WO2006042481A1 - Procede de fabrication de clopidogrel - Google Patents

Procede de fabrication de clopidogrel Download PDF

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Publication number
WO2006042481A1
WO2006042481A1 PCT/CZ2005/000077 CZ2005000077W WO2006042481A1 WO 2006042481 A1 WO2006042481 A1 WO 2006042481A1 CZ 2005000077 W CZ2005000077 W CZ 2005000077W WO 2006042481 A1 WO2006042481 A1 WO 2006042481A1
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Prior art keywords
formula
mixture
compounds
compound
solution
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PCT/CZ2005/000077
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English (en)
Inventor
Josef Hajicek
Pavel Pihera
Hana Stepankova
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Zentiva A.S.
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Publication date
Application filed by Zentiva A.S. filed Critical Zentiva A.S.
Publication of WO2006042481A1 publication Critical patent/WO2006042481A1/fr

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    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to a new method of preparation of known antithrombic agent, the S(+) isomer of (2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridme-5(4H)-acetic acid, known under the INN name clopidogrel.
  • INN name clopidogrel is an effective antithrombic agent, indicated especially for prevention of atherosclerotic events in patients after experienced infarction, apoplectic stroke or with the ischemic disease of lower limbs. It is, therefore, fundamental in preventing relapse of these diseases and it prevents fatal consequences of said diseases.
  • patent EP 99 802 a group of agents with antiaggregation effect was described, which includes also the compound of formula I.
  • optically active isomers of the compounds are also reported.
  • Preparation of compounds of the type of clopidogrel (I) was, according to the patent, performed via reaction of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine with an alpha-chloro-derivative of an ester of alpha-(chlorophenyl)-acetic acid in the presence of a base.
  • Further development reported in patent EP 281 459 showed that of the compounds described in the above-mentioned patent, hydrogen sulfate (the HSO 4 " anion) of the compound of formula I is the most advantageous.
  • the salt was tested with respect to its antiaggregation effects and compared with some other salts.
  • EP 281 459 describes also a method of preparation of this salt. It consists in resolving the racemic mixture of the compound of formula I with the R isomer of formula II
  • US patent 6,737,411 describes an improved method of this resolution. It consists in preparation of camphorsulfonic acid in a mixture Of C 1 to C 12 hydrocarbons with a suitable co- solvent, which is selected from the group of dimethylformamide, butanol or acetone.
  • camphorsulfonic acid is dissolved in dimethylformamide and added to a solution of a mixture of compounds I and II in toluene. No procedure of further recrystallization, leading to a pure salt of form I, is, however, discussed in the patent.
  • the present invention introduces a new solution to resolution of compound I from compound II via a selection of set of solvents, which will ensure the optimal ratio of solubilities of compounds I and II as such, of the diastereoisomeric salt of compound II and of the diastereoisomeric salt of compound I, which is recovered from the solution.
  • a method of resolving according to the invention consists in separation of camphorsulfonic salts of the compounds of formulae I and II via one or more crystallizations from a mixture of two solvents, both R(-)-10-camphorsulfonic acid and its salts with the compounds of formulae
  • the solvent in which the compounds of formulae I and II are better soluble is used in excess in ratios from 1 : 2 to 1 : 100, usually though more than 1 :4.
  • the actual method of resolving the mixture of the compounds of formulae I and II consists in dissolving camphorsulfonic acid or a mixture of its salts with the compounds of formulae I and
  • the solution can be further inoculated with several crystals of the respective camphorsulfonic salt or the temperature of the solution can be decreased to 5 to 10 0 C.
  • esters, ethers or ketones have turned out as suitable solvents in case of these compounds (esters of substituted glycine).
  • the total number of carbons in the molecule of these oxygen derivates ranges from 2 to 10, from 4 to 7 carbons turning out to be preferable.
  • the particularly advantageous mixtures generally include those which require as few recrystallizations as possible. With respect to yields, such method turns out as more preferable which allows to obtain, already in the first operation, a practically pure product, which can merely be refined.
  • Another aspect of this invention includes the discovery of an appropriate method for obtaining the starting mixture of the compounds of formulae I and II.
  • the method having proved as very advantageous starts from the compound of formula V
  • reaction which is then converted to a mixture of the compounds of formulae I and II via reaction with tetrahydrothienopyridine hydrochloride in an organic solvent in the presence of an organic or inorganic base.
  • This reaction is preferably performed in the two-phase arrangement in a system of a chlorinated solvent and an aqueous solution of an inorganic base, preferably of sodium or potassium carbonates. The reaction is performed at temperatures of 40 to 120 °C.
  • Another aspect of the invention includes another method for obtaining a mixture of the compounds of formulae I and II, which starts from the unwanted compound of formula II, or from a mixture of the compounds of formulae I and II enriched with compound II.
  • the method uses the indicated reaction of potassium salts II - ⁇ I 5 wherein the equilibrium constant of this reaction is equal to 1.
  • the reaction proceeds preferably in an alcohol (C 1 to C 5 ), in water or in an aqueous alcoholic solution.
  • Esterification is then performed with methyl iodide in solvents of the type of acetone, dimethylformamide, or in a heterogeneous system organics-water under action of a phase- transfer catalyst.
  • reaction mixture was then extracted with 5 ml of IN HCl and the dichloromethane solution was added to a previously prepared mixture of 6.9 g K 2 CO 3 (49.84 mmol) in 25 ml of water, 25 ml of dichloromethane and the compound of formula III.
  • the resulting reaction mixture was refiuxed for 20.5 hours. After cooling down to room temperature, the aqueous layer was separated from the mixture.
  • the organic fraction was extracted with 15 ml of IN HCl, dried with anhydrous magnesium sulfate, and the solvent was evaporated in a rotary vacuum evaporator. The resulting evaporation residue was dissolved in 50 ml of toluene and extracted with 2x10 ml of 4N HCl.
  • the combined acidic extracts were alkalized with a 10% solution of NaHCO 3 and extracted with 2x30 ml of dichloromethane.
  • the combined dichloromethane fractions were extracted with 10 ml of water and dried with anhydrous magnesium sulfate. After evaporation of the dichloromethane solution, clopidogrel (II) was obtained as a viscous honey-like evaporation residue (11.16 g; 69.6 % of theoretical).
  • the unwanted enantiomer was reprocessed into a racemic mixture of compounds I and II.
  • Example 16 34.42 g of the compound of formula VII was dissolved in 30 ml of ethyl alcohol and added to a 50% solution of KOH, which was prepared via dissolving 50 g of KOH in 50 ml of water. The reaction mixture was heated to boil and ethyl alcohol was distilled off. Subsequently, the reaction mixture was heated for another 1 hour at 100 0 C. After cooling, the undissolved matter was filtered off on sintered glass and washed with ca 200 ml of acetone. A brownish solid of formula VII was obtained in the amount of 39.8 g.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne la séparation des sels camphosulfoniques des composés ayant la formule (I) et (II) au moyen d'une ou plusieurs cristallisations à partir d'un mélange de deux solvants, l'acide R(-)-10-camphosulfonique et ses sels avec les composés correspondant aux formules (I) et (II) étant fortement solubles dans au moins un des composants dont la formule peut être écrite sous la forme de RaOH, dans laquelle Ra est un alkyle C1 à C5 droit ou ramifié. Dans d'autres composants, l'acide camphosulfonique et ses sels sont moins solubles; ils permettent cependant de dissoudre fortement les composants ayant la formule (I) et (II).
PCT/CZ2005/000077 2004-10-18 2005-10-17 Procede de fabrication de clopidogrel WO2006042481A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ20041048A CZ20041048A3 (cs) 2004-10-18 2004-10-18 Způsob výroby klopidogrelu
CZPV2004-1048 2004-10-18

Publications (1)

Publication Number Publication Date
WO2006042481A1 true WO2006042481A1 (fr) 2006-04-27

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ID=35265647

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2005/000077 WO2006042481A1 (fr) 2004-10-18 2005-10-17 Procede de fabrication de clopidogrel

Country Status (2)

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CZ (1) CZ20041048A3 (fr)
WO (1) WO2006042481A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008034912A2 (fr) * 2006-09-22 2008-03-27 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de synthèse du clopidogrel et nouvelles formes de sels pharmaceutiquement acceptables de celui-ci
WO2008046792A1 (fr) * 2006-10-17 2008-04-24 Adamed Sp. Z O.O. FORME CRISTALLINE DE L'ACÉTATE RACÉMIQUE DE MÉTHYL-α-(2-CHLOROPHÉNYL)-2-(6,7-DIHYDROTHIÉNO[3,2-C]PYRIDIN-5(4H)), SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
WO2008130642A2 (fr) * 2007-04-18 2008-10-30 Teva Pharmaceutical Industries Ltd. Procédé perfectionné pour la préparation de clopidogrel
WO2009006859A2 (fr) * 2007-07-09 2009-01-15 Zentiva A.S. Procédé de fabrication d'acétate de 5-[2-cyclopropyl-1-(2-fluorophényl)-2-oxoéthyl]-4,5,6,7-tétrahydrothiéno[3,2-c]pyridin-2-yle (prasugrel)
KR100887655B1 (ko) 2007-08-01 2009-03-11 (주)바이오켐넷 클로피도그렐의 제조방법
CN101402556A (zh) * 2008-11-11 2009-04-08 上海现代制药股份有限公司 新化合物1-环丙基-2-(2-氟苯基)-2-羟基乙酮及其制备方法和用途
CN101402593A (zh) * 2008-11-11 2009-04-08 上海现代制药股份有限公司 用于制备普拉格雷的中间体及其制备方法
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
CN101402642B (zh) * 2008-11-11 2013-01-09 上海现代制药股份有限公司 一种新型环保制备普拉格雷的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4847265A (en) * 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
WO2002059128A2 (fr) * 2001-01-24 2002-08-01 Cadila Healthcare Ltd. Procede de preparation de clopidogrel
US6573381B1 (en) * 1997-10-06 2003-06-03 Sanofi-Synthelabo Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates
WO2004074215A1 (fr) * 2003-02-03 2004-09-02 Sunil Sadanand Nadkarni Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4847265A (en) * 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
US6573381B1 (en) * 1997-10-06 2003-06-03 Sanofi-Synthelabo Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates
WO2002059128A2 (fr) * 2001-01-24 2002-08-01 Cadila Healthcare Ltd. Procede de preparation de clopidogrel
WO2004074215A1 (fr) * 2003-02-03 2004-09-02 Sunil Sadanand Nadkarni Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008034912A2 (fr) * 2006-09-22 2008-03-27 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de synthèse du clopidogrel et nouvelles formes de sels pharmaceutiquement acceptables de celui-ci
WO2008034912A3 (fr) * 2006-09-22 2008-08-07 Krka Tovarna Zdravil D D Novo Procédé de synthèse du clopidogrel et nouvelles formes de sels pharmaceutiquement acceptables de celui-ci
WO2008046792A1 (fr) * 2006-10-17 2008-04-24 Adamed Sp. Z O.O. FORME CRISTALLINE DE L'ACÉTATE RACÉMIQUE DE MÉTHYL-α-(2-CHLOROPHÉNYL)-2-(6,7-DIHYDROTHIÉNO[3,2-C]PYRIDIN-5(4H)), SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
WO2008130642A3 (fr) * 2007-04-18 2009-06-04 Teva Pharma Procédé perfectionné pour la préparation de clopidogrel
WO2008130642A2 (fr) * 2007-04-18 2008-10-30 Teva Pharmaceutical Industries Ltd. Procédé perfectionné pour la préparation de clopidogrel
JP2009532508A (ja) * 2007-04-18 2009-09-10 テバ ファーマシューティカル インダストリーズ リミティド クロピドグレルの改良された調製方法
WO2009006859A2 (fr) * 2007-07-09 2009-01-15 Zentiva A.S. Procédé de fabrication d'acétate de 5-[2-cyclopropyl-1-(2-fluorophényl)-2-oxoéthyl]-4,5,6,7-tétrahydrothiéno[3,2-c]pyridin-2-yle (prasugrel)
WO2009006859A3 (fr) * 2007-07-09 2009-03-19 Zentiva As Procédé de fabrication d'acétate de 5-[2-cyclopropyl-1-(2-fluorophényl)-2-oxoéthyl]-4,5,6,7-tétrahydrothiéno[3,2-c]pyridin-2-yle (prasugrel)
CZ302135B6 (cs) * 2007-07-09 2010-11-10 Zentiva, A. S. Zpusob výroby 5-[2-cyklopropyl-1-(2-fluorfenyl)-2-oxoethyl]-4, 5, 6, 7-tetrahydrothieno[3,2-c]pyridin-2-yl acetátu (prasugrelu)
EA016207B1 (ru) * 2007-07-09 2012-03-30 ЗЕНТИВА, а.с. СПОСОБ ПОЛУЧЕНИЯ 5-[2-ЦИКЛОПРОПИЛ-1-(2-ФТОРФЕНИЛ)-2-ОКСОЭТИЛ]-4,5,6,7-ТЕТРАГИДРОТИЕНО[3,2-с]ПИРИДИН-2-ИЛА АЦЕТАТА (ПРАСУГРЕЛЯ)
KR100887655B1 (ko) 2007-08-01 2009-03-11 (주)바이오켐넷 클로피도그렐의 제조방법
CN101402556A (zh) * 2008-11-11 2009-04-08 上海现代制药股份有限公司 新化合物1-环丙基-2-(2-氟苯基)-2-羟基乙酮及其制备方法和用途
CN101402593A (zh) * 2008-11-11 2009-04-08 上海现代制药股份有限公司 用于制备普拉格雷的中间体及其制备方法
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
CN101402642B (zh) * 2008-11-11 2013-01-09 上海现代制药股份有限公司 一种新型环保制备普拉格雷的方法

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Publication number Publication date
CZ295920B6 (cs) 2005-11-16
CZ20041048A3 (cs) 2005-11-16

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