EFFICIENT KG-SCALE SYNTHESIS OF THROMBIN INHIBITOR CRC-220

Potent thrombin inhibitor 2 is prepared in 10 steps with 20% overall y ield from commercial 4 on a kg-scale by the convergent approach depict ed in Schemes 1 and 2. The (R)-configuration of the 4-amidinophenylala nine piperidide moiety is controlled by asymmetric hydrogenation A nov el method, the hydrogenolysis of amidoximes 11 and 21, is employed to attain a particularly clean transformation of the cyano into the amidi nium functionality. Despite of the amorphous nature of target compound 2, the approach is devoid of any chromatographic purification.