WO2006086921A1 - Procédé de préparation du clopidogrel - Google Patents

Procédé de préparation du clopidogrel Download PDF

Info

Publication number
WO2006086921A1
WO2006086921A1 PCT/CN2005/002289 CN2005002289W WO2006086921A1 WO 2006086921 A1 WO2006086921 A1 WO 2006086921A1 CN 2005002289 W CN2005002289 W CN 2005002289W WO 2006086921 A1 WO2006086921 A1 WO 2006086921A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
chlorophenyl
acid
nitrilase
methyl
Prior art date
Application number
PCT/CN2005/002289
Other languages
English (en)
Chinese (zh)
Inventor
Hongping Ye
Meg M. Sun
Zuolin Zhu
Original Assignee
Pficker Pharmaceuticals 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 Pficker Pharmaceuticals Ltd. filed Critical Pficker Pharmaceuticals Ltd.
Publication of WO2006086921A1 publication Critical patent/WO2006086921A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a process for the production of the antithrombotic drug clopidogrd, and more particularly to a biochemical synthesis process of clopidogrel. Background of the invention
  • Clopidogrd is a new generation of ADP-inducible platelet aggregation preparation that directly inhibits ADP-induced platelet aggregation by blocking ADP receptors and inhibiting ADP-mediated (GP)IIMIIa complex activity (US) 4, 847, 265).
  • the structure of clopidogrd is as shown in formula (1), that is, acetic acid [(S)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3] ,2-c]-pyridine)]methyl ester (methyl-(S)-a-(2- chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate)
  • the yield can be increased, but the production step is increased.
  • the synthesis method for the resolution of racemic products requires a relatively expensive high-purity chiral substance such as Camphorsulfonic acid, Tartaric acid, Mandelic acid, and Lactic acid. , Maleic acid, Amino acid, and derivatives of these acids.
  • the disadvantages of the methods of splitting are lower yields, more steps, and higher costs.
  • a process for the production of clopidogrel using a bioenzyme catalytic chemical synthesis process is provided.
  • the method for producing clopidogrel of the present invention comprises the following steps:
  • the amount of the nitrilase in step (a) is from 0.1 to 100% by weight, based on the amount of 2-chlorobenzaldehyde, or by ( ⁇ )2-(2'-chlorophenyl group The amount of 2-hydroxyacetonitrile is calculated.
  • the amount of the nitrilase in step (a) is from 1 to 30% (more preferably from 5 to 25%) by weight, based on the amount of 2-chlorobenzaldehyde, or ( ⁇ ) The amount of 2-(2'-chlorophenyl)-2-hydroxyacetonitrile was calculated. ''
  • 2-chlorobenzaldehyde in step (a) is reacted with hydrocyanic acid or with 2-methyl-2-hydroxypropionitrile in a methanol solvent at a temperature between -5 and 15 ° C. Carry out for about 2 to 24 hours.
  • a sodium phosphate buffer having a concentration e.g., a concentration of 100 ⁇ 20 mmol
  • the reaction condition of the step (b) is: reacting in a solvent of dichloromethane, tetrahydrofuran, toluene, or methanol in the presence of sulfuric acid at room temperature to reflux for 1-20 hours. .
  • the reaction condition of the step (c) is: in the presence of 4-dimethylaminopyridine in a solvent of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, or toluene, The reaction is carried out at a temperature between minus 20 ° C and room temperature for 4 to 12 hours.
  • reaction conditions of the step (d) are: reacting in an inert solvent in the presence of potassium carbonate or sodium carbonate at a temperature between 20 ° C and reflux for 4 to 24 hours.
  • a nitrilase (Nitri lases EC 3. 5.5.1) which is used in the process for producing the (S)-enantiomer clopidogrel.
  • the inventors have for the first time developed a method for directly synthesizing the (S)-enantiomer clopidogrel using a nitrilase after extensive and intensive research.
  • the process does not need to be split, so the yield is high, the cost is low, and the process is simplified, thereby solving the problem that the existing synthesis method needs to be recrystallized and split to obtain the desired (S)-enantiomer.
  • the nitrilase (Nitri lases EC 3. 5. 5. 1) is capable of catalyzing the hydrolysis of organic cyanide (also known as nitrile) to the corresponding organic acid under mild conditions.
  • the nitrilase can be prepared by conventional methods (e.g., isolated or recombinantly produced), or it can be purchased (e.g., from a company such as Sigma).
  • the method of the invention comprises the following steps:
  • reaction (1) 2-chlorobenzaldehyde is used as a starting material, and racemic ( ⁇ ) 2-(2'-chlorophenyl)-2-hydroxyacetonitrile can be obtained by reaction with hydrocyanic acid.
  • the hydrocyanic acid used in the reaction may be a pure gas, or may be prepared by a reaction with an organic acid or a mineral acid with a metal cyanide (e.g., sodium cyanide, potassium cyanide, etc.) in the reaction system.
  • a metal cyanide e.g., sodium cyanide, potassium cyanide, etc.
  • the organic acid used in the reaction may be formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid; the inorganic acid may be hydrochloric acid, sulfuric acid, and phosphoric acid.
  • a preferred organic acid is acetic acid; a preferred inorganic acid is hydrochloric acid or sulfuric acid.
  • the reaction is generally carried out using a protonic solvent such as methanol as a solvent at a temperature between minus 5 ° C and 15 ° C (preferably about 0 ° C).
  • the reaction time is usually about 2 to 24 hours, preferably 2 to 4 hours.
  • Racemic ( ⁇ )2-(2'-chlorophenyl)-2-hydroxyacetonitrile can also be prepared by the reaction of 2-chlorobenzaldehyde and 2-methyl-2-hydroxypropanenitrile.
  • the amount of 2-methyl-2-hydroxypropionitrile is 1-20 molar equivalents (based on the amount of 2-chlorobenzaldehyde), and generally 1.5 to 5 molar equivalents are used.
  • 1% to 10% by mole of diisopropylethylamine is used as a catalyst.
  • the reaction temperature is generally between minus 5 ° C and 15 ° C. C, more preferably around 0 °C.
  • the reaction time is usually about 1-10 hours, preferably 1-2 hours.
  • Nitrile hydrolase hydrolyzes racemic ( ⁇ ) 2-(2'-chlorophenyl)-2-hydroxyacetonitrile:
  • the nitrilase is used to hydrolyze racemic ( ⁇ )2-(2'-chlorophenyl)-2-hydroxyacetonitrile to give the corresponding (R)-2'-chlorophenyl group.
  • 2-hydroxyacetic acid ie (R)-mandelic acid organic acid.
  • the hydrolysis reaction is carried out in a buffer solution of pure water or a pH of 6.5 to 8.5.
  • the reaction system may generally comprise 10% by volume of methanol to increase the solubility of the reactants.
  • the nitrilase is used in an amount of from 1 to 100% by weight, usually 10 to 30% by weight, based on the amount of the substrate ( ⁇ ) 2-(2'-chlorophenyl)-2-hydroxyacetonitrile.
  • the reaction can be carried out under the protection of an inert gas such as nitrogen, and the reaction temperature is usually between room temperature and 65 ° C, preferably about 37 ° C.
  • the reaction time is usually about 1 to 24 hours, preferably 3 to 6 hours
  • reaction (1) and (2) may be combined, that is, the solution containing 2-chlorobenzaldehyde and hydrogen cyanide may be directly hydrolyzed by a nitrilase to obtain a (R)-mandelic acid organic acid.
  • the ketone hydrogen cyanide is in a dynamic equilibrium in the solution, and the nitrilase selectively catalyzes the hydrolysis of one of the enantiomers.
  • the hydrolysis reaction can be monitored by a high pressure liquid chromatography (HPLC) method.
  • HPLC high pressure liquid chromatography
  • the reaction can generally achieve a yield of more than 90% and an optical purity of 96% (% ee).
  • the temperature of the reaction (3) is usually from room temperature to 50 ° C, and the reaction time is usually about 4 to 24 hours, preferably 6 to 10 hours.
  • (R) - mandelic acid is converted into the corresponding methyl mandelate by esterification;
  • the mandelic acid is further converted into the corresponding methyl mandelate by an esterification reaction.
  • This step is generally carried out in an organic solvent such as methylene chloride, tetrahydrofuran, toluene or methanol.
  • the usual organic solvent is methanol.
  • the catalyst used in the reaction is generally a mineral acid (the concentration of the inorganic acid such as sulfuric acid is usually 0.01 - 0.1 M.
  • the reaction temperature is usually from room temperature to reflux temperature, preferably reflux temperature ° C.
  • the reaction time is usually between 1 -20 hours.
  • Ph is a substituted or unsubstituted phenyl group, and the substituent is selected from the group consisting of halogen, ( ⁇ 4 alkyl, nitro.
  • methyl mandelate passes and the corresponding sulfonyl halide or sulfonic anhydride Reaction to obtain a sulfonate intermediate, namely methyl-(10 -2-benzenesulfonyl-2-(2'-chlorophenyl) acetate.
  • the leaving group which it can be used also includes various substituted benzenesulfonic acid groups such as p-toluenesulfonic acid group, p-chlorobenzenesulfonic acid group, o-chlorobenzenesulfonic acid group, and p-nitrobenzenesulfonic acid group, and the like.
  • other compounds which can be used as the leaving group also include phosphate [- 0P0 (OR) 2 ] and phosphite [- OP (OR) 2 ], wherein R is a C 4 fluorenyl group.
  • This step is generally carried out in an aprotic solvent.
  • organic solvents include methylene chloride, 1,2-dichloroethane, tetrahydrofuran, toluene, and the like.
  • the catalyst commonly used in the reaction is 4-dimethylaminopyridine (DMAP), and the usual acid neutralizing agent is triethylamine or pyridine.
  • DMAP 4-dimethylaminopyridine
  • the reaction temperature is usually between minus 20 ° C and room temperature, preferably between 0 and 5 ° C.
  • the reaction time is usually about 4 to 12 hours, preferably 4 to 5 hours.
  • the (S)-enantiomer clopidogrel is obtained by the reaction of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine and a sulfonate intermediate.
  • the reaction is usually carried out in an inert solvent such as dichloromethane, and the reaction temperature is usually room temperature - reflux temperature, preferably reflux temperature.
  • the base used in the reaction is potassium carbonate or sodium carbonate.
  • the reaction time is usually about 4 to 24 hours, preferably 4 to 5 hours.
  • the production process in the present invention does not involve the use of any chiral compound, and since the chiral product is directly obtained without splitting, the production process has high yield, low cost, and simplified process. .
  • the detection method is the method described in the literature Hoover, J. R. E.; Dunn, G. L.; Jakas, D. R.; Lam, L. L.; Taggart, J. J.; Guarini, J. R.; Phillips, L. J. Med. Chem. 1974, 17, 34-41.
  • 0.3 mole of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine was dissolved in 400 ml of dichloromethane under stirring, and then 140 g of 30% carbonic acid was added to the solution. Potassium aqueous solution.
  • 0.25 mole of methyl-(R)-2-benzenesulfonyl-2-(2'-chlorophenyl)acetate was dissolved in 100 ml of methylene chloride to prepare a homogeneous solution for use.
  • Example 2 was repeated except that the nitrilase was 1 wt%, and as a result, a solid (R)-mandelic acid product (a yield of about 80%) was obtained.
  • Example 8
  • Example 3 was repeated except that the nitrilase was 0.5% by weight, and as a result, a solid (R)-mandelic acid product (yield about 70%) was obtained.
  • the production process of the invention directly obtains a chiral product without splitting, so the production process has high yield.
  • the yield of the (S)-enantiomer clopidogrel can be as high as about 881 because of the low cost and process simplification since no expensive chiral compounds are used. Because the use of biological enzymes catalyzes key reactions, the entire production process produces less waste and is environmentally friendly.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention décrit un procédé de préparation du clopidogrel. Le procédé de la présente invention fait appel à la nitrilase pour hydrolyser le prussiate organique racémique en ses acides organiques correspondants dont la rotation optique est élevée, produisant ainsi du clopidogrel (S) après quelques réactions. Le procédé ne comprend pas l’étape de clivage, ce qui augmente ainsi le rendement, réduit le coût et simplifie le procédé et, par conséquent, résout le problème qui survient dans le procédé synthétique, procédé qui requiert une cristallisation pour cliver la substance afin d'obtenir l’énantiomère (S).
PCT/CN2005/002289 2005-02-18 2005-12-22 Procédé de préparation du clopidogrel WO2006086921A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2005100532589A CN100406568C (zh) 2005-02-18 2005-02-18 氯吡格雷新生产工艺
CN200510053258.9 2005-02-18

Publications (1)

Publication Number Publication Date
WO2006086921A1 true WO2006086921A1 (fr) 2006-08-24

Family

ID=36769391

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2005/002289 WO2006086921A1 (fr) 2005-02-18 2005-12-22 Procédé de préparation du clopidogrel

Country Status (2)

Country Link
CN (1) CN100406568C (fr)
WO (1) WO2006086921A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101402643B (zh) * 2008-11-11 2012-11-28 上海现代制药股份有限公司 一种适于工业生产的普拉格雷的制备方法
CN101987854A (zh) * 2009-08-04 2011-03-23 北京万全阳光医学技术有限公司 一种氯吡格雷及其盐的制备方法
CN101864464B (zh) * 2010-04-29 2012-10-10 重庆凯乐尔生物催化技术有限公司 一种制备氯吡格雷手性中间体(s)-邻氯苯甘氨酸甲酯的化学-酶法
CN106928251B (zh) * 2015-12-30 2021-05-04 江苏天士力帝益药业有限公司 一种高纯度氯吡格雷的制备方法
CN107417570B (zh) * 2017-09-14 2020-04-14 哈尔滨理工大学 利用丙酮氰醇制备α-羟基腈的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6573381B1 (en) * 1997-10-06 2003-06-03 Sanofi-Synthelabo Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates
WO2003093276A1 (fr) * 2002-05-03 2003-11-13 Dipharma S.P.A. Procede de preparation de clopidogrel

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1353928B1 (fr) * 2001-01-24 2006-12-27 Cadila Healthcare Ltd. Procede de preparation de clopidogrel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6573381B1 (en) * 1997-10-06 2003-06-03 Sanofi-Synthelabo Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates
WO2003093276A1 (fr) * 2002-05-03 2003-11-13 Dipharma S.P.A. Procede de preparation de clopidogrel

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHN Z. ET AL.: "Graphical Synthetic Routes of Clopidogrel", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 33, no. 4, 2002 *
WANG P. ET AL.: "Chiral Chemistry Promotes Development of Monoenantiomer", FINE AND SPECIALITY CHEMICALS, vol. 12, no. 14, 12 July 2004 (2004-07-12), pages 2 *

Also Published As

Publication number Publication date
CN1778936A (zh) 2006-05-31
CN100406568C (zh) 2008-07-30

Similar Documents

Publication Publication Date Title
JP5000841B2 (ja) クロピドグレルの製造方法
JP3840662B2 (ja) ２−シリルオキシ−テトラヒドロチエノピリジン類、その塩およびその製造方法
CN107501112B (zh) 一种手性β-氨基酸的手性合成方法及医药中间体的合成方法
WO2006086921A1 (fr) Procédé de préparation du clopidogrel
US6858734B2 (en) Preparation of (S)-Clopidogrel and related compounds
EP1501838B1 (fr) Procede de preparation de clopidogrel
EP0351126B1 (fr) Procédé pour la préparation de O2,2'-anhydro-1-(bêta-D-arabinofuranosyl)thymine
CN112851652B (zh) 一种2-(取代氧杂蒽基)苯并呋喃类化合物的催化氧化合成方法
KR101130717B1 (ko) ＨＭＧ-ＣｏＡ 환원 저해제의 제조를 위한 키랄 중간체의제조방법
US8895780B2 (en) Process for preparing N-H or N-alkyl 2-propynamide
HUT65252A (en) Process for producing of quinolin-2-yl-methoxybenzylhydroxyureas and pharmaceutical compositions comprising them
CN113816955B (zh) 一种ret激酶抑制剂中间体及其制备方法
JP4336913B2 (ja) アミド誘導体の製造方法
PL209416B1 (pl) Sposób otrzymywania (3-cyjano-1H- indol-7- ilo) [4-( 4-fluorofenetylo) piperazyn-1- ylo] metanonu i jego soli oraz cyjanoindoloestry i kwas 3-cyjano-1H-indolo-7-karboksylowy będące związkami pośrednimi takiego sposobu
KR100424341B1 (ko) 1-메틸인다졸-3-카르복실산의 제조방법
JP4061333B2 (ja) ２−（ピラゾール−１−イル）ピリジン誘導体
KR100856133B1 (ko) 아토르바스타틴의 개선된 제조방법
JP2006176531A (ja) 光学活性ベンズイミダゾール誘導体の光学異性体
KR100466797B1 (ko) 벤조아제핀 유도체 및 인듐을 이용하는 그의 제조방법
JPH07278141A (ja) 光学活性ベンズイミダゾール誘導体の製造法および中間体
KR0157511B1 (ko) 2-술포닐티아졸 카르복사미드 유도체의 제조방법
CN118063427A (zh) 一种3-羟基-2-烯-1-环己酮类衍生物的制备方法
US20050137401A1 (en) Process for the preparation of tetrahydrothieno [3,2-C] pyridine derivatives
FI66863C (fi) Foerfarande foer framstaellning av tiazolidin-4-onaettiksyraderivat
EP1577310A1 (fr) Procedes de production de derive d'acide 2-thiomethyl-3-phenylpropionique optiquement actif et de production d'intermediaire de celui-ci

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05822290

Country of ref document: EP

Kind code of ref document: A1

WWW Wipo information: withdrawn in national office

Ref document number: 5822290

Country of ref document: EP