One‐Pot Catalytic Synthesis of Optically Active Drug (S)‐Clopidogrel

Abstract

A first catalytic preparation of the popular antiplatelet drug (S)‐clopidogrel, known with the tradename of Plavix, has been developed in a one‐pot innovative approach. The synthesis can be performed using commercially available ortho‐chlorobenzaldehyde, 1‐naphthylsulfonyl acetonitrile, tert‐butyl hydroperoxide (TBHP), 4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine and 20 mol% of a quinidine derived organocatalyst in a single solvent. A Knoevenagel/asymmetric epoxidation/domino ring‐opening esterification (DROE) sequence enabled to obtain (S)‐clopidogrel in 61% overall yield and 62% ee. Fine optimization of the reaction conditions proved to be crucial to set up a selective and efficient process