Process to prepare clopidogrel

Details Process to prepare clopidogrel Process to prepare clopidogrel

2001-10-22

2003-10-21

Dentz, Bernard (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06635763

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of thieno[3,2-c]pyridine derivatives of general formula (I), in either racemic or optionally active (+) or (−) forms and their salts, wherein X, the substituent on benzene ring represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine.
Preferably, X represents 2-chloro.
The present invention also describes a process for preparing the compounds of general formula (II), in either racemic or optically active (+) or (−) forms and their salts, where X, the substituent on benzene ring represents either a hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine.
Preferably X represents 2-chloro. These compounds are useful intermediates to prepare compounds of general formula (I).
The compounds represented by formulae (I) and (II) have one asymmetric carbon and hence, to obtain optically active compounds of formula (I) or of formula (II), option available is either to resolve the racemic intermediate/final product or use an optically active intermediate.
BACKGROUND OF THE INVENTION
Thieno[3,2-c]pyridine derivatives disclosed in FR 2,215,948, FR 2,530,247 and FR 2,612,929, are pharmacologically active and have significant anti-aggregating and anti-thrombotic properties. One such example is ‘Clopidogrel’, (S)-(+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) acetic acid methyl ester and its pharmaceutically acceptable salts. Later, it was found that the biological activity resides only with (S)-(+)stereoisomer (U.S. Pat. No. 4,847,265). As ‘Clopidogrel base’ is an oily liquid, in order to prepare a convenient formulation, the base is converted into a pharmaceutically acceptable salt. Suitable salts of ‘Clopidogrel base’ can be formed with taurocholate, hydrobromide and sulfuric acid.
DESCRIPTION OF THE PRIOR ART
The reported methods to synthesize the compounds of general formula (I) (U.S. Pat. No. 4,529,596, GB 0420706 and GB 0466569), use &agr;-halophenylacetic acid derivatives, which are lacrimatory and irritant in nature. The processes to synthesize such compounds involve multiple steps, and have other drawbacks due to the chemicals/reagents used, which usually are difficult to handle, scale-up and unfavorable from human health as well as environmental point of view. Moreover, overall yields of these processes range from poor to average. Various other synthetic approaches found in literature, involve expensive or hazardous chemicals, which do not significantly improve the yield of the desired product.
Recently, radiolabelled (bezene-U-
13
C) racemic(±)-Clopidogrel has been prepared as a standard for metabolic studies in an overall yield of 7% using orthometalation/chlorination of benzoic acid derivative (
Chem. Abst,
133:281711, 2000). Various other strategies are disclosed in: WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110, U.S. Pat. Nos. 4,876,362, 5,036,156, 5,132,435, 5,139,170, 5,204,469 and 6,080,875.
Recently, a new polymorph of Clopidogrel bisulfate (named as form II) has been disclosed in patent application (WO 99/65915), which has a melting point of 176±3° C. It also mentions that the compound disclosed in the earlier US patent (U.S. Pat. No. 4,847,265), had a different melting point of about 184±3° C. (now referred as, form I). It has been shown that both the polymorphs have distinct and characteristic XRD and IR spectrum.
Consequently, the present invention aims to provide an inexpensive and commercially viable process to prepare compounds of formula (I) in good yields.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a novel process to prepare thieno[3,2-c]pyridine derivatives, represented by the general formula (I), in either racemic or optically active (+) or (−) forms and their salts, wherein X represents either hydrogen or halogen atom such as fluorine, chlorine, bromine or iodine.
Another the object of the present invention is to provide a novel process to prepare thieno[3,2-c]pyridine derivatives, represented by the general formula (I), in either racemic or optically active (+) or (−) forms and their salts, through a commercially viable route.
A particular object of the present invention is to provide a novel process to manufacture (S)-(+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester as bisulfate salt, i.e. Clopidogrel bisulfate, where X is 2-chloro substituent.
The preferred object of the present invention is to provide a novel process to manufacture Clopidogrel bisulfate, through a commercially viable process.
Another important object of the present invention is to provide a novel process to manufacture polymorph form I of Clopidogrel having melting point 184±3° C., through commercially viable route.
Yet another object of the present invention is to recycle through a novel process the laevoisomer of Clopidogrel or a variable mixture of (+) and (−) stereoisomers to make (+)-Clopidogrel bisulfate.
Another object of the present invention is to provide a process to prepare a compound (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide of formula (A), either in racemic or as optically active (+) or (−) forms and their salts.
Another object of the present invention is to provide a process for the preparation of a compound of formula (I) where X is 2-chloro, in racemic as well as optically active (+) or (−) forms having suitable chemical and chiral purity and along with their salts. The dextro isomer of compound with formula (II) with suitable purity or its salts, are useful intermediates for the synthesis of (+)-Clopidogrel bisulfate.
Still another object of the present invention is to provide a novel process to convert (R)-(−)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide or its mixture with variable minor amounts of its optical antipode, into almost a 1:1 mixture of (+) and (−) isomer.
It is also an object of the present invention is to provide a process to prepare compound of formula (III), (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid, in racemic (±) or in either of the optically active (+) or (−) form, and their salts.
Still another object of the present invention is to provide a novel process to convert (R)-(−)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid in a mixture to (S)-(+) stereoisomer.
Another object of the present invention is to provide a process for the preparation of a compound of formula (IV), (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitrile, and their salts.
Still another object of the present invention is to provide a novel process to convert (R)-(−)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetonitrile or its mixture with variable minor amounts of its optical antipode, into almost a 1:1 mixture of (+) and (−) isomer.
The process described herein provides a simple and alternative method to prepare compounds of the general formula (I), particularly (S)-(+)Clopidogrel bisulfate, polymorph form I.
SUMMARY OF THE INVENTION
The above and other objects of the present invention are achieved by the process of the present invention by employing compounds of formula (II)
or its salts, in either racemic or optically active (+) or (−) forms, as outlined in Scheme 1.
Optionally, the present invention provides a method to resolve (−)-2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide into optically active (+) or (−) forms, which can be used to prepare (+)-Clopidogrel bisulfate.
Optionally, the present invention provides a method to resolve (±)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid into optica

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