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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Pyritinol


Pyritinol.svg
ChemSpider 2D Image | pyritinol | C16H20N2O4S2
Pyritinol.png

Pyritinol

  • Molecular FormulaC16H20N2O4S2
  • Average mass368.471 Da

1098-97-1[RN]

1308

214-150-1[EINECS]

233-178-5[EINECS]

3,3′-[Dithiobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]

4-Pyridinemethanol, 3,3′-[dithiobis(methylene)]bis[5-hydroxy-6-methyl-

пиритинол[Russian][INN]

بيريتينول[Arabic][INN]

吡硫醇[Chinese][INN]

 Pyritinol, CAS Registry Number: 1098-97-1

CAS Name: 3,3¢-[Dithiobis(methylene)]bis[5-hydroxy-6-methyl-4-pyridinemethanol]

Additional Names: bis(4-hydroxymethyl-5-hydroxy-6-methyl-3-pyridylmethyl) disulfide; bis[(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)methyl] disulfide; dipyridoxolyldisulfide; pyridoxine-5-disulfide; pyrithioxin

Molecular Formula: C16H20N2O4S2, Molecular Weight: 368.47

Percent Composition: C 52.15%, H 5.47%, N 7.60%, O 17.37%, S 17.40%

Literature References: Prepn: Zima, Schorre, US3010966 (1961 to E. Merck); Iwanami et al.,Bitamin36, 122 (1967); J. Vitaminol.14, 321, 326 (1968). HPLC determn in urine: K. Kitao et al.,Chem. Pharm. Bull.25, 1335 (1977). Pharmacokinetics and metabolism: Darge et al.,Arzneim.-Forsch.19, 5, 9, (1969); Nowak, Schorre, ibid. 11. Clinical trial in dementia: S. Hoyer et al.,ibid.27, 671 (1977); A. J. Cooper, R. V. Magnus, Pharmacotherapeutica2, 317 (1980); in cerebrovascular disorders: Y. Tazaki et al.,J. Int. Med. Res.8, 118 (1980).

Properties: Crystals, mp 218-220°.

Melting point: mp 218-220°

Derivative Type: Dihydrochloride monohydrate

Trademarks: Biocefalin (Benvegna); Bonifen (Merck KGaA); Enbol (Chugai); Encephabol (Merck KGaA); Enerbol (Polfa); Epocan (Merck KGaA); Life (SIT)

Molecular Formula: C16H20N2O4S2.2HCl.H2O, Molecular Weight: 459.41

Percent Composition: C 41.83%, H 5.27%, N 6.10%, O 17.41%, S 13.96%, Cl 15.43%

Properties: mp 184°. Note: Has no vitamin B6 activity.

Melting point: mp 184°

Therap-Cat: Nootropic.

Keywords: Nootropic.

Derivatives

Dihydrochloride monohydrate

  • Formula:C16H20N2O4S2 • 2HCl • H2O
  • MW:459.42 g/mol
  • CAS-RN:10049-83-9
  • EINECS:233-178-5
  • LD50:221 mg/kg (M, i.v.); 5786 mg/kg (M, p.o.);
    300 mg/kg (R, i.v.); 6 g/kg (R, p.o.)

Pyritinol has been used in trials studying the treatment of Dementia, Depression, Schizophrenia, Anxiety Disorders, and Psychosomatic Disorders.

Pyritinol also called pyridoxine disulfide or pyrithioxine (European drug names Encephabol, Encefabol, Cerbon 6) is a semi-synthetic water-soluble analog of vitamin B6 (Pyridoxine HCl). It was produced in 1961 by Merck Laboratories by bonding 2 vitamin B6 compounds (pyridoxine) together with a disulfide bridge. Since the 1970s, it has been a prescription and OTC drug in several countries for cognitive disorders, rheumatoid arthritis,[1] and learning disorders in children. Since the early 1990s it has been sold as a nootropic dietary supplement in the United States.

SYN

CAS-RNFormulaChemical NameCAS Index Name
39984-49-1C8H10Br3NO3,4-bis(bromomethyl)-5-hydroxy-6-methylpyridine hydrobromide3-Pyridinol, 4,5-bis(bromomethyl)-2-methyl-
92147-37-0C11H15NO3S2ethylxanthic acid [5-hydroxy-4-(hydroxymethyl)-6-methyl-3-pyridyl]methyl esterXanthic acid, ethyl-, [5-hydroxy-4-(hydroxymethyl)-6-methyl-3-pyridyl]methyl ester
140-89-6C3H5KOS2potassium ethylxanthogenateCarbonodithioic acid, O-ethyl ester, potassium salt
File:Pyritinol synthesis01.svg

PATENT

PATENT

https://patents.google.com/patent/CN103992268A/en

Pyritinol, it is the derivative of vitamin B6, for nootropic agents, can promote glucose and amino acid metabolism in brain, improve whole body assimilation, increase Flow of carotid artery, improve cerebral blood flow (CBF), be applicable to the dizzy distending pain, insomnia, hypomnesis of cerebral trauma sequela, encephalitis and meningitis sequela etc., the improvement of absent minded, emotional change; Also for cerebral arteriosclerosis, senile dementia mental symptom etc.

The pyritinol of applying clinically at present, it is pyritinol hydrochloride, be specially the monohydrate of hydrochloride, its chemical name is 3,3-(dithio methylene radical) two (5-hydroxyl-6-methyl-pyridine methane) dihydrochloride monohydrate, has recorded in < < Chinese Pharmacopoeia version > > in 2010.The preparation of this product listing has sheet, capsule and sterile powder injection, and its injection easily causes venous stimulation when clinical application, has greatly limited clinical application.The powder injection of pyritinol hydrochloride easy caking after standing storage, not soluble or dissolve and thoroughly cause liquid unclarity, particulate matter to exceed standard and easily cause the untoward reactions such as Microembolization during use.

CN101003509A discloses hydrobromate and the mesylate of pyritinol, record its stability having had, solvability and bland advantage, but in fact, Hydrogen bromide pyritinol, methylsulfonic acid pyritinol store easy moisture absorption under normal condition, in purification refine, be difficult to separate out with conventional crystallization method, need loaded down with trivial details aftertreatment technology, Hydrogen bromide and methylsulfonic acid have strong corrodibility in addition, comparatively difficult to its suitability for industrialized production.

CN101066266A discloses organic acid salt of pyritinol and preparation method thereof, wherein preferred pyritinol nicotinate.Yet, in nicotinic acid pyritinol water solvability a little less than, and nicotinic acid pyritinol preparation technology used dry-out benzene, toxicity is larger, and aftertreatment technology is complicated, is not suitable for suitability for industrialized production.

Yet, existing pyritinol or its salt, or pyritinol salt exists defect in the use, or the production technique that obtains this pyritinol salt is unsuitable for suitability for industrialized production.For this reason, need to provide a kind of safe, pyritinol salt and production method thereof of stablizing, meeting industrialization production requirements.

Embodiment 1: pyritinol maleate synthetic

Get 5.0g pyritinol powder, drop in reaction flask, add 100ml purified water, then under agitation add toxilic acid 3.8g, finish, be heated to 60-65 ℃ and stir 30min and all dissolve to solid, remove heating fluid, stirred crystallization under room temperature, separate out a large amount of white solids, use a small amount of cold water washing, 45 ℃ of vacuum-dryings, obtain white powder 5.97g, yield 72.9%.Purity: 99.5%; M.p.:134~137 ℃; Ultimate analysis (C16H20N2O4S22C4H4O4): C:47.9%, H:4.8%, N:4.6%, S:10.6%, O:32.1% (theory: C:48.0%, H:4.7%, N:4.7%, S:10.7%, O:32.0%); 1H-NMR (600MHz, DMSO) δ: 2.39 (6H, s), 3.93 (4H, s), 4.76 (4H, s), 6.18 (4H, s), 7.87 (2H, s).By the 1H-NMR (Fig. 2) of toxilic acid pyritinol and the 1H-NMR (Fig. 1) of pyritinol contrast, in a part toxilic acid pyritinol, contain 2 molecule toxilic acids.

Embodiment 2: pyritinol maleate synthetic

Get 5.0g pyritinol powder, drop in reaction flask, add 100ml ethanol, then under agitation add toxilic acid 3.0g, finish, be heated to return stirring 30min and all dissolve to solid, remove heating fluid, stirred crystallization under room temperature, separate out a large amount of white solids, use a small amount of cold water washing, 45 ℃ of vacuum-dryings, obtain white powder 5.50g, yield 67.5%.After measured, the toxilic acid pyritinol that structure makes with embodiment 1.

PATENT

https://patents.google.com/patent/CN105153021A/en

Embodiment 1

Toxilic acid 3.8g is dissolved in 100ml ethanol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1 hour, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid toxilic acid pyritinol crystal form A 4.9g.X-ray powder diffraction analysis, as Fig. 1, its 2 θ value is as following table.

Embodiment 2

Toxilic acid 3.8g is dissolved in 100ml acetone, be warming up to 45 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1.5 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.2g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.

Embodiment 3

Toxilic acid 3.8g is dissolved in and adds 100ml Virahol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 2 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.1g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.

PATENT

https://patents.google.com/patent/CN101066266A/en

Specific embodiment:

Embodiment 1: nicotinic acid pyritinol salt synthetic

Get nicotinic acid 24.6g, fully be dissolved in the 300ml anhydrous benzene, heated and stirred is to molten entirely, under complete molten state, add pyritinol 40.5g, reflux mixture 3 hours, TLC thin layer identification (developing solvent: ethyl acetate: ethanol: glacial acetic acid=5: 6: 0.6) fully, the cooling back adds the 200ml dehydrated alcohol slightly, mixture is put into refrigerator fully cool off, sucking filtration is separated out white crystals, with a small amount of cold absolute ether washing solid.65 ℃ of vacuum dryings get 62.1g nicotinic acid pyritinol salt, yield 89.7%.Determination of acid-basetitration nicotinic acid and pyritinol content are measured moisture with the karl Fischer method.The result is: nicotinic acid 37.2%, and pyritinol 62.0%, water 5.8%, approaching with theoretical value, contain 2 water of crystallization.Elementary analysis: theoretical value C52.8% H5.3% O25.2%N6.6% S10.1%; Measured value C52.4% H5.2% O25.1%N6.5% S10.0%.

Embodiment 2: fumaric acid pyritinol salt synthetic

Get fumaric acid 11.6g, fully be dissolved in the 300ml anhydrous benzene, heated and stirred is to molten entirely, under complete molten state, add pyritinol 40.5g, reflux mixture 3 hours, TLC thin layer identification (developing solvent: ethyl acetate: ethanol: glacial acetic acid=5: 4: 0.8) fully, the cooling back adds the 200ml dehydrated alcohol slightly, mixture is put into refrigerator fully cool off, sucking filtration is separated out white crystals, with a small amount of cold absolute ether washing solid.65 ℃ of vacuum dryings get 49.9g fumaric acid pyritinol salt, yield 88.9%.Determination of acid-basetitration fumaric acid and pyritinol content are measured moisture with the karl Fischer method.The result is: fumaric acid 20.8%, and pyritinol 72.7%, water 6.5%, approaching with theoretical value, contain 2 water of crystallization.Elementary analysis: theoretical value C49.6% H5.0%O26.4% N5.8% S13.2%; Measured value C49.4% H5.2% O26.5% N5.9%S13.1%.

PATENT

https://patents.google.com/patent/CN102516297A/en

Embodiment 1: the preparation of compd A

With Pyrithioxine hydrochloride 10g, be dissolved in the 20ml pyridine, slowly drip POCl3 solution 10ml under the room temperature; Drip and finish, stirring at room reaction 12 hours slowly adds the 100g frozen water and stirred hydrolysis reaction 2 hours; Toluene gradation extraction 30ml * 3, water layer evaporated under reduced pressure, Virahol dissolution residual substance; Filter, evaporate to dryness gets compd A 4.2g.

Embodiment 2: the preparation of compd B

With Pyrithioxine hydrochloride 10g, be dissolved in the 40ml THF, add 4gNaH, 30 ℃ were stirred 2 hours; Add the 20ml POCl3, stirring reaction 16 hours slowly adds the 100g frozen water and stirred hydrolysis reaction 2 hours; ETHYLE ACETATE gradation extraction 30ml * 3, the water layer evaporated under reduced pressure adds 80ml Virahol dissolution residual substance; Add 40ml water, freezing crystallization gets compd B 5.6g.

Embodiment 3: the preparation of Compound C

With Pyrithioxine hydrochloride 10g, be dissolved in the 40ml THF, add 4gNaH, 30 ℃ were stirred 2 hours; Add the 20ml chloroiodomethane, stirring reaction 16 hours, 60 ℃ of evaporated under reduced pressure add 20ml acetonitrile dissolution residual substance; As midbody, other gets triethylamine 9ml and is dissolved in the 10ml acetonitrile, drips 3.6ml phosphoric acid, after dropping finishes; Stir down and slowly splash into midbody, continued 60 ℃ of stirring reactions 12 hours, steaming desolventizes; Residue adds water 20ml dissolving, and water layer filters clarification, and freeze-drying promptly gets compd B 6.7g.

Embodiment 4: the preparation of Compound D

Serine 3 grams, ethylene bromohyrin 2.5g, N with the BOC protection; N-Dimethylamino pyridine 3g and NSC 57182 3g are dissolved in the THF; Stirring at room 10 hours, vacuum concentration is with the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 30%); Merging filtrate, evaporate to dryness gets intermediate A; Pyrithioxine hydrochloride 2g and intermediate A 2.5g are dissolved with THF 30ml, add triphenyl phosphorus 2g, slowly drip diethyl azodiformate solution 2ml, room temperature reaction 5 hours; Reaction is finished, and evaporated under reduced pressure adds ETHYLE ACETATE 50ml dissolving, filters insolubles; With the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 10%), merging filtrate, evaporate to dryness dissolves with methylene dichloride 20ml then; Feed hydrogen chloride gas to saturated, stirring reaction 5 hours filters; Get the hydrochloride of Compound D, transferring pH behind the use dissolved in distilled water is about 8, and the water layer lyophilize gets Compound C 0.27g.

Embodiment 5: the preparation of compd E

Get compd A 10g, be dissolved in the 30ml Virahol, add 25gBoc-Ser-OBZL in batches, 50 ℃ of stirring reactions; HPLC monitoring react to compd B less than 5%, add 0.1M hydrochloric acid soln 20ml, 60 ℃ of heating hydrolysis 5 hours are regulated pH to 7; Evaporated under reduced pressure adds anhydrous alcohol solution, removes by filter insolubles, evaporated under reduced pressure; Add the 5ml water dissolution, filtering, lyophilize get compd E 6.9g

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Availability

It is approved for “symptomatic treatment of chronically impaired brain function in dementia syndromes” and for “supportive treatment of sequelae of craniocerebral trauma” in various European countries, including Austria, Germany, France, Italy, Portugal, and Greece. In France it is also approved for rheumatoid arthritis as a disease modifying drug, on the basis of the results of clinical trials. In many countries it is available over the counter and is widely advertised on the internet as being for “memory disturbances.”

Effects

review refs needed

Adverse effects

Adverse effects include nausea, headache,[2] and rarely allergic reaction (mild skin reactions).[3] A 2004 survey of six case reports suggested a link between pyritinol and severe cholestatic hepatitis when on several drugs for certain diseases.[4]

Other rare side effects: acute pancreatitis[5] and photoallergic eruption.[6]

References

  1. ^ Lemmel EM (May 1993). “Comparison of pyritinol and auranofin in the treatment of rheumatoid arthritis. The European Multicentre Study Group”. British Journal of Rheumatology32 (5): 375–82. doi:10.1093/rheumatology/32.5.375PMID 8495257.
  2. ^ Nachbar F, Korting HC, Vogl T (1993). “Erythema multiforme-like eruption in association with severe headache following pyritinol”. Dermatology187 (1): 42–6. doi:10.1159/000247196PMID 8324277.
  3. ^ de Groot, Anton C.; Nater, Johan Pieter; Weyland, J. Willem. Unwanted Effects of Cosmetics and Drugs Used in Dermatology.[full citation needed][page needed]
  4. ^ Maria V, Albuquerque A, Loureiro A, Sousa A, Victorino R (March 2004). “Severe cholestatic hepatitis induced by pyritinol”BMJ328 (7439): 572–4. doi:10.1136/bmj.328.7439.572PMC 381054PMID 15001508.
  5. ^ Straumann A, Bauer M, Pichler WJ, Pirovino M (August 1998). “Acute pancreatitis due to pyritinol: an immune-mediated phenomenon”. Gastroenterology115 (2): 452–4. doi:10.1016/S0016-5085(98)70212-4PMID 9679051.
  6. ^ Tanaka M, Niizeki H, Shimizu S, Miyakawa S (October 1996). “Photoallergic drug eruption due to pyridoxine hydrochloride”. The Journal of Dermatology23 (10): 708–9. doi:10.1111/j.1346-8138.1996.tb02685.xPMID 8973037S2CID 28810619.
  •  Media related to Pyritinol at Wikimedia Commons
Clinical data
ATC codeN06BX02 (WHO)
Pharmacokinetic data
Elimination half-life2.5 hours
Identifiers
showIUPAC name
CAS Number1098-97-1 
PubChem CID14190
ChemSpider13561 
UNIIAK5Q5FZH2R
KEGGD02160 
ChEMBLChEMBL488093 
CompTox Dashboard (EPA)DTXSID3048362 
ECHA InfoCard100.012.864 
Chemical and physical data
FormulaC16H20N2O4S2
Molar mass368.473 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
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//////////////Pyritinol, пиритинол , بيريتينول , 吡硫醇 , Nootropic,

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PIRACETAM


Piracetam.svg

Piracetam

  • ATC:N06BX03
  • MW:142.16 g/mol
  • CAS-RN:7491-74-9
  • InChI Key:GMZVRMREEHBGGF-UHFFFAOYSA-N
  • InChI:InChI=1S/C6H10N2O2/c7-5(9)4-8-3-1-2-6(8)10/h1-4H2,(H2,7,9)
  • EINECS:231-312-7
  • LD50:9200 mg/kg (M, i.v.); 2 g/kg (M, p.o.)

CAS Registry Number: 7491-74-9 
CAS Name: 2-Oxo-1-pyrrolidineacetamide 
Additional Names: 2-pyrrolidoneacetamide; 2-pyrrolidinoneacetamide; 2-ketopyrrolidine-1-ylacetamide; 1-acetamido-2-pyrrolidinone 
Manufacturers’ Codes: UCB-6215 
Trademarks: Avigilen (Riemser); Axonyl (Pfizer); Cerebroforte (Azupharma); Encetrop (Alpharma); Gabacet (Sanofi-Synthelabo); Geram (UCB); Nootrop (UCB); Nootropil (UCB); Nootropyl (UCB); Norzetam (UCB); Normabraïn (UCB); Piracebral (Hexal); Piracetrop (Holsten); Sinapsan (Rodleben)Molecular Formula: C6H10N2O2 
Molecular Weight: 142.16 
Percent Composition: C 50.69%, H 7.09%, N 19.71%, O 22.51% 
Literature References: Prepn: H. Morren, NL6509994eidem,US3459738 (1966, 1969 both to U.C.B.). Pharmacology: Giurgea et al.,Arch. Int. Pharmacodyn. Ther.166, 238 (1967); Giurgea, Moyersoons, ibid.188, 401 (1970); Giurgea et al.,Psychopharmacologia20, 160 (1971). Metabolism and biochemical studies: Gobert, J. Pharm. Belg.27, 281 (1972). Clinical studies: W. J. Oosterveld, Arzneim.-Forsch.30, 1947 (1980); G. Chouinard et al.,Psychopharmacol. Bull.17, 129 (1981); in dyslexia: M. Di Ianni et al.,J. Clin. Psychopharmacol.5, 272 (1985).Properties: Crystals from isopropanol, mp 151.5-152.5°. 
Melting point: mp 151.5-152.5° 
Therap-Cat: Nootropic. 
Keywords: Nootropic.

Piracetam is in the racetams group, with chemical name 2-oxo-1-pyrrolidine acetamide. It is a derivative of the neurotransmitter GABA[5] and shares the same 2-oxo-pyrrolidone base structure with pyroglutamic acid. Piracetam is a cyclic derivative of GABA (gamma-aminobutyric acid). Related drugs include the anticonvulsants levetiracetam and brivaracetam, and the putative nootropics aniracetam and phenylpiracetam.Piracetam is a drug marketed as a treatment for myoclonus[3] and a cognitive enhancer.[4] Evidence to support its use is unclear, with some studies showing modest benefits in specific populations and others showing minimal or no benefit.[5][6] Piracetam is sold as a medication in many European countries. Sale of piracetam is not illegal in the United States, although it is not regulated nor approved by the FDA so it must be marketed as a dietary supplement.[4]

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Efficacy

Dementia

A 2001 Cochrane review concluded that there was not enough evidence to support piracetam for dementia or cognitive problems.[6] A 2005 review found some evidence of benefit in older subjects with cognitive impairment.[5] In 2008, a working group of the British Academy of Medical Sciences noted that many of the trials of piracetam for dementia were flawed.[7]

There is no good evidence that piracetam is of benefit in treating vascular dementia.[8]

Depression and anxiety

Some sources suggest that piracetam’s overall effect on lowering depression and anxiety is higher than on improving memory.[9] However, depression is reported to be an occasional adverse effect of piracetam.[10]

Other

Piracetam may facilitate the deformability of erythrocytes in capillary which is useful for cardiovascular disease.[5][3]

Peripheral vascular effects of piracetam have suggested its use potential for vertigodyslexiaRaynaud’s phenomenon and sickle cell anemia.[5][3] There is no evidence to support piracetam’s use in sickle cell crisis prevention[11] or for fetal distress during childbirth.[12] There is no evidence for benefit of piracetam with acute ischemic stroke,[13] though there is debate as to its utility during stroke rehabilitation.[14][15]

Anti-vasospasm

Piracetam has been found to diminish erythrocyte adhesion to vascular wall endothelium, making any vasospasm in the capillary less severe. This contributes to its efficacy in promoting microcirculation, including to the brain and kidneys.[5][3]

Side effects

Symptoms of general excitability, including anxietyinsomniairritabilityheadacheagitationnervousnesstremor, and hyperkinesia, are occasionally reported.[10][16][17] Other reported side effects include somnolenceweight gainclinical depressionweakness, increased libido, and hypersexuality.[10]

According to a 2005 review, piracetam has been observed to have the following side effects: hyperkinesia, weight gain, nervousness, somnolence, depression and asthenia.[5]

Piracetam reduces platelet aggregation as well as fibrinogen concentration, and thus is contraindicated to patients suffering from cerebral hemorrhage.[5][3]

Toxicity

Piracetam does not appear to be acutely toxic at the doses used in human studies.[6][18][19]

The LD50 for oral consumption in humans has not been determined.[20] The LD50 is 5.6 g/kg for rats and 20 g/kg for mice, indicating extremely low acute toxicity.[21] For comparison, in rats the LD50 of vitamin C is 12 g/kg and the LD50 of table salt is 3 g/kg.

Mechanisms of action

Piracetam’s mechanism of action, as with racetams in general, is not fully understood. The drug influences neuronal and vascular functions and influences cognitive function without acting as a sedative or stimulant.[5] Piracetam is a positive allosteric modulator of the AMPA receptor, although this action is very weak and its clinical effects may not necessarily be mediated by this action.[22] It is hypothesized to act on ion channels or ion carriers, thus leading to increased neuron excitability.[20] GABA brain metabolism and GABA receptors are not affected by piracetam[23]

Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors[citation needed], which are implicated in memory processes.[24] Furthermore, piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes. Piracetam is thought to increase cell membrane permeability.[24][25] Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na+, K+).[20] It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brains.[26][27] Piracetam, while in the brain, appears to increase the synthesis of cytochrome b5,[28] which is a part of the electron transport mechanism in mitochondria. But in the brain, it also increases the permeability of some intermediates of the Krebs cycle through the mitochondrial outer membrane.[26]

Piracetam inhibits N-type calcium channels. The concentration of piracetam achieved in central nervous system after a typical dose of 1200 mg (about 100 μM)[29] is much higher than the concentration necessary to inhibit N-type calcium channels (IC50 of piracetam in rat neurons was 3 μM).[30]

History

Piracetam was first made some time between the 1950s and 1964 by Corneliu E. Giurgea.[31] There are reports of it being used for epilepsy in the 1950s.[32]

Society and culture

In 2009 piracetam was reportedly popular as a cognitive enhancement drug among students.[33]

Legal status

Piracetam is an uncontrolled substance in the United States meaning it is legal to possess without a license or prescription.[34]

Regulatory status

In the United States, piracetam is not approved by the Food and Drug Administration.[1] Piracetam is not permitted in compounded drugs or dietary supplements in the United States.[35] Nevertheless, it is available in a number of dietary supplements.[4]

In the United Kingdom, piracetam is approved as a prescription drug Prescription Only Medicine (POM) number is PL 20636/2524[36] for adult with myoclonus of cortical origin, irrespective of cause, and should be used in combination with other anti-myoclonic therapies.[37]

In Japan piracetam is approved as a prescription drug.[38]

Piracetam has no DIN in Canada, and thus cannot be sold but can be imported for personal use in Canada.[39]

In Hungary, piracetam was a prescription-only medication, but as of 2020, no prescription is required and piracetam is available as an over-the-counter drug under the name Memoril Mite, and is available in 600 mg pills.

According to the literature reports, the synthetic route of piracetam can be divided into four synthetic methods: α-pyrrolidone method, glycine method, succinic anhydride method and one-step synthesis method:[0009] I. α-pyrrolidone method, 2-pyrrolidone is a lactam, which can react with a strong base (sodium hydride or potassium hydride, sodium methoxide) to generate pyrrolidone metal salt, which can be further combined with halogenated ester or halogen Substitute amide reaction to generate N-alkylated product.[0010] In 1966, a method for preparing piracetam by reacting pyrrolidone and chloroacetamide in 1,4-dioxane with sodium hydrogen as a strong base was reported. The specific synthetic route is shown in Scheme 1:[0011]

Figure CN104478779AD00032

[0012] In this process, due to the high price of dioxane, industrial production is still difficult. On the basis of the above process, Xu Yungen used dimethyl sulfoxide as the solvent and sodium methoxide as the acid binding agent to synthesize piracetam in the presence of the phase transfer catalyst benzyltriethylammonium chloride. Due to the difficulty of solvent recovery, the cost of this route is relatively high.[0013] In 1981, Zhou Renxing et al. used sodium methoxide as a strong base to extract methanol in toluene by fractional distillation to convert pyrrolidone into the corresponding sodium salt, and then react with ethyl chloroacetate. The resulting ethyl pyrrolidone ethyl acetate was subjected to ammonolysis. Piracetam can be produced. The specific synthetic route is shown in Scheme 2.[00141

Figure CN104478779AD00041

[0015] Because the ammonolysis is carried out in a methanol solution of ammonia, the calculated amount of ethanol generated during the ammonolysis contaminates the methanol solution of ammonia used, which affects the recycling of the methanol solution of ammonia, and is therefore not conducive to process production.[0016] 2. Glycine method, glycine and its derivatives can be used as starting materials for the synthesis of pyroacetamide. Glycine can be prepared by γ-chlorination butylation, amination and cyclization.[0017] According to a British patent report in 1979, glycine trimethylsilyl ester was first condensed with γ-chlorobutyryl chloride, and the corresponding acid chloride was subjected to ammonolysis, and finally cyclized to produce piracetam. The specific synthesis method is as Scheme 3 Shown[0018]

Figure CN104478779AD00042

[0019] In this type of synthesis route, some raw materials are not easily available, which restricts industrial production.[0020] 3. Succinic acid method, succinic acid is heated and dehydrated to generate succinic anhydride, succinic anhydride then reacts with glycine to generate an aminolysis product, and the aminolysis product is reduced by sodium tetrafluoroborate, and piracetam can be synthesized by aminolysis , The specific synthetic route is shown in SCheme4. [0021]

Figure CN104478779AD00043

[0022] Because sodium tetrafluoroborate is used as a reducing agent, it is expensive, and it is difficult to expand the scale of industrial production. Succinimide generates sodium salt under the action of metal sodium, and its sodium salt reacts with chloroacetamide to generate N-alkylated product. The alkylated product can be electrolytically reduced to obtain piracetam. Since electrolytic reduction is still in the research stage in our country, the production cost of this method is relatively high.[0023] 4. One-step synthesis method, using ethyl 4-chloro-n-butyrate in the presence of sodium bicarbonate, using anhydrous ethanol as a solvent, and glycinamide hydrochloride under heating and refluxing to obtain piracetam in one step, The specific synthetic route is shown in S Cheme5.[0024]

Figure CN104478779AD00044

[0025] In this route, glycinamide hydrochloride is very easy to absorb moisture and agglomerate to affect the reaction rate, and the reaction is not easy to control, so it is difficult to achieve industrial production.

SYN

File:Piracetam synthesis02.svg - Wikimedia Commons
File:Piracetam synthesis01.svg

SYN

http://www.cjph.com.cn/EN/abstract/abstract373.shtml

With absolute ethanol as the solvent, ethyl 4-chloro-n-butanoate and glycinamide hydrochloride were refluxed for 20 h in the presence of sodium bicarbonate to obtain central stimulant piracetam. After recrystallization from isopropanol, the yield was about 58% with a purity of 99.6%.

CN104478779A - 促智药吡拉西坦的合成新方法 - Google Patents

SYN

CAS-RNFormulaChemical NameCAS Index Name
79-07-2C2H4ClNO2-chloroacetamideAcetamide, 2-chloro-
105-39-5C4H7ClO2ethyl chloroacetateAcetic acid, chloro-, ethyl ester
61516-73-2C8H13NO3ethyl 2-oxo-1-pyrrolidineacetate1-Pyrrolidineacetic acid, 2-oxo-, ethyl ester
616-45-5C4H7NO2-pyrrolidone2-Pyrrolidinone

PATENT

https://patents.google.com/patent/CN104478779A/zh

Figure CN104478779AD00051

Example 1[0036] A method for synthesizing piracetam, which includes the following steps:[0037] Preparation of α-pyrrolidone sodium salt: A 1000 mL three-necked flask was equipped with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving flask. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added to the three-necked flask. When the temperature of the reaction system reached 70°C, a methanol solution of sodium methoxide (28.4% (w/w); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition is completed, the temperature is increased, and the normal pressure is distilled until the distillate is completely distilled out, and the reaction is completed.[0038] Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condenser, and connect a dropping funnel above the condenser. When the temperature of the reaction system drops to 60°C, a toluene solution of 58 mL (0.66 mol) of methyl chloroacetate is slowly added dropwise, and the reaction temperature is controlled to 80-100°C. Oh。 After the addition is complete, the insulation reaction is 5. Oh. Cool to room temperature, filter with suction, and distill the filtrate under reduced pressure. Collect the fraction (18mmHg) at 100~105°C to obtain α-pyrrolidone methyl acetate, and measure its content by HPLC (area normalization method). [C18 column (4.6mmX 200mm, 5 μm) was used for purity determination; acetonitrile-dipotassium hydrogen phosphate/phosphate buffer solution (10:90) was used as the mobile phase (the pH value of phosphoric acid was adjusted to 6.0); the flow rate was 1 . OmL/min; detection wavelength is 205nm; injection volume is 20yL][0039] Preparation of Piracetam: Put about 130 mL of methanol in a 500 mL three-necked flask, and vent ammonia to saturation. The obtained ammonia/methanol solution was mixed with 100. Og α-pyrrolidone methyl acetate and placed in a reaction kettle, reacted at 50~65°C for 10 h, allowed to cool, filtered with suction, and the filter cake was dried.[0040] The purification of piracetam: 25.50g crude piracetam and 100mL isopropanol were sequentially added in a 500mL three-necked flask, heated to reflux for 40min, activated carbon was added, reflux stirring, hot filtration, and the resulting properties were all white As a powdery solid, the filter cake was dried overnight at 50°C in a vacuum drying oven to obtain 20.85 g of a white solid with a yield of 81.76% (calculated as α-pyrrolidone, the same below).Example 2[0042] Preparation of α-pyrrolidone sodium salt: A 1000 mL three-necked flask was equipped with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving flask. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added to the three-necked flask. When the temperature of the reaction system reached 100°C, a methanol solution of sodium methoxide (28.4% (w/w)); 114. Og; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the addition is complete, add toluene, increase the temperature, and distill at normal pressure until the distillate is completely distilled out, and the reaction is complete.[0043] Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condenser, and connect a dropping funnel above the condenser. When the temperature of the reaction system drops to 60°C, a mixed solution of 63 mL (0.72 mol) of methyl chloroacetate and 30 mL of toluene is slowly added dropwise, and the reaction temperature is controlled to 80-100°C. Oh。 After the addition is complete, the insulation reaction is 5. Oh. Cool to room temperature, filter with suction, and distill the filtrate under reduced pressure. Collect the fraction (18mmHg) at 100~105°C to obtain methyl α-pyrrolidone acetate, and measure its content by HPLC (area normalization method). [C18 column (4.6mmX 200mm, 5 μm) was used for purity determination; acetonitrile-dipotassium hydrogen phosphate/phosphate buffer solution (10:90) was used as the mobile phase (the pH value of phosphoric acid was adjusted to 6.0); the flow rate was 1 .OmL/ min; detection wavelength is 205nm; injection volume is 20 μL][0044] Preparation of Piracetam: Put about 130 mL of methanol in a 250 mL three-necked flask, and ventilate ammonia to saturation. The obtained ammonia/methanol solution was mixed with 50.0 g of α-pyrrolidone methyl acetate and placed in a reaction kettle, reacted at 50~65°C for 12 hours, allowed to cool, filtered with suction, and the filter cake was dried.[0045] Purification of piracetam: 25.50g crude piracetam and 75mL methanol were sequentially added to a 500mL three-necked flask, heated to reflux for 40min, added activated carbon 0.5g, refluxed for 1h, hot filtered, magnetically stirred Under the conditions, the activated carbon was filtered out, and the properties were all white powdery solids, and the filter cake was dried overnight at 50°C in a vacuum drying oven to obtain 21.02g of white solids with a yield of 82.42%.Embodiment 3[0047] Preparation of α-pyrrolidone sodium salt: A 1000 mL three-necked flask was equipped with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionating column is connected with a thermometer, a condenser and a 1000 mL receiving bottle. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added to the three-necked flask. When the temperature of the reaction system reached 70°C, a methanol solution of sodium methoxide (28.4% (w/w)); 114. Og; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition is completed, the temperature is increased, and the normal pressure is distilled until the distillate is completely distilled out, and the reaction is completed.[0048] Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condenser, and connect a dropping funnel above the condenser. A mixed solution of 79 mL (0.90 mol) of methyl chloroacetate and 50 mL of toluene was slowly added dropwise, and the reaction temperature was controlled to 70-90°C. Oh。 After the addition is complete, the insulation reaction is 5. Oh. Cool to room temperature, filter with suction, and distill the filtrate under reduced pressure. Collect the fraction (18mmHg) at 100~105°C to obtain methyl α-pyrrolidone acetate, and measure its content by HPLC (area normalization method). [C 18 column (4.6mmX 200mm, 5 μm) was used for purity determination; acetonitrile-dipotassium hydrogen phosphate/phosphate buffer solution (10:90) was used as the mobile phase (the pH value of phosphoric acid was adjusted to 6.0); the flow rate was 1.0mL/min; The detection wavelength is 205nm; The injection volume is 20 μL)[0049] Preparation of Piracetam: Put about 130 mL of methanol in a 250 mL three-necked flask, and vent ammonia to saturation. The obtained ammonia/methanol solution was mixed with 100. Og α-pyrrolidone methyl acetate and placed in a reaction kettle, reacted at 50~65°C for 14h, allowed to cool, filtered with suction, and the filter cake was dried.[0050] Purification of piracetam: 25.50g crude piracetam and 125mL ethanol were sequentially added in a 500mL three-necked flask, heated to reflux for 40min, added activated carbon 0.5g, refluxed for 1h, hot filtered, magnetically stirred Activated carbon was filtered off under conditions to obtain white powdery solids in all properties, and the filter cake was dried overnight at 50°C in a vacuum drying oven to obtain 20.24 g of white solids with a yield of 79.37%.Example 4[0052] Preparation of α-pyrrolidone sodium salt: A 1000 mL three-necked flask was equipped with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving flask. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added to the three-necked flask. When the temperature of the reaction system reached 60°C, a methanol solution of sodium methoxide (28.4% (w/w); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition is completed, the temperature is increased, and the normal pressure is distilled until the distillate is completely distilled out, and the reaction is completed.[0053] Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condenser, and connect a dropping funnel above the condenser. A mixed solution of 105 mL (1.20 mol) of methyl chloroacetate and 70 mL of toluene was slowly added dropwise, and the reaction temperature was controlled to be 60~70°C. Oh。 After the addition is complete, the insulation reaction is 5. Oh. Cool to room temperature, filter with suction, and distill the filtrate under reduced pressure. Collect the fraction (18mmHg) at 100~105°C to obtain methyl α-pyrrolidone acetate, and measure its content by HPLC (area normalization method). [C 18 column (4.6mmX 200mm, 5 μm) was used for purity determination; acetonitrile-dipotassium hydrogen phosphate/phosphate buffer solution (10:90) was used as the mobile phase (the pH value of phosphoric acid was adjusted to 6.0); the flow rate was 1.0mL/min; The detection wavelength is 205nm; The injection volume is 20 μL)[0054] Preparation of Piracetam: Put about 130 mL of methanol in a 500 mL three-necked flask, and ventilate ammonia to saturation. The obtained ammonia/methanol solution was mixed with 100. Og α-pyrrolidone methyl acetate and placed in a reaction kettle, reacted at 50~65°C for 16h, allowed to cool, filtered with suction, and the filter cake was dried.[0055] The purification of piracetam: 25.50g crude piracetam and 100mL methanol were sequentially added into a 500mL three-necked flask, heated to reflux for 40min, added activated carbon, refluxed for dissolution, hot filtered, and the properties were all white powders The solid, the filter cake was dried overnight at 50°C in a vacuum drying oven to obtain 20.69 g of a white solid, with a yield of 81. 13%.[0056] Chemical analysis of the white crystals synthesized in each of the foregoing examples, and the obtained physical property values are as follows, thereby confirming that the synthesized product is piracetam.[0057] Melting point: 151.6-152. (TC[0058] ESI-MS m / z: 165. 06 [M + Na] +[0059] 1H-NMR (400MHz, DMS〇-d6, ppm) δ : 7. 38 (s, 1H), 7. 09 (s, 1H), 3. 74 (s, 2H), 3. 36 (t, J =7. 08Hz, 2H), 2. 23 (t, J = 7. 84Hz, 2H), I. 93 (m, 2H).[0060] 13C-NMR(100MHz, DMS0-d6, ppm) δ : 17. 80, 30. 42, 45. 28, 47. 74, 170. 21,174. 90. 
PATENTCN110903230A *2019-12-042020-03-24Beijing Yuekang Kechuang Pharmaceutical Technology Co., Ltd.An industrialized preparation method of Pramiracetam sulfate 
PATENTCN104478779A2015-04-01New synthetic method of nootropic drug Piracetam

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External links

Gouliaev AH, Senning A (May 1994). “Piracetam and other structurally related nootropics”. Brain Research. Brain Research Reviews19 (2): 180–222. doi:10.1016/0165-0173(94)90011-6PMID 8061686S2CID 18122566.

Clinical data
Trade namesBreinox, Dinagen, Lucetam, Nootropil, Nootropyl, Oikamid, Piracetam and many others
AHFS/Drugs.comInternational Drug Names
Routes of
administration
By mouth, parenteral, or vaporized
ATC codeN06BX03 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)CA: UnscheduledUK: POM (Prescription only)US: Unscheduled (Not permitted as drug or supplement[1])
Pharmacokinetic data
Bioavailability~100%
Onset of actionSwiftly following administration. Food delays time to peak concentration by 1.5 h approximately to 2–3 h since dosing.[2]
Elimination half-life4–5 h
ExcretionUrinary
Identifiers
showIUPAC name
CAS Number7491-74-9 
PubChem CID4843
IUPHAR/BPS4288
DrugBankDB09210
ChemSpider4677 
UNIIZH516LNZ10
KEGGD01914 
ChEMBLChEMBL36715 
CompTox Dashboard (EPA)DTXSID5044491 
ECHA InfoCard100.028.466 
Chemical and physical data
FormulaC6H10N2O2
Molar mass142.158 g·mol−1
3D model (JSmol)Interactive image
Melting point152 °C (306 °F)
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///////////UCB 6215, Nootropic, PIRACETAM

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