple, and the yield coefficient is high.
CN106699724A
Method for recovering articaine hydrochloride or intermediate products thereof in self-synthetic mother liquor
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A technology for synthesizing articaine hydrochloride and mother liquor, applied to medical preparations containing active ingredients, pharmaceutical formulas, drug combinations, etc., can solve problems such as waste, high cost, and difficult processing, and achieve the effect of reducing waste
https://www.agd.org/docs/default-source/self-instruction-%28gendent%29/gendent_nd14_brockmann.pdf
Mepivacaine: a closer look at its properties and current utility
William G. Brockmann, DDS, PhD
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The use of mepivacaine in dentistry has remained strong since its introduction in the 1960s. It has retained its place as a valuable local anesthetic, either as a primary agent or as an alternative to lidocaine or articaine. Mepivacaine is commonly used in medically compromised patients—for whom elevations in blood pressure or heart rate are not advisable—in a formulation with a vasoconstrictor, or in pediatric populations in a formulation without a vasoconstrictor. Pharmacologically, these are the 2 groups most susceptible to side effects and toxicity, thus mepivacaine is commonly indicated. Most often the decision to use mepivacaine is based on its vasoconstrictor effect or lack thereof (depending on the formulation). However, the pharmacokinetics of mepivacaine are not well understood or assumed to be similar to that of other local anesthetics. It is important to understand the unique pharmacologic characteristics of mepivacaine in order to minimize the potential for inadvertent toxicity.
https://www.sciencedirect.com/topics/chemistry/mepivacaine
Mepivacaine
...Mepivacaine is N-(2,6-dimethylphenyl)-1-methyl-2-piperindincarboxam-ide (2.2.3). Two primary methods of synthesis have been suggested. According to the first, mepivacaine is synthesized by reacting the ethyl ester of 1-methylpiperindine-2-carboxylic acid with 2,6-dimethylanilinomagnesium bromide, which is synthesized from 2,6-dimethylaniline and ethylmagnesium bromide [12–14].
https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejoc.201700824
Synthesis of Mepivacaine and Its Analogues by a Continuous-Flow Tandem Hydrogenation/Reductive Amination Strategy
Nícolas S. Suveges, et al.
Abstract -- Herein we report a convenient, fast, and high-yielding method for the generation of the racemic amide anaesthetics mepivacaine, ropivacaine, and bupivacaine. Coupling of α-picolinic acid and 2,6-xylidine under sealed-vessel microwave conditions generates the intermediate amide after a reaction time of only 5 min at 150 °C. Subsequent reaction in a continuous-flow high-pressure hydrogenator (H-Cube ProTM) in the presence of the respective aldehyde directly converts the intermediate to the final amide anaesthetics in a continuous, integrated, multi-step ring-hydrogenation/reductive amination protocol. Merits and limitations of the protocol are discussed.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10875724/
Rapid production of the anaesthetic mepivacaine through continuous, portable technology
Pablo Díaz-Kruik a, Francesca Paradisi a,✉
Abstract
Local anaesthetics such as mepivacaine are key molecules in the medical sector, so ensuring their supply chain is crucial for every health care system. Rapid production of mepivacaine from readily available commercial reagents and (non-dry) solvents under safe conditions using portable, continuous apparatus could make an impactful difference in underdeveloped countries. In this work, we report a continuous platform for synthesising mepivacaine, one of the most widely used anaesthetics for minor surgeries. With a focus on sustainability, reaction efficiency and seamless implementation, this platform afforded the drug in 44% isolated yield following a concomitant distillation–crystallisation on a gram scale after N-functionalisation and amide coupling, with full recovery of the solvents and excess reagents. The use of flow chemistry as an enabling tool allowed the use of “forbidden” chemistry which is typically challenging for preparative and large scale reactions in batch mode. Overall, this continuous platform presents a promising and sustainable approach that has the potential to meet the demands of the healthcare industry.
CN103073483A
Preparation method of mepivacaine and optical enantiomer of mepivacaine
Abstract
[ PDF ] [ PDF Translation ]
The invention discloses a novel preparation method of mepivacaine and an optical enantiomer of the mepivacaine. The method comprises the steps of taking N-(2,6-dimethyl phenyl)-2-piperidinecarboxamide or an optical enantiomer thereof as a starting material, taking formaldehyde as a methylation reagent, stirring in formic acid at 60-100 DEG C for reaction, and obtaining the mepivacaine or the optical enantiomer thereof. The raw materials adopted with the method are commercially available, extensive and sufficient in source and low in price, reaction conditions of the method are mild, a process is simple, and the disadvantages that hazardous reagents such as dimethyl sulfate and sodium cyanoborohydride are used and anhydrous reaction conditions are required are avoided.