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

A first catalytic preparation of the popular antiplatelet drug (S)-clopidogrel, known with the tradename of Plavix, has been developed in a one-pot and 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.