Syntheses of clopidogrel

The original Sanofi synthesis of ( )-clopidogrel (2) began with the formation of the methyl ester 13. Thus methyl mandelate 13 was prepared by refluxing chlorinated mandelic acid 12 with methanol in the presence of concentrated HCl. Chlorination of 

13 using thionyl chloride gave methyl a-chloro-(2-chlorophenyl)acetate (14). Sn2 displacement of 14 with thieno[3,2-c]pyridine (8) then delivered ( )-clopidogrel (2). 

Interestingly, only the enantiomencally pure (-t-)-clopidogrel (2) exhibits platelet aggregation inhibiting acuvity, while the (-)-(2) is inactive. Moreover, the inactive (-)- 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

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