[go: up one dir, main page]

WO2009087650A2 - Nouveau procédé de synthèse de la prégabaline à partir d'un intermédiaire cyclopropane substitué et procédé pour la résolution enzymatique de la prégabaline racémique - Google Patents

Nouveau procédé de synthèse de la prégabaline à partir d'un intermédiaire cyclopropane substitué et procédé pour la résolution enzymatique de la prégabaline racémique Download PDF

Info

Publication number
WO2009087650A2
WO2009087650A2 PCT/IN2008/000669 IN2008000669W WO2009087650A2 WO 2009087650 A2 WO2009087650 A2 WO 2009087650A2 IN 2008000669 W IN2008000669 W IN 2008000669W WO 2009087650 A2 WO2009087650 A2 WO 2009087650A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
compound
pregabalin
acid
reaction
Prior art date
Application number
PCT/IN2008/000669
Other languages
English (en)
Other versions
WO2009087650A3 (fr
Inventor
Kiran Chaudhari
Mahendra Yeole
Chandrashekar Batchu
Rakesh Ratnam
Sundeep Aurora
Munishwar Nath Gupta
Abir B. Majumder
Original Assignee
V.B. Medicare Pvt. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by V.B. Medicare Pvt. Ltd. filed Critical V.B. Medicare Pvt. Ltd.
Publication of WO2009087650A2 publication Critical patent/WO2009087650A2/fr
Publication of WO2009087650A3 publication Critical patent/WO2009087650A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/008—Preparation of nitrogen-containing organic compounds containing a N-O bond, e.g. nitro (-NO2), nitroso (-NO)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/002—Nitriles (-CN)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures

Definitions

  • the present invention is directed to new "substituted cyclopropane" intermediate for synthesis of racemic pregabalin.
  • the present invention also relates to a method for stereoselective bioconversion of racemic 3-aminomethyl-5-methylhexanoic acid alkyl ester to 3-aminomethyl-5-methylhexanoic acid.
  • Pregabalin is a Gamma-aminobutyric acid (GABA) analogue that is reported in various ' patents to prevent and treat a range of diseases.
  • GABA Gamma-aminobutyric acid
  • pregabalin has been disclosed in US 5563175 in treating seizure disorders, in US 6127418 to dramatically reduce the gastrointestinal damage caused by drugs and alcohol, treat the conditions resulting from ethanol withdrawal syndrome, and Gl disorders characterized as inflammatory bowel disorders, functional bowel disorders, dyspepsia, visceral pain; in US 6194459 for treating gastrointestinal damage and disorders and a composition comprising a GABA analog and a non-steroidal antiinflammatory drug; in US 6194459 for treating physiological conditions associated with the use, or sequelae of use, of psychomotor stimulants including cocaine, amphetamine
  • US 6242488 for preventing or treating pain comprising a GABA analog and a non-steroidal anti-inflammatory drug such as a composition comprising pregabalin and naproxen sodium
  • US 6306910 for treating insomnia
  • US 6326374 for eliciting an enhanced analgesic response comprising administering an analgesically effective amount of a GABA analog
  • caffeine in US 6329429 for preventing and treating inflammatory diseases; in US 6359005 for treating mania and treating and preventing bipolar disorder; in US 6372792 for preventing or treating alcoholism, irritable bowel disorder or irritable bowel o/ndrome; in US 6451857 as an anti-epiieptic compound; in US 6566400 for treating physiological conditions associated with, the use, or sequelae of use, of psychomotor stimulants including cocaine; in US .6593368 for treating acute pain by a combination, comprising a synergistic amounts of gabapentin and cele
  • Pregabalin is also shown to be effective in combination with NMDA receptor antagonists (US 6942876), in buccal sprays (US 6977070); as lactose conjugates (US 7022678) in combination with 2-(7- chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolino-ne or 2-(7 ⁇ chloro- 1 ,8-naphthyridine-2-yl)-3-(5-methyl-5-hydroxy-2-oxohexyl- )-1-isoindolinone for obsessive-compulsive disorder (US 7026332); and can be gave as an ingredient of a liquid pharmaceutical composition. Many more examples not mentioned here exist and may be added in future on applications of pregabalin.
  • pregabalin The therapeutic effects of pregabalin including seizure suppressive effect while avoiding the undesirable side effect of ataxia is attributed to the S-enantiomer, the racemic compound (.+-.)-3 ⁇ (aminomethyl)-5-methylhexanoic acid (also known as racemic isobutyl-GABA or also known as Pregabalin).
  • the commercial utility of pregabalin requires an efficient method for directly preparing the S-enantiomer substantially free of the R-enantiomer or comprises following up of the synthesis process that results in a racemic mixture with a method of resolution of the two enantiomera from each other.
  • Pregabalin 3-(aminornethyl)-5-methylhexanoic acid, is a-compound, a racemic mixture of which is indicated as having chemical Structure (I)
  • S-pregabalin having structure Ia 1 given in the following,
  • GABA gamma-aminobutyric acid
  • This invention embodies a novel process that comprises cyclopropane ring formation as intermediate and followed by ring opening by reduction to yield racemic pregabalin while the bioconversion yields the desired active isomer.
  • This invention embodies novel • processes for preparation of enantiometrically pure pregabalin from various precursors such as its eswrs by enzymatic hydrolysis, bioconversion for obtaining (S)-(+) pregabalin by use of enzymes.
  • U.S.2003225161, WO9209560 and WO9323383 disclosed synthesis of pregabaiin using azide as an intermediate.
  • the enantioselectivity of the pregabaiin is achieved by 4- methyl 5-phenyl oxazolidinone ring formation.
  • this method can be represented by following route for steriospecific pregabaiin synthesis;
  • This prior art differs from the process of this invention that comprises preparation of nitroalkene and Michael addition type reaction of sulfur ylide.
  • 3- ⁇ aminomethyl)-5- methylhexanoic acid is prepared in four -steps from isovaleraldehyde that include condensation, cyanide addition, selective monocarboxylation and reduction of cyanide to amine followed by resolution with (S)-mandelic acid.
  • This prior art method comprises use the hazardous metal cyanides as amine source.
  • the process of this invention avoids use of the toxic metal cyanide as it proceeds through cyclopropane ring opening metathesis using nitromethane as amine source.
  • pregabalin was prepared from highly substituted butyrolactams.
  • Butyrolactams were prepared from reductive amination of mucobromic acid by ammonium formate. Route of reactions used is shown in the following :
  • Process of this invention comprises reduction of nitro group by simple Raney Ni, and stereochemistry is imparted by bioconverion of nitrile group to acid.
  • Burk et al. in WO 99/31041 and WO 99/52852, describes the asymmetric tiydrogenation of .beta.-substituted and .beta.,. beta. -disubstituted itaconic acid derivatives to provide enantiomerically enriched 2-substituted succinic acid derivatives which is intermediate precursor for pregabalin.
  • Patent US 6488964 refers to the manufacture of coated pregabalin.
  • the method mentioned in patent WO 2003/104184 discloses method for synthesis of acyloxy derivatives of GABA analogues.
  • a process published by G. M. Sammis, et al., J. Am. Chem. Soc. 125(15), 4442-3(2003) takes advantages of the asymmetric catalysis of cyanide conjugate addition reactions.
  • the method discloses the application of aluminium salen catalyst to the conjugate addition of hydrogen cyanide to ⁇ , ⁇ -unsaturated imides .
  • Reportedly TMSCN is useful source of cyanide that can be used in place of hydrogen cyanide.
  • the route of reaction is given below:
  • R3 may be several alkyl; aryl groups
  • the method of this invention proceeds through an entirely different route that comprises formation of a di-substituted cyclopropane ring, shown as structure III in the following, which in this invention is used for the first time as a precursor of pregabalin:
  • R1 Alkyl, Aryl, allyl, heterocycle, straight chain or branch chain
  • X -CN or - COOR, wherein R may be hydrogen or straight chain or branched chain alky! or aryl group.
  • R is H
  • R 1 -alkylr aryl, heterocycle, straight chain or branch chain
  • First step of one embodiment of this invention to prepare pregabalin comprises reductive ring opening of compound 111 to form a compound of structure IV ; the said reductive ring opening being achieved using reducing agent like Raney Ni/ H 2 or Pd/C or Zn/HCOONH 4 or Zn/HCOOH or Fe/OH 3 COOH or Fe/HCI at 25 0 C in polar solvent:
  • racemic mixture formed by chemical process can be subjected to a prior art process of resolving them to get (SH+) pregabalin, including use of agent for resolution like (S)- ⁇ +)-mandelic acid in -IPA M/ater or (+)- ⁇ -phenyl ethyiamine in ethanol/chl ⁇ roform or / - ephedrine:
  • this invention opens up and shall include in it, another possibility of subjecting the compound of structure IVa having nitrile group at first carbon atom to the action of nitrilase that may regioselectively as well as sterioselectively convert nitriie group to carboxyl group by enzymatic action of nitrilase leading to production of ⁇ S)-(+) pregabalin as the only isomer as shown below:
  • Structure of IVa is prepared by reduction of i compound of structure Ilia to compound IVa by Fe/acetic acid or Fe/HCI, Raney Ni,/H 2 as reducing agent.
  • a suitable enzyme including but not limited to, hydrolases, further including esterases, lipases or proteoses that may regioselectively as well as sterioselectively convert ester group to carboxyl acid group by enzymatic action of lipases or proteases leading to production of (S)-(+) pregaba ⁇ n.
  • Protocol for ⁇ egioselctive conversion by an esterase or a hydrolase of a (R) pregabalin ester has been demonstrated in the following.
  • the enzyme capable of stereoselective conversion to (S) pregabalin is added and shaken for a time period and at a temperatures range sufficient for conversion of substantial portion of R- 3-aminomethyl-5- methylhexanoic acid methyl ester to 3-aminomethyl-5-methylhexanoic acid.
  • water miscible organic solvent shall vary between 0.1 % - 40 %, v/v, and included at least an acetonitrile, N,N-dimethyl formamide, dimethyl sulphoxide, or lctrahydrofuran,.time period of shaking is about 6 -18 h, and the temperature is kept within the range of about 20 0 C -130 0 C.
  • the enzyme used - may be a nitrilase.
  • the present invention provides 99.5 % enantiomeric excess of (S)- 3-aminomethyi-5-methy!hexanotc acid by using an appropriate enzyme. In another embodiment, the present invention provides (R)-3-aminomethyl-5-methylhexanoic acid with more than 98% enantiomeric excess by using an appropriate enzyme for (R) enantiomeric selectivity.
  • a further embodiment of the present invention provides process for preparation of pregabalin alkyl esters of structure Il wherein R is preferably methyl or more preferably ethyl, or any linear chain or branch chain alkyl group .
  • a further embodiment of the present invention provides process for stereoselective hydrolysis of alkyl esters of pregabalin to R-isomer of pregabalin by enzymes esterases, lipases and proteases either in free form or in immobilized form (scheme A)
  • the present invention provides stereoselective hydrolysis of alkyl esters of pregabalin to S-isonier of pregabalin of structure (Ia) by enzymes esterases, lipases and proteases capable of selectively acting on (S) isomer of structure II, the said enzyme being either in free form or in immobilized form (Scheme B).
  • Scheme B In yet another embodiment the present invention provides process for chemical hydrolysis of S-Pregabalin alkyl esters or " R-Pregabalin alkyl -ester to corresponding S- Pregabalin or R- Pregabalin as shown in scheme C
  • the reaction medium may contain one or more of a water immiscible organic solvent.
  • a water immiscible organic solvent may include, witout. limitation, acetonitrile, N,N-dimethyl formamide, dimethyl sulphoxide or tetrahydrofuran. I agree with You but We don't have any data of solvent study except Acetonitrile
  • a further embodiment of this invention comprises use of enzyme catalyst isolated from microorganisms. Yet further embodiment of this invention comprises isolation of the said enzyme from a microorganism of one or more of a group including, but not limited to, Rhodococcus species, Pseudomonas species, Arthrobactor species, Bacilius species and Aspergillus nigar.
  • Sulphur or phosphorus ylide can be prepared preferably by a prior art process comprising mixing ethyl bromoacetate and dimethylsulfide with or without solvents, more preferably without solvent. Thereafter neutralizing the sulfonium salt by using saturated potassium carbonate and NaOH solution at 0-25 0 C.
  • the compound of Structure VII is prepared by known standard procedure as mentioned by Kulkami (1995) (Synthesis 1995, p. 1545). Under basic condition preferably 50% aqueous NaOH or more preferably sodium metal in ethanol, or more preferably methanolic sodium hydroxide, isovaleraldehyde and nitromethane were stirred for about three hour to get a mixture of compound of structure IV and compound of structure V as shown in the following reaction:
  • the compound of structure V is converted to compound of structure VII by acylation followed by elimination.
  • Acyl chloride or anhydride especially acetyl chloride is the acylating reagent in chlorinated solvents like chloroform, dichloromethane, ethylene dichloride.
  • Example 1 gives a method that directly affords 50 % nitroalkene if we use aqueous sodium hydroxide as a base in 1 st step.
  • the product is purified by column chromatography using silica gel column and cyclohexane and ethylacetat ⁇ (9:1) as elution phase.
  • Example 3 constitutes preparation of cyclopropane ring from nitroaike ⁇ e and sulphur ylide.
  • This method to a solution of 4-methyl-1-nitropentene in dry CH 2 CI 2 is added a freshly prepared solution of EDSA, ethyl(dimethylsulphuralidene)acetate in dry CH 2 CI 2 and the mixture is refluxed for six hours. After removal of solvent, residue is purified by column chromatography using silica gel and Petroleum ether as eluent to give ethyl-2- isobutyl-3-nitrocyclopropane carboxylate as a liquid.
  • This invention provides new route for preparation of racemic pregabalin through hydrolysis of cyclopropane ester (example 4) of structure Ilia to compound of structure MIb followed by reduction (example 5).
  • Present invention also discloses preparation of racemic pregabalin through novel intermediate of structure IHc.
  • the process involve hydrolysis of nitrile to corresponding amide (example 6) and then amide to corresponding acid (example 7) followed by reduction with reducing agents. Or other way is direct hydrolysis of nitrile to acid followed by reduction.
  • the invention discloses a process for the preparation of pure (S)-(+)-3-aminomethyl-5- methylhexanoic acid from its ester via enzymatic kinetic resolution.
  • the method includes preparation of pure (S)-(+)-3-aminomethyl-5-methylhexa ⁇ oic acid with an enantiomeric excess exceeding 99 %.
  • This invention also includes obtaining the (R)-(-)-3- aminomethyl-5-methylhexanoic acid with an enantiomeric excess exceeding 98 %.
  • enzymes in general and esterases, lipases and proteases in particular are used to achieve enantioseiective preparation of pregabalin.
  • Another embodiment of this invention includes use of such enzymes in free form and all modified forms including immobilized preparations.
  • a further embodiment of this invention includes the use of such enzymes in water as well as in co-solvent mixtures with organic solvents and ionic liquids.
  • Yet another embodiment of this invention includes the use of such enzymes in organic solvents, ionic liquids, biphasic mixtures thereof and reverse micellar media. is invention aiso nc u es oac es ou ne n c eme an c eme . option would depend upon the stereoselectivity of the enzyme chosen for the kinetic resolution purposes.
  • the invention includes racemization of (R)-(-)-3-aminomethyl-5-methylhexanoic acid 5 ester and or (ft)-(-)-3-aminomethyl-5-methylhexanoic acid to convert total starting material to the (S)-(+)-3-aminomethyl-5-methylhexanoic acid by repeating either Scheme A or Scheme B.
  • Example 1a Preparation of 4-methyi-1-nitropentan-2-ol To 200 ml of -ethanol or ' .methanol - 6.97.gm of sodium hydroxide was added slowly . To this vigorously stirred solution at 0-5 degree C was added 15 gm (0.174 moles) of isovaleraldehyde and 10.6 gm (0.174 moles) of nitromethane drop wise for 1 hour maintaining interna! temperature between 0-5 degree C . Soon solid separate out. After 1 hour, 50 ml of excess of ethanol or methanol was added to make a slurry, the resultant slurry was filtered and the cake obtained was then neutralized by using 10 ml of cone.
  • Example 1c Conversion of 3-methyl-1-(nitromethyl)butyl acetate to 4-methyl-1-nitropet- 1-ene
  • the resultant reaction mixture was refluxed for 3 hour. Reaction was monitored by GC and TLC. After completion -of reaction, mass was filtered and solvent was evaporated under vacuum. The residue-was then diluted with 500 ml of dichloromethane and washed with 200x2 ml of water to remove acetic acid. The organic layer was then evaporated to yield 10.46 gm (76%) of 4-methy!-1-nitropet-1 ⁇ ene.
  • Saturated potassium carbonate solution was prepared by dissolving 130 gm of K2CO3 'R 100 ml of water stirring for 2 hour. As sulfur methyl j de degrades at room temperature, it was totally used for next reaction.
  • Example 9 A In 500 ml round bottom flask 5 gm of Racemic pregabalin acid was dissolved in 300 ml of methanol . Dry HCi gas was passed through this solution at 5-10 degree C (Absorption of HCI in methanol must be minimum 10 gm) . The whole reaction muixitire was allowed to stir at room temperature for 5 hours. After completion of reaction, mass was quenched with methano ⁇ c ammonia maintaining pH about 5. Solvent was evaporated under high vacuum, the solid obtained was then filtered by diluting the mixture with DCM (dichloromethane) (150 ml). DCM was evaporated under vacuum to get 4 gm of pregabalin methyl ester.
  • DCM dichloromethane
  • Example 9 B In 500 ml round bottom flask 5 gm of Racemic pregabalin acid was dissolved in 300 ml of methanol and 5 ml of sulphuric acid . The whole reaction mixture was allowed to stir at room temperature for 5 hours at 60 degree C. After completion of reaction, mass was quenched with methanolic ammonia maintaining pH about 5. Solvent was evaporated under high vacuum, the solid obtained was then filtered by diluting the mixture with DCM (150 ml). DCM was evaporated under vacuum to get 2 gm of pregabalin methyl ester.
  • Lipozyme 100 mg, ⁇ 10 % enzyme load (active units -20,000 U/g) and shaken for a time period of 15 h at temperatures within the range of 20 0 C -60 0 C most preferably at 45-50 degree C. Conversion obtained was 49% .
  • DCM dichloromethane
  • Acid R-isomer was isolated in a yield of about 0.450 gm with optical purity of 90% by evaporation of water layer and 'S' ester was obtained in 0.487 gm by evaporating the DCM layer, Further 'S' ester was subjected for chemical hydrolysis to get S-pregabalin in 0.39 gm of optical -purity 94%.
  • Example 12 ENZYMATIC HYDROLYSIS BY SUBTILISIN CARLSBERG (FROM Bacillus licheniformis) PROTEASE (SIGMA, USA):
  • High performance liquid chromatography The reaction aliquots (20 ⁇ l) were diluted by acetonitrile (2X) to precipitate the soluble enzyme out of the medium aided by centrifugation. The supernatant was analyzed in a Zorbax C-18 column by a mixture of acetonitrile and water (30:70, v/v) using UV-DAD at 210 nm with a flow rate of 1ml /min (Ref. van Langen, LM et a/. FEBS Lett, 1999, 456, 89-92; Lovdahl, MJ ⁇ t a/., J. Pharm. Biomed. Anal. 2002,28,917-24).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention porte sur un nouveau procédé de préparation de la prégabaline racémique à partir d'un intermédiaire de structure III comprenant l'ouverture de cycle réductrice pour former une structure IV suivie par quelques voies alternatives qui conduisent à la prégabaline racémique qui est résolue pour fournir la (S)(+)-prégabaline par l'utilisation de méthodes chimiques ou enzymatiques. Une nouvelle entité chimique de structure IHc li|c est également décrite comme nouvel intermédiaire. Une partie du nouveau procédé comprend également un nouveau procédé de fabrication d'un composé de structure VII comprenant l'acylation du composé de structure V suivie par une élimination et l'amélioration d'un procédé de production d'un composé de structure VII comprenant la réaction d'isovaléraldéhyde avec du nitrométhane par l'intermédiaire des composés 4-méthyl-1-nitropentan-2-ol, acétate de 3-méthyl-1-(nitrométhyl)butyle et acétate de 3-méthyl-1-(nitrométhyl)butyle dans des conditions appropriées pour donner du 4-méthyl-1-nitropent-1-ène. L'invention porte également sur des procédés enzymatiques de résolution d'esters racémiques de la prégabaline en (S)-prégabaline et (R)-prégabaline.
PCT/IN2008/000669 2007-10-15 2008-10-14 Nouveau procédé de synthèse de la prégabaline à partir d'un intermédiaire cyclopropane substitué et procédé pour la résolution enzymatique de la prégabaline racémique WO2009087650A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2055/MUM/2007 2007-10-15
IN2055MU2007 2007-10-15

Publications (2)

Publication Number Publication Date
WO2009087650A2 true WO2009087650A2 (fr) 2009-07-16
WO2009087650A3 WO2009087650A3 (fr) 2009-10-15

Family

ID=40853538

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000669 WO2009087650A2 (fr) 2007-10-15 2008-10-14 Nouveau procédé de synthèse de la prégabaline à partir d'un intermédiaire cyclopropane substitué et procédé pour la résolution enzymatique de la prégabaline racémique

Country Status (1)

Country Link
WO (1) WO2009087650A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014080345A3 (fr) * 2012-11-20 2014-07-24 Shasun Pharmaceuticals Limited Procédé perfectionné pour la préparation de prégabaline
CN109503401A (zh) * 2018-12-21 2019-03-22 江苏卓和药业有限公司 一种普瑞巴林的制备方法
CN112368266A (zh) * 2018-06-06 2021-02-12 浙江华海药业股份有限公司 一种制备普瑞巴林的方法
WO2025077036A1 (fr) * 2023-10-13 2025-04-17 重庆普佑生物医药有限公司 Intermédiaire de ticagrélor, son procédé de préparation et procédé de synthèse utilisant ledit intermédiaire

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8600245D0 (en) * 1986-01-07 1986-02-12 Shell Int Research Preparation of 2-arylpropionic acids
UA82292C2 (uk) * 2004-04-14 2008-03-25 Пфайзер Продактс Инк. Спосіб стереоселективного біоперетворення аліфатичних динітрилів в ціанокарбонові кислоти (варіанти)
EP1768950A2 (fr) * 2005-04-11 2007-04-04 Teva Pharmaceutical Industries Ltd. Procede de fabrication de (s)-pregabaline
CA2649117A1 (fr) * 2006-05-31 2007-12-13 Teva Pharmaceutical Industries Ltd. Utilisation de la resolution enzymatique pour la preparation d'intermediaires de pregabaline
WO2008117305A2 (fr) * 2007-03-28 2008-10-02 Glenmark Pharmaceuticals Limited Nouveau procédé pour préparer de la prégabaline et ses sels d'addition avec les acides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014080345A3 (fr) * 2012-11-20 2014-07-24 Shasun Pharmaceuticals Limited Procédé perfectionné pour la préparation de prégabaline
CN112368266A (zh) * 2018-06-06 2021-02-12 浙江华海药业股份有限公司 一种制备普瑞巴林的方法
CN112368266B (zh) * 2018-06-06 2023-08-22 浙江华海药业股份有限公司 一种制备普瑞巴林的方法
CN109503401A (zh) * 2018-12-21 2019-03-22 江苏卓和药业有限公司 一种普瑞巴林的制备方法
WO2025077036A1 (fr) * 2023-10-13 2025-04-17 重庆普佑生物医药有限公司 Intermédiaire de ticagrélor, son procédé de préparation et procédé de synthèse utilisant ledit intermédiaire

Also Published As

Publication number Publication date
WO2009087650A3 (fr) 2009-10-15

Similar Documents

Publication Publication Date Title
AU2005256945B2 (en) Preparation of pregabalin and related compounds
EP2294207B1 (fr) Procédé pour l'hydrolyse enzymatique stéréosélective d'un ester d'acide 5-méthyl-3-nitrométhyl-hexanoïque
EP2916832B1 (fr) Procédé de préparation de prégabaline
EP2071032A2 (fr) Utilisation d'une résolution enzymatique pour la préparation d'intermédiaires de la prégabaline
NO335624B1 (no) Fremgangsmåte for fremstilling av (S)-3-cyano-5-metyl heksansyre og (S)-3-aminometyl-5-metyl heksansyre
ME00005B (fr) Preparation d'acides gamma-amines ayant une affinite pour la proteine alpha-2-delta
WO2009087650A2 (fr) Nouveau procédé de synthèse de la prégabaline à partir d'un intermédiaire cyclopropane substitué et procédé pour la résolution enzymatique de la prégabaline racémique
Roy et al. Eco-friendly, industrial process for synthesis of (S)-3-(aminomethyl)-5-methylhexanoic acid [pregabalin]
WO2014181359A1 (fr) Procédé pour la préparation d'un agent anticonvulsivant : le chlorhydrate de prégabaline
JP7402935B2 (ja) ブリバラセタムの合成のための重要な中間体である（ｒ）－４－プロピルピロリジン－２－オンの調製のための改良されたプロセス
JP5329973B2 (ja) リパーゼ触媒を用いるエナンチオ選択的アシル化とその後の硫酸による沈殿によって、ラセミ体の４−（１−アミノエチル）安息香酸メチルエステルから（ｒ）−および（ｓ）−４−（１−アンモニウムエチル）安息香酸メチルエステル硫酸塩を調製する方法
WO2010004577A1 (fr) Procédé de préparation d'acide gamma-nitro enrichi en énantiomère et de prégabaline
HK1125916A (en) Preparation of gamma-amino acids having affinity for the alpha-2-delta protein

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08870399

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 766/MUMNP/2010

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08870399

Country of ref document: EP

Kind code of ref document: A2