Clopidogrel synthesis

Highly Enantioselective and Efficient Synthesis of Methyl (R)-o-Chloromandelate, Key Intermediate for Clopidogrel Synthesis, with Recombinant Escherichia coli... 

Scheme 5 Stereoselective synthesis of Clopidogrel (Plavix ) starting from...

Ema, T., Okita, N., Ide, S. and Sakai, T. (2007) Highly enantioselective and efficient synthesis of methyl (R)-o-chloromandelate with recombinant E. coli toward practical and green access to clopidogrel. Organic and Biomolecular Chemistry, 5 (8), 1175-1176. 

In these synthesis, the optically active (R)-cyanohydrin is transformed into the corresponding a-hydroxy carboxylic ester and the hydroxyl funchon is achvated by sulfonylahon. The treatment of the corresponding intermediate with tetra-hydrothieno[3,2-c]pyridine stereoselectively yields the (S)-configured clopidogrel (Scheme 10.23). In the second case, a mutant of the recombinant almond (Pmnus amigdalus) (R)-oxynitrilase isoenzyme 5 catalyzes the formation of enantiopure (R)-2-hydroxy-4-phenylbutyronitrile [54]. Reaction of the sulfonylated hydroxyester derivative with the corresponding dipeptide leads to the formation of enalapril or lisinopril (Scheme 10.24). 

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... 

Scheme 4. The Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2).

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. 

Ema T, Ide S et al (2008) Highly efficient chemoenzymatic synthesis of methyl (R)-o-chloromandelate, a key intermediate for clopidogrel, via asymmetric reduction with recombinant Escherichia coli. Adv Synth Catal 350 2039-2044... 

Clopidogrel (12) is marketed by Sanofi-Synthlebo and BMS as the hydrogen sulfate salt under the trade name Plavix. It is a platelet aggregation inhibitor that is used as an antithrombotic agent for the reduction of cardiovascular events. The synthesis is straightforward (Scheme 31.8).102 107 The asymmetry is obtained by a classical resolution.103 It is possible to recycle the undesired isomer.108... 

Methyl (R)-o-chloromandelate represents the key building block for the synthesis of clopidogrel, a platelet aggregation inhibitor widely administered to atherosclerotic patients with the risk of a heart attack or stroke that are caused by the formation of a clot in the blood. The worldwide sales of this pharmaceutical... 

Fig. 45 Synthesis of methyl (/J)-o-chloromandelate as the main precursor of the pharmaceutical compound clopidogrel...

Scheme 5.3 Modified Prunus amygdalus HNL is applied for the synthesis of enantiopure R-o-chloromandelonitrile, a precursor for the synthesis of clopidogrel.

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