rexresearch.com

Gilberto CHIERICE
PhosphoEthanolamine vs Cancer


http://www.sciencemag.org/news/2016/04/brazil-president-signs-law-legalizing-renegade-cancer-pill

Brazil president signs law legalizing renegade cancer pill

By Herton Escobar

Responding to political pressure and popular demand for a largely untested cancer drug, Brazilian President Dilma Rousseff signed into law today a measure that allows the renegade compound—synthetic phosphoethanolamine—to be produced and sold legally as a cancer therapy in Brazil.

Scientists poured scorn on the decision, contending it puts patients at risk and undermines the authority of the Brazilian Health Surveillance Agency (the equivalent of the U.S. Food and Drug Administration) to regulate research and approval of new drugs based on internationally accepted safety and efficacy protocols. This was a “political decision inspired by a messianic surge of pseudoscience,” says Gustavo Fernandes, president of the Brazilian Society of Clinical Oncology in Brasília. “It was the worst possible way of dealing with this problem.”

The “cancer pill” sparked a national debate last year after Brazilian media carried testimonials of patients claiming that it relieved symptoms or even cured their cancer. The compound was developed in the early 1990s by Gilberto Chierice, an analytical chemist at the University of São Paulo whose lab distributed it to patients free of charge for several years, without any regulatory approval or clinical oversight.

Apart from a few studies in mouse models and in cell lines, there is no laboratory evidence that synthetic phosphoethanolamine works as a cancer drug. The university tried to shut down Chierice’s operation in June 2014, but since then more than 15,000 people sued the university, forcing it to continue providing them with the pills. Advocacy groups, meanwhile, pressured politicians and health authorities to legalize use of the compound as a cancer drug. Brazil’s congress passed a bill to do just that last month.

Officials in the ministries of health, industry, and science advised Rousseff to veto the bill, according to O Estado de S. Paulo newspaper. But with Rousseff fighting for her political life—the congress is attempting to impeach her over allegations of fiscal improprieties—her executive office recommended signing the bill, sources say.

The law authorizes production, prescription, and consumption of synthetic phosphoethanolamine as a cancer therapy “independently” of registration with the Brazilian Health Surveillance Agency. To acquire the pills, consumers must show medical proof that they have a malignant tumor and sign a consent form.

Under the new law, the substance can only be produced and distributed by “licensed agents.” On 1 April, the University of São Paulo closed Chierice’s former research lab, which had until then been producing the pills under court orders. The only place the compound is currently being produced is a private lab contracted by the São Paulo state government to supply it for an upcoming clinical trial. The lab is preparing the pills according to a formula patented by Chierice and six colleagues; they claim their preparation is different from the synthetic phosphoethanolamine available on the international market as a dietary supplement.  

Late last year, the science ministry committed to spending nearly $3 million on preclinical studies of synthetic phosphoethanolamine. Initial results, made public last month, were not promising. According to the experiments, conducted at four academic and private labs, the pills produced by Chierice’s group contained only 30% synthetic phosphoethanolamine, and the substance failed to kill cancer cells. It doesn’t appear to be toxic.

At a 5 April hearing in Brazil’s Federal Senate, Chierice charged that the government-sponsored studies are being done in “bad faith,” and stated that his group is obtaining clinical data from overseas. The University of São Paulo in 2015 lodged a complaint with the police accusing Chierice of “curandeirismo,” or illegally dispensing unproven medical treatments. A criminal investigation is underway, according to news reports. “Maybe [Chierice] was well intentioned, but he did a lot of wrongs,” Fernandes says.

The new law may please desperate cancer patients, but it’s an unfortunate move, says biochemist Luiz Fernando Lima Reis, research director at Hospital Sírio-Libanês in São Paulo, where high-profile politicians have been treated for cancer, including Rousseff in 2009 and former President Luiz Inácio Lula da Silva in 2011. “Decisions like this should be based on scientific evidence,” Reis says.


http://onlinenewsads.com/latest-news/discovery-rare-that-substance-to-cure-cancer-patients/

Phosphoethanolamine

...What substance is this? It is the combination of a very common substance used in many hair shampoos, called monoethanolamine, and phosphoric acid, which is a food preservative. The combination of these two compounds produces a substance called phosphoethanolamine, which is a marker of differentiated cells, which are considered cancer cells.

 As it acts in the body? This substance ourselves manufacture within the long muscle cells and liver endoplasmic reticulum. So we can not call it natural product because it is synthesized, but your body already makes for the same purpose: to defend you at all times of your life cells that differentiate.

In practice, this substance reinforces what we already have? How it acts in the cancer cell? First, it passes the digestive tract to the bloodstream, it goes to the liver and forms a reaction with the fatty acid. What is this fatty acid? It is the substance that is fed to the tumor. It tumor energy. And it goes along with this substance inside the cell. When she comes in, that cell is relatively still, ie the main organelle her, called mitochondria, is stopped. It forces the mitochondria to work and when it forces, it denounces to the immune system and the cell is settled, is called apoptosis…

Is there any contraindications? The capsule has to be ingested before the person to do chemotherapy? There is no “before” because it does not work as an adjunct. If you blow the immune system of the person, the results are not good because the action of fosfoamina requires that the immune system is intact. If there is no chemotherapy which destroys the immune system, perfect, may be combined. You have an idea of ​​how many people have benefited from this substance in the last 20 years? Lately we made about 50,000 capsules per month. This equates to 60 each person, 800 people or close to a thousand people a month. Now how many people have benefited I am not able to say because many of them, who were terminally ill, are there, alive. So I can not say how many people were healed. You published this study in several scientific journals. How many in total? Today I suppose there are nine to ten work in the best oncology journals in the world, which are international journals, along with the staff of the [Institute] Butantan, and explain the fosfoamina mechanism of action…



BRPI0800463
Fosfoetanolamina como precursor de fosfolipìdeo para correção de disfunções celulares e metabólicas


Inventor(s):     NETO SALVADOR CLARO; AL-ASFOUR SANDRA VASCONCELLOS; DE ALMEIDA MARCOS VINICIUS; MENEGUELO RENATO; CHIERICE GILBERTO ORIVALDO; REIMER ANTONIO JOSE

Que representa uma aplicação inovadora para um composto precursor de síntese de lipídeos, denominado fosfoetanolamina, o qual possui atividade de correção de disfunção celular e metabólica, incluindo atividades antiproliferativas, apoptóticas, neuroprotetora e antiepiléptica.



Related :
WO2015093588
ANTI-CANCER AGENT


Inventor(s):     NISHIZAKI TOMOYUKI [JP]; NAKANO TAKASHI [JP] +
Applicant(s):     KTN BIOTEC INC [JP] +
 
The present invention provides an anti-cancer agent containing 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine as an active ingredient, an agent to induce cell death, a protein phosphatase 2A activation potentiator, and a protein tyrosine phosphatase 1B activation potentiator, and the like.



WO 2008119146
CHEMICAL COMPOSITION IN MASS OF COMPOUND FOR THE TREATMENT OF BRONCHIAL ASTHMA..

The object of the invention is a composition for the treatment of bronchial asthma and chronic obstructive pulmonary disease, characterized in that the composition comprises phosphoethanolamine and Omega-3 folly acids in pre-established proportions. The preferred dose is 400 to 1200 mg/day, more specifically 800 mg/day for the phosphoethanolamine and 500 to 3200 mg/day, more specifically 1000 mg/day for the cicosapentaenoic acid 'EPA' and 350 to 2000 mg/day, more specifically 750 mg/day for the cocosahexaenoic acid 'DHA'.



https://www.facebook.com/PhosphoethanolamineSynthetic/info?tab=page_info

Phosphoethanolamine Synthetic - The Cancer cure

http://www.fosfo.etanolamina.com.br











USP 3644603
Method of Making 2-AminoEthylPhosphate


[ PDF ]



http://www1.folha.uol.com.br/internacional/en/scienceandhealth/2016/06/1777072-effectiveness-of-cancer-pill-disproved-in-new-test.shtml
06/01/2016

Effectiveness of 'Cancer Pill' Disproved in New Test

REINALDO JOSÉ LOPES


The hope in the therapeutic potential of phosphoethanolamine, the "cancer pill", suffered a new setback in tests sponsored by the federal government.

Mice and rats with cancer that received doses of the substance had no improvement - the tumors in the animals' organisms continued to grow.

Posted on the website of the Ministry of Science, Technology, Innovation and Communications (MCTIC, in its Portuguese acronym), the results add to other evidence that "phospho", as it is called, may not have a good performance against cancer.

Until now, the only positive result was the indication that phosphoethanolamine would not be toxic even when ingested at relatively high concentrations.

The data have been challenged by researchers who work with the substance, led by chemist Gilberto Chierice, a retired professor at the University of São Paulo.

Chierice and colleagues as Durvanei Augusto Maria, of Butantan Institute, argued that the concentration of "phospho" used in the in vitro tests were much lower than those employed in their own studies, and that the individual's metabolism as a whole (and not single cells) would be necessary for the pill to work.

The team published some studies showing anti-tumor effects of "phospho", both in vitro and in vivo (in live animals), involving different types of tumor.

Folha tried to speak to the researchers that vouch for the benefits of phospho, but they did not answer until the conclusion of this edition.



https://www.mpbio.com/product.php?pid=05217802&country=223


05217802 MP BIOMEDICALS

o-PHOSPHOETHANOLAMINE

White Crystalline Powder
Synonyms O-Phosphorylethanolamine, 2-Aminoethyl dihydrogen phosphate, O-Phosphocolamine, Colaminephosphoric acid

CAS Number 1071-23-4
Molecular Formula C2H8NO4P
Molecular Weight 141.06
Beilstein Registry Number 1758916
EC Number 213-988-5
MDL Number MFCD00008178

Properties
Keywords     Glycerolipid Metabolism, Lipid, Lipid Library, Lipids and Related Products, Metabolic Libraries, Metabolic Pathways, Metabolomics, Research Essentials
Product Type     Biochemicals
Biochemical Category     Organophosphorus
Chemical Class     Organophosphorus
Melting Point     245 °C(Lit.)



http://www.sciencemadness.org/talk/viewthread.php?tid=64374

 Phosphoethanolamine

Hi anyone have any information on the simple synthesis of phosphoethanolamine, because here in Brazil is much talked about for its anticancer properties.
View user's profile View All Posts By User      
It should be pretty easy to make. It's just the phosphoric acid mono-ester of monoethanolamine.

I'd say reflux monoethanolamine with a large excess of phosphoric acid for a couple hours, basify with sodium carbonate, then see what can be distilled off under vacuum. Or, extract it with some inorganic solvent.

Not sure though. Sigma calls for -20C as a storage temp. Could be unstable.

Boiling with phosphoric acid will not give any product. You need a specialized phosphorylating agent such as, for example, dibenzyphopshoryl chloride. There is a huge literature on this subject (phosphorylation reactions and reagents) and it is relatively easy to find and learn from.
 
Hi, i find the simple way, i see various syntheses with complex molecules, gold chloride, barium, etc. Already the largest university researchers have invented a process by the reaction of the two compounds(mea and phosphoric acid) in an alcoholic medium, washinhg with ethanol and heating at 190 degrees to transform phosphate in phospho and neutralization with calcium and magnesium carbonates with yeld of 90%. the problem is the details, here patents has no free access. [*] posted on 18-11-2015 at 05:28    

Well, phooey. For some reason I assumed phosphates were like borates. It does seem pretty straightforward with the right reagents though. All the preps in Brauer use POCl3 so they're kind of prohibitive for amateur use.

This paper has an interesting route:
http://www.sciencedirect.com/science/article/pii/S0040403908...
Facile synthesis of simple mono-alkyl phosphates.png - 8kB

The only difficult thing to get here is the pyridine.



http://www.tandfonline.com/doi/abs/10.3109/01485019708994876
Archives of Andrology: Journal of Reproductive Systems, Volume 38, Issue 3, 1997
DOI: 10.3109/01485019708994876
 
Synthesis of Ether Lipids and Phosphatidylethanolamine by Ejaculated Human Spermatozoa

E. Jones

Abstract

Ether lipids are the 1-O-alkyl derivatives of phospholipids. In contrast to nongerminal tissues where the plasma membrane content of ether lipids is low, over 40% of the phospholipids present in sperm plasma membranes are ether lipids. This study was undertaken to determine whether ejaculated human sperm could synthesize ether lipids either through reacylation of l-alkyl-jn-2-lysophos-phatidylcholine or through direct incorporation of 1-hexadecanol into diacyl phosphatidylcholine or diacyl phosphatidylethanolamine. The ability of sperm to reacylate l-acyl-jn-2-lysophosphatidyl-ethanolamine was also assessed. In these experiments, freshly ejaculated sperm were unable to reacylate a phosphocholine lyso ether lipid with either palmitic (16:0) or docosahexaenoic (22:6) acids. In contrast, sperm readily incorporated both 16:0 and 22:6 into 1-acyl lysophosphatidylethanolamine. Similarly, sperm freely incorporated 1-hexadecanol into diacyl phosphatidylethanolamine thus forming a 1-alkyl phosphoethanolamine ether lipid. Diacyl phosphatidylcholine could not serve as a substrate in this reaction. It is apparent, based on these data, that human spermatozoa can directly synthesize phosphoethanolamine ether lipids that may subsequently undergo exhaustive methylation to form phosphocholine ether lipids.



https://www.wikigenes.org/e/chem/e/1015.html
 2-aminoethoxyphosphonic acid 

Chemical Compound Review
CHEMBL146972     2-aminoethoxyphosphonic acid
Synonyms: CHEBI:17553, P0503_SIGMA, HMDB00224, ANW-43177, GEO-00129, ...
Pessi, G. et al., Bottazzi, B. et al., Menon, A.K. et al., Kennedy, E.P. et al., Fedde, K.N. et al., et al.  

 Table of contents


    Disease relevance of ethanolamine phosphate
    Psychiatry related information on ethanolamine phosphate
    High impact information on ethanolamine phosphate
    Chemical compound and disease context of ethanolamine phosphate
    Biological context of ethanolamine phosphate
    Anatomical context of ethanolamine phosphate
    Associations of ethanolamine phosphate with other chemical compounds
    Gene context of ethanolamine phosphate
    Analytical, diagnostic and therapeutic context of ethanolamine phosphate
 
Disease relevance of ethanolamine phosphate

    Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5'-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study [1].
    Unique modifications with phosphocholine and phosphoethanolamine define alternate antigenic forms of Neisseria gonorrhoeae type IV pili [2].
    The human lymphoma cell line MOLT-4 was also found to contain high levels of phosphocholine and phosphoethanolamine [3].
    Identification of sn-glycero-1-phosphate and phosphoethanolamine residues linked to the membrane-derived Oligosaccharides of Escherichia coli [4].
    Lipid A modifications in polymyxin-resistant Salmonella typhimurium: PMRA-dependent 4-amino-4-deoxy-L-arabinose, and phosphoethanolamine incorporation [5].

Psychiatry related information on ethanolamine phosphate

    Ethanolamine and phosphoethanolamine inhibit mitochondrial function in vitro: implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder [6].
    Phosphoethanolamine (PE) is a metabolite of the phospholipid metabolism which is decreased in Alzheimer's disease brain [7].

High impact information on ethanolamine phosphate

    We show that trypanosome GPIs can be labelled via CDP-[3H]ethanolamine or [beta-32P]CDP-ethanolamine in a cell-free system, indicating that phosphoethanolamine is acquired en bloc [8].
    GPI anchors are synthesized in the endoplasmic reticulum by stepwise glycosylation of phosphatidylinositol (via UDP-GlcNAc and dolichol-P-mannose) followed by the addition of phosphoethanolamine [8].
    (ii) The phosphoethanolamine and the phosphocholine head group conformation were found to be remarkably similar in pure lipid bilayers and in intact L-M cell membranes with the head group dipoles being oriented parallel to the membrane surface [9].
    S-Adenosyl-L-methionine:phosphoethanolamine N-methyltransferase (PEAMT; EC 2.1.1.103) catalyzes the key step in choline (Cho) biosynthesis, the N-methylation of phosphoethanolamine [10].
    Here, we describe in P. falciparum a plant-like S-adenosyl-l-methionine-dependent three-step methylation reaction that converts phosphoethanolamine into phosphocholine, a precursor for the synthesis of phosphatidylcholine [11].

Chemical compound and disease context of ethanolamine phosphate

    Ca2+-induced phosphoethanolamine transfer to the outer 3-deoxy-D-manno-octulosonic acid moiety of Escherichia coli lipopolysaccharide. A novel membrane enzyme dependent upon phosphatidylethanolamine [12].
    Pig-o knockout F9 embryonal carcinoma cells expressed very little GPI-anchored proteins and accumulated the same major GPI intermediate as the mouse class F mutant cell, which is defective in transferring phosphoethanolamine to the third mannose due to mutant Pig-f gene [13].
    Identification of a gene (lpt-3) required for the addition of phosphoethanolamine to the lipopolysaccharide inner core of Neisseria meningitidis and its role in mediating susceptibility to bactericidal killing and opsonophagocytosis [14].
    The increase of the 3.2 ppm peak in the glioma was found to result from the increase of taurine and phosphoethanolamine contents [15].
    We conclude that a dysfunction of the BBB, of a degree known to induce brain edema (10 mg of protamine sulfate), significantly increases the extracellular concentration of excitatory amino acids, GABA, taurine, and phosphoethanolamine in the extracellular space [16].

Biological context of ethanolamine phosphate

    A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation [11].
    Despite substantial ALP activity, in cell homogenates, toward the artificial substrate 4-methyl-umbelliferyl phosphate (4-MUP), there was a marked deficiency in ALP activity toward the natural substrates pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA), indicating altered substrate specificity [17].
    ATP analogs such as ADP and AMP exerted marked inhibitory effects on both [gamma-32P]ATP hydrolysis and ATP-initiated calcification by intact MVs, whereas phosphomonoesters such as beta-glycerophosphate or phosphoethanolamine had no effect [18].
    The N-methylation of phosphoethanolamine is the committing step in choline biogenesis in plants and is catalyzed by S-adenosyl-L-methionine:phosphoethanolamine N-methyltransferase (PEAMT, EC ) [19].
    The changes in gene expression were not due to a direct effect of beta-GP itself, because similar gene changes occurred in the presence of phosphoethanolamine, another agent which induces mineralization [20].

Anatomical context of ethanolamine phosphate

    Phosphoethanolamine as a growth factor of a mammary carcinoma cell line of rat [21].
    A possible role of phosphoethanolamine in the growth of mammary tumor cells as well as of normal mammary epithelial cells and other tissues is discussed [21].
    Phosphoethanolamine contents were significantly reduced at autopsy in frontal and occipital cortex, and in the substantia innominata [22].
    Both patients had subnormal serum alkaline phosphatase activity, absence of leukocyte alkaline phosphatase, increased amounts of urinary phosphoethanolamine, and normal levels of immunoreactive calcitonin and parathyroid hormone [23].
    Phosphocholine is synthesized in the cytosol by three successive S-adenosyl-Met-dependent N-methylations of phosphoethanolamine [24].

Associations of ethanolamine phosphate with other chemical compounds

    Serine, which is actively transported by Plasmodium from human serum and readily available in the parasite, is subsequently converted into phosphoethanolamine [11].
    After the higher doses the relative concentrations (in percentage of total phosphate as visible in the nuclear magnetic resonance spectrum) of phosphomonoesters (mainly phosphoethanolamine) and phosphocreatine also decreased in favor of Pi [25].
    Although the formation of CDP-ethanolamine is regarded as the rate-limiting step for phosphatidylethanolamine biosynthesis, choline was found to inhibit ethanolamine kinase, but did not have any effect on phosphoethanolamine cytidylyltransferase [26].
    The phosphoethanolamine residues are linked to position 6 of glucose units, as proved by the isolation of glucose 6-phosphate as a product of partial acid hydrolysis [4].
    Matrix-assisted laser desorption ionization/time of flight mass spectrometry of purified EV1 to EV6 indicated that these compounds were lipid A species substituted singly or in combination with palmitoyl, phosphoethanolamine, and/or aminodeoxypentose residues [27].

Gene context of ethanolamine phosphate

    Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol [28].
    Glycosylphosphatidylinositol biosynthesis defects in Gpi11p- and Gpi13p-deficient yeast suggest a branched pathway and implicate gpi13p in phosphoethanolamine transfer to the third mannose [29].
    Unlike the classical pentraxins CRP and SAP, PTX3 did not bind phosphoethanolamine, phosphocholine, or high pyruvate agarose [30].
    Isolation and characterization of ECT1 gene encoding CTP: phosphoethanolamine cytidylyltransferase of Saccharomyces cerevisiae [31].
    On the other hand, low-molecular-mass (monomeric or dimeric) AQN-3 and AWN-1 were the only spermadhesins retained in a phosphorylethanolamine affinity column [32].

Analytical, diagnostic and therapeutic context of ethanolamine phosphate

    Electrospray ionization-mass spectrometry analysis of the O-deacylated LOS oligosaccharide indicated a modification of the core structure characterized in part by a net loss in phosphoethanolamine [33].
    Using in vitro pH titration data to calculate intracellular pH, it was found that pH values from the phosphoethanolamine peak (pH 6.84 to 6.80) were lower than pH estimates from the inorganic phosphate peak (pH 7.22 to 6.99) [34].
    Superfusate aspartate, glutamate, phosphoethanolamine, taurine, and GABA were significantly elevated by cerebral ischemia, then declined during reperfusion [35].
    Significant perturbations in tissue phosphoethanolamine (3.84 delta resonance) content were evident at various time points during ischemia and postischemic recovery, which varied according to the perfusion conditions [36].
    L3,7,9 phosphoethanolamine (PEA) group-containing oligosaccharide-tetanus toxoid conjugates evoked high immunoglobulin G (IgG) antibody levels in rabbits which were detected by an L2-, L3,7,9-, and, depending on the antiserum, L1-specific enzyme-linked immunosorbent assay (ELISA) [37].

References

    Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5'-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study. Fedde, K.N., Whyte, M.P. Am. J. Hum. Genet. (1990)
    Unique modifications with phosphocholine and phosphoethanolamine define alternate antigenic forms of Neisseria gonorrhoeae type IV pili. Hegge, F.T., Hitchen, P.G., Aas, F.E., Kristiansen, H., Løvold, C., Egge-Jacobsen, W., Panico, M., Leong, W.Y., Bull, V., Virji, M., Morris, H.R., Dell, A., Koomey, M. Proc. Natl. Acad. Sci. U.S.A. (2004)
    Regulation of the cytidine phospholipid pathways in human cancer cells and effects of 1-beta-D-arabinofuranosylcytosine: a noninvasive 31P nuclear magnetic resonance study. Daly, P.F., Zugmaier, G., Sandler, D., Carpen, M., Myers, C.E., Cohen, J.S. Cancer Res. (1990)
    Identification of sn-glycero-1-phosphate and phosphoethanolamine residues linked to the membrane-derived Oligosaccharides of Escherichia coli. Kennedy, E.P., Rumley, M.K., Schulman, H., Van Golde, L.M. J. Biol. Chem. (1976)
    Lipid A modifications in polymyxin-resistant Salmonella typhimurium: PMRA-dependent 4-amino-4-deoxy-L-arabinose, and phosphoethanolamine incorporation. Zhou, Z., Ribeiro, A.A., Lin, S., Cotter, R.J., Miller, S.I., Raetz, C.R. J. Biol. Chem. (2001)
    Ethanolamine and phosphoethanolamine inhibit mitochondrial function in vitro: implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder. Modica-Napolitano, J.S., Renshaw, P.F. Biol. Psychiatry (2004)
    Inactivity of phosphoethanolamine, an endogenous GABA analog decreased in Alzheimer's disease, at GABA binding sites. Klunk, W.E., Debnath, M.L., McClure, R.J., Pettegrew, J.W. Life Sci. (1995)
    Phosphatidylethanolamine is the donor of the terminal phosphoethanolamine group in trypanosome glycosylphosphatidylinositols. Menon, A.K., Eppinger, M., Mayor, S., Schwarz, R.T. EMBO J. (1993)
    Structure and dynamics of the phosphatidylcholine and the phosphatidylethanolamine head group in L-M fibroblasts as studied by deuterium nuclear magnetic resonance. Scherer, P.G., Seelig, J. EMBO J. (1987)
    Silencing of phosphoethanolamine N-methyltransferase results in temperature-sensitive male sterility and salt hypersensitivity in Arabidopsis. Mou, Z., Wang, X., Fu, Z., Dai, Y., Han, C., Ouyang, J., Bao, F., Hu, Y., Li, J. Plant Cell (2002)
    A pathway for phosphatidylcholine biosynthesis in Plasmodium falciparum involving phosphoethanolamine methylation. Pessi, G., Kociubinski, G., Mamoun, C.B. Proc. Natl. Acad. Sci. U.S.A. (2004)
    Ca2+-induced phosphoethanolamine transfer to the outer 3-deoxy-D-manno-octulosonic acid moiety of Escherichia coli lipopolysaccharide. A novel membrane enzyme dependent upon phosphatidylethanolamine. Kanipes, M.I., Lin, S., Cotter, R.J., Raetz, C.R. J. Biol. Chem. (2001)
    Requirement of PIG-F and PIG-O for transferring phosphoethanolamine to the third mannose in glycosylphosphatidylinositol. Hong, Y., Maeda, Y., Watanabe, R., Inoue, N., Ohishi, K., Kinoshita, T. J. Biol. Chem. (2000)
    Identification of a gene (lpt-3) required for the addition of phosphoethanolamine to the lipopolysaccharide inner core of Neisseria meningitidis and its role in mediating susceptibility to bactericidal killing and opsonophagocytosis. Mackinnon, F.G., Cox, A.D., Plested, J.S., Tang, C.M., Makepeace, K., Coull, P.A., Wright, J.C., Chalmers, R., Hood, D.W., Richards, J.C., Moxon, E.R. Mol. Microbiol. (2002)
    In vivo, ex vivo, and in vitro one- and two-dimensional nuclear magnetic resonance spectroscopy of an intracerebral glioma in rat brain: assignment of resonances. Rémy, C., Arús, C., Ziegler, A., Lai, E.S., Moreno, A., Le Fur, Y., Décorps, M. J. Neurochem. (1994)
    Concentrations of amino acids in extracellular fluid after opening of the blood-brain barrier by intracarotid infusion of protamine sulfate. Westergren, I., Nyström, B., Hamberger, A., Nordborg, C., Johansson, B.B. J. Neurochem. (1994)
    Pseudohypophosphatasia: aberrant localization and substrate specificity of alkaline phosphatase in cultured skin fibroblasts. Fedde, K.N., Cole, D.E., Whyte, M.P. Am. J. Hum. Genet. (1990)
    Evidence of the presence of a specific ATPase responsible for ATP-initiated calcification by matrix vesicles isolated from cartilage and bone. Hsu, H.H., Anderson, H.C. J. Biol. Chem. (1996)
    cDNA cloning of phosphoethanolamine N-methyltransferase from spinach by complementation in Schizosaccharomyces pombe and characterization of the recombinant enzyme. Nuccio, M.L., Ziemak, M.J., Henry, S.A., Weretilnyk, E.A., Hanson, A.D. J. Biol. Chem. (2000)
    Deep zone articular chondrocytes in vitro express genes that show specific changes with mineralization. Sun, Y., Kandel, R. J. Bone Miner. Res. (1999)
    Phosphoethanolamine as a growth factor of a mammary carcinoma cell line of rat. Kano-Sueoka, T., Cohen, D.M., Yamaizumi, Z., Nishimura, S., Mori, M., Fujiki, H. Proc. Natl. Acad. Sci. U.S.A. (1979)
    Amino acids, glutathione, and glutathione transferase activity in the brains of patients with Alzheimer's disease. Perry, T.L., Yong, V.W., Bergeron, C., Hansen, S., Jones, K. Ann. Neurol. (1987)
    Heterogeneity of adult hypophosphatasia. Report of severe and mild cases. Weinstein, R.S., Whyte, M.P. Arch. Intern. Med. (1981)
    Maintaining methylation activities during salt stress. The involvement of adenosine kinase. Weretilnyk, E.A., Alexander, K.J., Drebenstedt, M., Snider, J.D., Summers, P.S., Moffatt, B.A. Plant Physiol. (2001)
    Murine mammary tumor response to hyperthermia and radiotherapy evaluated by in vivo 31P-nuclear magnetic resonance spectroscopy. Sijens, P.E., Bovée, W.M., Seijkens, D., Koole, P., Los, G., van Rijssel, R.H. Cancer Res. (1987)
    Choline regulates phosphatidylethanolamine biosynthesis in isolated hamster heart. Zelinski, T.A., Choy, P.C. J. Biol. Chem. (1982)
    Lipid A modifications characteristic of Salmonella typhimurium are induced by NH4VO3 in Escherichia coli K12. Detection of 4-amino-4-deoxy-L-arabinose, phosphoethanolamine and palmitate. Zhou, Z., Lin, S., Cotter, R.J., Raetz, C.R. J. Biol. Chem. (1999)
    Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol. Hong, Y., Maeda, Y., Watanabe, R., Ohishi, K., Mishkind, M., Riezman, H., Kinoshita, T. J. Biol. Chem. (1999)
    Glycosylphosphatidylinositol biosynthesis defects in Gpi11p- and Gpi13p-deficient yeast suggest a branched pathway and implicate gpi13p in phosphoethanolamine transfer to the third mannose. Taron, C.H., Wiedman, J.M., Grimme, S.J., Orlean, P. Mol. Biol. Cell (2000)
    Multimer formation and ligand recognition by the long pentraxin PTX3. Similarities and differences with the short pentraxins C-reactive protein and serum amyloid P component. Bottazzi, B., Vouret-Craviari, V., Bastone, A., De Gioia, L., Matteucci, C., Peri, G., Spreafico, F., Pausa, M., D'Ettorre, C., Gianazza, E., Tagliabue, A., Salmona, M., Tedesco, F., Introna, M., Mantovani, A. J. Biol. Chem. (1997)
    Isolation and characterization of ECT1 gene encoding CTP: phosphoethanolamine cytidylyltransferase of Saccharomyces cerevisiae. Min-Seok, R., Kawamata, Y., Nakamura, H., Ohta, A., Takagi, M. J. Biochem. (1996)
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BRPI0800460
nova metodologia de sìntese da fosfoetanolamina na forma sólida com cálcio, magnésio e zinco e na forma de solução com monoetanolamina

Inventor(s):     NETO SALVADOR CLARO; CHIERICE GILBERTO ORIVALDO; REIMER ANTONIO JOSE; AL-ASFOUR SANDRA VASCONCELLOS; RIBEIRO OTAVIANO MENDONCA JR; MENEGUELO RENATO; DE ALMEIDA MARCOS VINICIUS +

NEW METHODOLOGY synthesis phosphoethanolamine in solid form with calcium, magnesium and zinc SOLUTION AND HOW TO MONOETHANOLAMINE. Using espeetroscopia vibrational techniques in the infrared and elemental analysis, and has a final yield of 90% being added to the pure crystal, calcium carbonate, magnesium and zinc, for complete neutralization of phosphoethanolamine in solid form, and where adding monoethanolamine for neutralization can be a strategy for obtaining a buffer may be used in cellular and metabolic disorders.



CN101974029
Method for preparing phosphorylethanolamine compound

Inventor(s):     HAIYAN HU; YUCHUAN LI; JINGLING CHANG +
 
The invention relates to a method for preparing a phosphorylethanolamine compound, which belongs to the technical field of biochemistry. The method comprises the following steps of: adding ethanolamine or ethanolamine solution into one of phosphorus pentoxide, the solution of phosphoric acid, phosphorus oxychloride or the solution of phosphorus oxychloride at a certain reaction temperature to form a reaction mixture; heating the reaction mixture for vacuum-drying by using a direct program to form phosphorylethanolamine or phosphorylethanolamine hydrochloride; and dissolving the reaction product into water in a certain amount and then adding ethanolamine or the ethanolamine solution, wherein the mass ratio of the reaction product to the water in the certain amount is 1:1-100.; As the water serves as a solvent, the method of the invention ensures high yield, vast raw material sources, low production cost, simple, safe and rational process, short production cycle and high purity of the prepared product, and avoids wastewater, waste gases and waste residues.

The present invention relates to a process for preparing the compound phosphoethanolamine, belonging to the technical field of biochemistry. At a certain temperature the reaction solution was added to ethanolamine or ethanolamine pentoxide, phosphoric acid, phosphorus oxychloride or phosphorus oxychloride in a solution to obtain a reaction mixture; and the reaction mixture was dried under vacuum through direct temperature program after the ethanolamine obtained ethanolamine phosphate or phosphoric acid chloride; the reaction can be first dissolved in a certain amount of water was then added a solution of ethanolamine or ethanolamine; the reaction mass with an amount of water in the ratio of 1 to 100. The present invention is a solvent with water, which has high yield, wide source of raw materials, low production cost, no waste, the process is simple and safe and reasonable, short production cycle, high purity of the product prepared.

TECHNICAL FIELD

The present invention relates to a process for preparing the compound phosphoethanolamine, belonging to the technical field of biochemistry.

Background technique

Phosphoethanolamine structured into ethanolamine phosphate (CAS: 1071-23-4), phosphoric acid diethanolamine (CAS: 6094-81-1) and triethanolamine phosphate (CAS: 29901-63-1). Wherein monoethanolamine phosphate dihydrogen phosphate, also known as 2-aminoethanol, 2-aminoethanol phosphate, amine phosphates, o- phosphoethanolamine, phosphoric acid, 2-ethyl-aminoethanol phosphate, phosphoric acid, cholestyramine, 2-aminoxy ethyl dihydrogen phosphate, phosphoric acid, cholestyramine, 2- hydroxyethylamine and phosphoric acid.

Ethanolamine phosphate compounds are widely used in the fields of biotechnology, medicine, etc., can also be used as feed additives, special lubricants. Synthetic methods and technology related ethanolamine phosphate compounds have been disclosed mainly phosphoric acid and ethanolamine, the first two were prepared with a solvent solution of a certain concentration, the two mixed in the reaction solvent and filtered to give ethanolamine phosphate Finally, in an organic solvent and then dehydrated to obtain a high temperature phosphoethanolamine; or phosphoric acid and ethanolamine in an aromatic hydrocarbon (e.g. benzene, toluene, xylene, etc.), bicyclic hydrocarbons, halogenated hydrocarbons and high-boiling ethers and ketones and other organic solvents, then azeotropic, in addition to the high temperature process water, etc. to obtain purified phosphoethanolamine, e.g. US 2,730,542; Tetrahedron Letters, (24), 1913-1916,1975; PL 196501, which reaction formula (1) below. The resulting presence of a single raw material, process complex, multi-step, long cycle, low yields (44% -80%), by-products, low purity, high cost, serious waste problems such above method.

[Image] formula (1)

In the two step reaction phosphoethanolamine large amount of solvent is required in both: the first reaction, ethanolamine phosphate precipitated in an organic solvent, while the reaction system in the lead, heavy metals such as inorganic ions are precipitated together with, resulting in impurities rich product, these impurities followed them into the subsequent reaction, and can not be directly removed in the second step reaction, the product quality decline, to improve the quality of the need to adopt further purification treatment such as activated carbon, increasing the cost and the amount of waste, while reducing the yield; the second reaction used in organic solvent impurities also enrichment in the final product, so that product quality to decline further. In addition, due to the production uses a lot of organic solvent, resulting in the production environment is poor, waste, high costs.

SUMMARY

Object of the present invention is to overcome the disadvantages of the prior art, a method for preparing a compound of ethanolamine phosphate, which has high yield, wide source of raw materials, low production cost, no waste, the process is simple and safe and reasonable, short production cycle, the the product prepared in high purity.

Object of the present invention is achieved by the following technical solutions.

A process for preparing ethanolamine phosphate compound of the present invention, wherein (2) the compound of formula phosphoethanolamine formula:

[Image]

Wherein, R1 is H or H2N-CH2-CH2, R2 is H or H2N-CH2-CH2, x is 1, 2 or 3;
Specific steps of the method are:

1) At a certain reaction temperature Ethanolamine (HOCH2CH2NH2) or ethanolamine was added to the reaction to obtain a reaction mixture;

2) The reaction mixture was temperature-programmed directly through vacuum dried to obtain ethanolamine or ethanolamine phosphate, phosphoric acid chloride;

Step 1) The reaction may be first dissolved in a certain amount of water was then added ethanolamine (HOCH2CH2NH2) or ethanolamine solution; the reaction mass with an amount of water in the ratio of 1 to 100;

Step a) of the reactants phosphorus pentoxide (the P2O5), phosphoric acid (of H3PO4) solution of phosphorus oxychloride (a POCl3) or phosphorus oxychloride (a POCl3) in a solution;
Solvent solution phosphoric acid (of H3PO4) or a high-boiling solvent is water, high-boiling solvent is preferably a ketone; phosphoric acid concentration (of H3PO4) solution of 1% to 85%;
Phosphorus oxychloride (a POCl3) solution, the solvent is an aromatic hydrocarbon, bicyclic hydrocarbon, a halogenated hydrocarbon of carbon atoms between 1 and 4, high-boiling ethers, high boiling ketones or carbon atoms in the ester of between 1 to 7, or a mixture thereof; wherein the aromatic hydrocarbon is preferably benzene, toluene or xylene; phosphorus oxychloride (a POCl3) solution concentration of 1% to 99%;

Step 1) ethanolamine in the solution, the solvent is an aromatic hydrocarbon, bicyclic hydrocarbon, a halogenated hydrocarbon of carbon atoms between 1 and 4, high-boiling ethers, high boiling ketones, carbon atoms between 1 and 7 carbon atoms, or an ester in an alcohol having 1 to 7 in between or a mixture thereof; wherein the aromatic hydrocarbon is preferably benzene, toluene or xylene; ethanolamine solution concentration of from 1% to 99%;

Step 1) The reaction is phosphorus pentoxide (the P2O5) when added phosphorus pentoxide (the P2O5) ethanolamine 1:2.0 to 6.0 molar ratio;
When step 1) is phosphoric acid reactant (of H3PO4) solution, the molar ratio of the added phosphoric acid (of H3PO4) ethanolamine is 1:1.0 to 3.0;
Step 1) as reactants in phosphorous oxychloride (a POCl3) or phosphorus oxychloride (a POCl3) solution, the molar ratio of phosphorus oxychloride was added (a POCl3) ethanolamine is 1:1.0 to 3.0;
Step 1) in a certain reaction temperature is -20 ~ 100 ° C;
Step 1) was added to the time of 5min to 72h;
Step 2) The temperature program in the range of -20 ~ 250 ° C, the heating time is 0.5 ~ 72h;
Step 2) the degree of vacuum dried in vacuo 0 ~ 101.18 * 10 <5> KPa.

Advantageous Effects


The present invention is a solvent with water, which has high yield, wide source of raw materials, low production cost, no waste, the process is simple and safe and reasonable, short production cycle, high purity of the product prepared.

detailed description


Below in conjunction with embodiments of the present invention is further described, but the scope of the present invention is not limited thereto.

Example 1

100After L autoclave, 50kg of water, heated to 80 ° C, 100% of phosphorus pentoxide was added 14.2 kg, and 12.2 kg of ethanolamine is added 100%, in addition to a vacuum degree of more water -0.098kPa 2 hours, then heated to 100 ° C, 120 ° C, 140 ° C, 160 ° C, 180 ° C, 200 ° C, respectively at a vacuum degree of vacuum than -0.098kPa 2 hours to remove water, and then pulverized and agglomerated at 160 ° C -0.098kPa degree of vacuum dried for more than 2 hours to give a white solid monoethanolamine phosphate powder 27.1kg, m.p. 236.6 ~ 237.6 ° C, yield 96%, purity ≥99.3%.

Example 2

1000L reaction kettle was added 85% phosphoric acid (of H3PO4) aqueous solution of 500kg, 100% at room temperature was added ethanolamine 265kg (61.05), the temperature rose to 80 ° C, at a vacuum degree of removal of water -0.098kPa than 2 hours, then warmed to 100 ° C, 120 ° C, 140 ° C, 160 ° C, 180 ° C, 200 ° C at a vacuum degree of vacuum to remove water -0.098kPa than 2 hours, respectively, after crushing the agglomerates to a vacuum degree of 160 ° C -0.098kPa dried over 2 hours, to give a white solid monoethanolamine phosphate powder 593kg, m.p. 239.8 ~ 242 ° C, 97% yield, 99.5% purity.

Example 3

100L reaction kettle was added 50% of a toluene solution of phosphorus oxychloride 61.4kg, and then 12.2 kg of ethanolamine is added 100%, the degree of vacuum at 80 ° C for 2 hours or more is -0.098kPa, then warmed to 100 ° C, 120 ° C, 140 ° C, 160 ° C, 180 ° C at a vacuum degree of -0.098kPa were maintained over two hours, an aqueous solution of hydrogen chloride in the exhaust gas was condensed, and then crushing the agglomerates to 160 ° C degree of vacuum -0.098kPa dried for 2 hours to give a phosphoric ethanolamine hydrochloride white solid powder 32.3kg, m.p. 247.5 ~ 248.9 ° C, yield 91%, purity ≥99.0%.

Example 4

10After L kettle was charged with 5.0kg of water, heated to 80 ° C, added 100% of phosphorus pentoxide (P2O5) 1.42kg, stir added 100% of ethanolamine 2.44kg (61.05), 100 ° C to remove water 2 hour, then heated 120 ° C, 140 ° C, 160 ° C, 180 ° C, 200 ° C, respectively at a vacuum degree of vacuum than -0.098kPa 2 hours to remove water, and then pulverized and agglomerated at 160 ° C in vacuo -0.098kPa drying degree than 2 hours, to give a white solid diethanolamine phosphate powder 3.46kg, 94% yield, purity ≥99.3%.

Example 5

10L reaction kettle was added 85% phosphoric acid (of H3PO4) aqueous solution of 2.3kg, was added 100% ethanolamine 2.44kg, the temperature rose to 60 ° C, at a vacuum degree of removal of water -0.098kPa than 2 hours, then warmed to 100 ° C , 120 ° C, 140 ° C, 160 ° C, 180 ° C, 200 ° C at a vacuum degree of vacuum to remove water -0.098kPa than 2 hours, respectively, after crushing the agglomerates to 160 ° C degree of vacuum of -0.098 kPa over 2 hours and dried to obtain a white solid diethanolamine phosphate powder 3.54kg, yield 96%, purity ≥99.0%.

Example 6

10L reaction kettle was added a 50% solution of phosphorus oxychloride in 3.07 kg of toluene, and then added ethanolamine 1.22kg 100%, the degree of vacuum at 80 ° C for 2 hours or more is -0.098kPa, then warmed to 100 ° C, 120 ° C, 140 ° C, 160 ° C, 180 ° C, 200 ° C at a vacuum degree of -0.098kPa were maintained over two hours, an aqueous solution of hydrogen chloride in the exhaust gas was condensed, and then crushing the agglomerates to 160 ° C vacuum degree -0.098kPa is dried for 2 hours to obtain dicalcium phosphate ethanol hydrochloride as a white solid powder 4.10kg, 93% yield, purity ≥98.0%.

Example 7


10After L autoclave, 4.0kg of water, heated to 80 ° C, phosphorus pentoxide is added 1.42kg 100%, 100% and then added ethanolamine 3.66kg, in addition to a vacuum degree of -0.098kPa more water for 2 hours, was heated to 100 ° C, 120 ° C, 140 ° C, 160 ° C, 180 ° C, 200 ° C, respectively at a vacuum degree of vacuum than -0.098kPa 2 hours to remove water to obtain phosphate triethanolamine 4.32kg, yield 95 %, purity ≥99.3%.

Example 8


10L reaction kettle was added 85% phosphoric acid (of H3PO4) aqueous solution of 2.50 kg, 100% at room temperature was added 3.97 kg of diethanolamine, the temperature rose to 60 ~ 80 ° C, at a vacuum degree of removal of water -0.098kPa than 2 hours, then warmed to 100 ° C, 120 ° C, 140 ° C, 160 ° C, 180 ° C, 200 ° C at a vacuum degree of vacuum, respectively, in addition to the above water -0.098kPa 2 hours to obtain a phosphate triethanolamine 4.77kg, 97% yield, purity ≥99.5%.