WO2008018779A1 - Procédé pour une production à haut rendement de clopidogrel par racémisation de liquide résiduel - Google Patents

Procédé pour une production à haut rendement de clopidogrel par racémisation de liquide résiduel Download PDF

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Publication number
WO2008018779A1
WO2008018779A1 PCT/KR2007/003868 KR2007003868W WO2008018779A1 WO 2008018779 A1 WO2008018779 A1 WO 2008018779A1 KR 2007003868 W KR2007003868 W KR 2007003868W WO 2008018779 A1 WO2008018779 A1 WO 2008018779A1
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WIPO (PCT)
Prior art keywords
clopidogrel
formula
carboxylic acid
preparing
racemization
Prior art date
Application number
PCT/KR2007/003868
Other languages
English (en)
Inventor
Nam Ho Kim
Jin Young Lee
Jae-Sun Kim
Nam Kyu Lee
Original Assignee
Sk Chemicals Co., 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 Sk Chemicals Co., Ltd. filed Critical Sk Chemicals Co., Ltd.
Publication of WO2008018779A1 publication Critical patent/WO2008018779A1/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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to a process for preparing S-(+)-clopidogrel in high yield by means of racemization of a filtrate, and particularly to a process comprising (a) conducting an optical resolution by converting racemic carboxylic acid of clopidogrel to diastereomer salt using (+)-cinchonine / (b) preparing carboxylic acid of S-(+)-clopidogrel by extraction using an appropriate solvent under an acidic condition, (c) preparing optically pure S-(+)-clopidogrel by reacting the carboxylic acid of S-(+)-clopidogrel with methanol, wherein a filtrate, which remains after collecting the diastereomer salt as solid precipitates, is recycled after being converted to racemic carboxylic acid of clopidogrel via racemization in the presence of a basic solution, thereby maximizing the yield of S-(+)-clopidogrel.
  • S-(+)-clopidogrel of Formula 1 i.e., methyl (+)-(S)- ⁇ -(o-chlorophenyl)-6,7- dihydrothieno[3,2-a]pyridine-5(4H)-acetate, has a strong inhibitory activity against platelet aggregation and anti-thrombotic activity and thus has been known useful for the treatment of peripheral arterial diseases (e.g., cerebral apoplexy, thrombus, embolus, etc.) and coronary arterial diseases (e.g., myocardial infarction, angina pectoris, etc.).
  • peripheral arterial diseases e.g., cerebral apoplexy, thrombus, embolus, etc.
  • coronary arterial diseases e.g., myocardial infarction, angina pectoris, etc.
  • S-(+)-clopidogrel is a very effective agent having a better inhibiting platelet aggregation than aspirin even with a less amount while its toxic effect on the gastrointestinal tract is much reduced as compared to that of aspirin.
  • S-(+)-clopidogrel is commercially available in the name of PIa vixTM. This product is provided in a tablet form containing about 98 mg of S-(+)-clopidogrel hydrogen sulfate, which is equivalent to about 75 mg of S-(+)-clopidogrel base as active ingredients.
  • 4,847,265 discloses an optical resolution method for preparing S-(+)-clopidogrel using a (lR)-(-)-camphosulfonic acid as an optically active acid.
  • WO 98/51689 discloses a process for preparing S-(+)-clopidogrel by conducting optical resolution and subsequent reactions from a compound of (e), wherein R is nitrile, carboxyamide or carboxylic acid.
  • WO 02/059128 discloses a process for preparing S-(+)- clopidogrel by conducting optical resolution and subsequent reactions from a compound of Formula (g) ), wherein R is nitrile, carboxyamide or carboxylic acid.
  • the known processes of preparing S-(+)-clopidogrel may involve the optical resolution inevitably in a specific step of the continuous preparation processes.
  • the optical resolution of clopidogrel racemates and an intermediate thereof is very disadvantageous environmentally and economically because it is unavoidable that all the levorotatory isomer and its intermediate are to be wasted, which could be at least 50% of the total amount of racemates.
  • the optical resolution process normally requires repetition of purification process such as recrystallization several times, thus causing the decrease in the yield.
  • Formula (m) is subjected to cyclization with formaldehyde in an acidic medium, thereby preparing clopidogrel.
  • X is a halogen or a sulfonate group.
  • WO 99/18110 discloses a process for preparing clopidogrel by a
  • An object of the present invention is to provide an efficient process for preparing S-(+)-clopidogrel with high optical and chemical purity in a simple manner that a diastereomer salt is formed from a racemic carboxylic acid of clopidogrel by using (+)-cinchonine through optical resolution followed by extraction with an appropriate solvent.
  • An other object of the present invention is to provide a process for the commercial mass production of S-(+)-clopidogrel by carrying out recycling of the racemic carboxylic acid of clopidogrel, which is recovered by racemizing the filtrate after separation of the diastereomer salt in a basic solution, at the same time along with the process for preparing S-(+)-clopidogrel.
  • the present invention relates to a process comprising: (i) preparing a diastereomer salt of Formula 4 as solid precipitates by reacting a racemic carboxylic acid of clopidogrel of Formula 2a and (+)-cinchonine of Formula 3 followed by a solid-liquid phase separation; (ii) preparing a carboxylic acid of S-(+)- clopidogrel of Formula 2b by desalting the diastereomer salt of Formula 4 under an acidic condition; and (iii) preparing S-(+)-clopidogrel of Formula 1 by reacting a carboxylic acid of S-(+)-clopidogrel of Formula 2b with methanol under an acidic condition; wherein a filtrate obtained after the phase separation of diastereomer salt in step i) is recycled after being converted to a racemic carboxylic acid of clopidogrel of Formula 2a by conducting sequential processes of desalting under an acidic condition and racemization under a basic
  • step i) a racemic carboxylic acid of clopidogrel of Formula 2a is reacted with (+)-cinchonine of Formula 3, thus providing a diastereomer salt of Formula 4.
  • the racemic carboxylic acid of clopidogrel of Formula 2a is easily obtained by the hydrolysis of racemic clopidogrel.
  • the (+)-cinchonine of Formula 3 has a chemical purity of 85% or higher and comprises less than about 15% of dihydrocinchonine.
  • the (+)-cinchonine of Formula 3 may be used in the amount of 0.5-1.0 equivalent relative to the racemic carboxylic acid of clopidogrel of Formula 2a.
  • the ratio of carboxylic acid isomer of (R)-clopidogrel contained in the mother liquor to a cinchonine in the diastereomeric salt may vary depending on the equivalent ratio of
  • (+)-cinchonine used.
  • Ordinary solvent such as water, ketones, alcohols, ethers, amides, esters, hydrocarbons, chlorohydrocarbons, nitriles and a mixture thereof may be used as a solvent.
  • Preferable examples of the solvent are ketones, alcohols, nitriles or a mixture thereof.
  • the optical resolution is conducted by the formation of diastereomer salt using (+)-cinchonine as an optical resolving agent. Specifically, the optical resolution is conducted by means of a process of stirring or shaking and a process of standing of reactants using an organic solvent after the reaction with (+)-cinchonine.
  • the optical resolution may be conducted at a temperature of between -30 °C and 60 °C, preferably at between -10 °C and 40 0 C.
  • step ii) a carboxylic acid of S-(+)-clopidogrel of Formula 2b is prepared by using the diastereomer salt of Formula 4.
  • the diastereomer salt of Formula 4 is dissolved in water, desalted by the addition of an acid to be adjusted to pH 3-5, and extracted with an ordinary organic solvent, thus providing carboxylic acid of S-(+)-clopidogrel of Formula 2b.
  • Inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid and organic acids such as acetic acid may be used as the acid.
  • Any solvent selected among ketones, alcohols, ethers, amides, esters, hydrocarbons, chlorohydrocarbons, nitriles and a mixture thereof may be used as an organic solvent.
  • Preferable examples of the solvents are acetone, acetonitrile, methanol, ethanol, isopropanol, n- butanol, f-butanol, ethylacetate, dichloromethane, toluene, diethylether, n-hexane and a mixture thereof.
  • the carboxylic acid of S-(+)-clopidogrel of Formula 2b which is obtained by the extraction using the organic solvent, may be highly purified easily by means of an ordinary filtration.
  • the optical purity may further increased by controlling the solvent condition, preferably by means of recrystallization using organic solvent comprising acetone or acetonitrile.
  • step iii) S-(+)-clopidogrel of Formula 1 is prepared by reacting the carboxylic acid of S-(+)-clopidogrel of Formula 2b under an acidic condition methanol.
  • the carboxylic acid of S-(+)-clopidogrel of Formula 2b is reacted with methanol under an acidic condition, where organic acid such as thionyl chloride is used in the amount of 1.0-2,0 equivalents, at a temperature of 40-80 °C, preferably at a reflux temperature, thus providing the desired S-(+)-clopidogrel of Formula 1.
  • organic acid such as thionyl chloride
  • another feature of the present invention lies in the maximization of the yield of S-(+)-clopidogrel by preparing and recycling a racemic carboxylic acid of clopidogrel of Formula 2a by using a filtrate, which remains after collecting the diastereomer salt of Formula 4 as solid precipitates.
  • the diastereomer salt of Formula 4 is separated and collected as solid precipitates by means of a solid-liquid ph ase separation method.
  • (R)-isomer is enriched in the remaining filtrate.
  • the present invention aims to improve the commercial utilization by collecting (R)-isomers as racemates and recycling them as a starting material.
  • the diastereomer salt is desalted by adding an acid in the filtrate to be adjusted to pH 3-5.
  • the racemic carboxylic acid of clopidogrel of Formula 2a is prepared and collected by conducting racemization of the diastereomer under a basic condition.
  • the obtained racemic carboxylic acid of clopidogrel of Formula 2a is reused in step i).
  • the acidic work-up of filtrate is an ordinary acid treatment, followed by extraction using an appropriate solvent.
  • This acid treatment desalts the diastereomer salt and provides two isomers, i.e., a mixture of carboxylic acid intermediate of clopidogrel of Formulas 2c and 2b. A most portion of this mixture is (R)-isomer, and a small amount of (S)-isomer exists in this mixture.
  • the racemization of the obtained racemates is conducted under a basic condition of pH 9 or higher.
  • Organic bases such as amines or inorganic bases such as alkali metal or alkaline earth metal may be used as a base.
  • Preferable examples of the base are basic aqueous solution of sodium hydroxide or potassium hydroxide.
  • the racemization may be conducted by using a base in the amount of 1-20 equivalents relative to carboxylic acid of clopidogrel at a temperature of 30-150 0 C, preferably at a reflux temperature.
  • the degree of the racemization is measured by using HPLC.
  • the reaction is terminated when optical purity decreases below 10% e.e.
  • Reaction mixtures are neutralized and extracted according to the conventional method, and crystallized into solids by using a solvent such as ethyl ether, hexane, ethyl acetate, dichloromethane, acetonitrile and a mixture thereof.
  • a solvent such as ethyl ether, hexane, ethyl acetate, dichloromethane, acetonitrile and a mixture thereof.
  • steps i), ii) and iii) may be conducted continuously without being interrupted by the process of removing intermediates.
  • S-(+)-clopidogrel of Formula 1 obtained according to the present invention may be manufactured into a pharmaceutically acceptable salt with an acid.
  • Examples of the acid are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic acid and tartaric acid.
  • S-(+)-clopidogrel of Formula 1 may also be reacted with alkali metal ion such as sodium or potassium ion or ammonium ion, thereby providing a pharmaceutically acceptable salt.
  • Example 1 Preparation of diastereomer salt (4) using racemic carboxylic acid of clopidogrel (2a)
  • Example 2 followed by a slow addition of c-HCl to adjust pH to 4. This solution was extracted with dichloromethane (60 mL x 3 times), and the organic layer was dried with Na 2 SO 4 , filtered and concentrated, thereby providing 1.12 g of carboxylic acid (2b) of S-(+)-clo ⁇ idogrel.
  • Example 6 Preparation of racemic carboxylic acid (2a) of clopidogrel using filtrate via racemization White solid diastereomer salt (4) prepared in Example 2 was separated, and the filtrate was concentrated and added with water (20 mL), followed by a slow addition of c-HCl, thereby adjusting pH to 4. This solution was extracted with dichloromethane (30 mL x 3 times), and the organic layer was dried with Na 2 SO 4 , filtered and concentrated, thereby providing 1.8 g (optical purity 67% (HPLC), R- isomer dominant) of racemates comprising carboxylic acid of S-clopidogrel(2b) and carboxylic acid of R-clopidogrel(2c).
  • racemates (1.8 g) was placed in a 50 mL flask, and added with a 20 mL aqueous solution of 10 N potassium hydroxide, followed by stirring at 110 °C for 40 hours. The temperature of the solution was lowered down to 5 °C, and added with c-HCl, thereby adjusting pH to 4. This solution was extracted with dichloromethane (30 mL x 3 times), and the organic layer was dried with Na2SO4, filtered and concentrated, thereby providing carboxylic acid of racemic clopidogrel (1.71 g, yield 95%, optical purity 0.3% (HPLC)).
  • Example 8 Preparation of (S)-(+)-clopidogrel (1) using racemic carboxylic acid of clopidogrel (2a) via continuous reaction
  • concentrates comprising carboxylic acid (2b) of S-(+)-clopidogrel was dissolved in 20 mL of methanol, and added with 0.35 mL of SOCl 2 0.35 mL, followed by stirring at 70 0 C for 6 hours. The temperature of this solution was lowered down to room temperature, and concentrated at a reduced pressure, followed by the addition of 10% NaHCO 3 (aq) to adjust pH to 7. This solution was extracted with dichloromethane (20 mL x 2 times), and the organic layer was dried with Na 2 SO 4 , filtered and concentrated at a reduced pressure.
  • a racemic carboxylic acid of clopidogrel is converted to a diastereomer salt by using (+)-cinchonine and optically resolved by using an appropriate solvent, thereby providing S-(+)-clopidogrel with relatively high optical and chemical purity.
  • R-isomer which is contained in a filtrate remaining after the purification of the diastereomer salt, is racemized under a basic condition and collected as an intermediate of racemic carboxylic acid for recycling as a starting material. Therefore, the process of the present invention is useful for the commercial mass production of S-(+)-clopidogrel.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé pour préparer du S-(+)-clopidogrel avec un haut rendement par la racémisation de filtrat, et en particulier un procédé comprenant les opérations consistant (a) à conduire une résolution optique par conversion de l'acide carboxylique racémique de clopidogrel en sel diastéréomère à l'aide de la (+)-cinchonine, (b) à préparer de l'acide carboxylique du S-(+)-clopidogrel par extraction à l'aide d'un solvant approprié dans une condition acide, (c) à préparer du S-(+)-clopidogrel optiquement pur par réaction de l'acide carboxylique de S-(+)-clopidogrel avec le méthanol, dans lequel un filtrat, qui reste après le ramassage du sel diastéréomere en tant que précipités solides, est recyclé après avoir été converti en un acide carboxylique racémique de clopidogrel par racémisation sous une condition basique, permettant ainsi de rendre maximal le rendement de S-(+)-clopidogrel.
PCT/KR2007/003868 2006-08-11 2007-08-13 Procédé pour une production à haut rendement de clopidogrel par racémisation de liquide résiduel WO2008018779A1 (fr)

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KR10-2006-0076310 2006-08-11
KR1020060076310A KR100834967B1 (ko) 2006-08-11 2006-08-11 여액의 라세미화 반응에 의한 ｓ-(＋)-클로피도그렐의고수율 제조방법

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007019A1 (fr) 2010-07-13 2012-01-19 Pharmathen S.A. Procédé de synthèse du clopidogrel et de ses sels

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6737411B2 (en) * 2002-08-02 2004-05-18 Teva Pharmaceutical Industries Ltd. Racemization and enantiomer separation of clopidogrel
US20040260110A1 (en) * 1997-10-06 2004-12-23 Andre Bousquet Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates
KR20050008692A (ko) * 2003-02-13 2005-01-21 헬름 아게 클로피도그렐을 함유하는 술폰산의 염 및 제약 제제를제조하기 위한 그의 용도
US20060074242A1 (en) * 2004-10-04 2006-04-06 Manoj Madhukarrao Deshpande Rapid resolution process of clopidogrel base and a process for preparation of clopidogrel bisulfate polymorph-form I

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20070023185A (ko) * 2005-08-23 2007-02-28 에스케이케미칼주식회사 Ｓ-(＋)-클로피도그렐 헤미나파디실레이트 염 및 그의제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040260110A1 (en) * 1997-10-06 2004-12-23 Andre Bousquet Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates
US6737411B2 (en) * 2002-08-02 2004-05-18 Teva Pharmaceutical Industries Ltd. Racemization and enantiomer separation of clopidogrel
KR20050008692A (ko) * 2003-02-13 2005-01-21 헬름 아게 클로피도그렐을 함유하는 술폰산의 염 및 제약 제제를제조하기 위한 그의 용도
US20060074242A1 (en) * 2004-10-04 2006-04-06 Manoj Madhukarrao Deshpande Rapid resolution process of clopidogrel base and a process for preparation of clopidogrel bisulfate polymorph-form I

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007019A1 (fr) 2010-07-13 2012-01-19 Pharmathen S.A. Procédé de synthèse du clopidogrel et de ses sels

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KR100834967B1 (ko) 2008-06-03
KR20080014510A (ko) 2008-02-14

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