Development of an Efficient Synthesis of Two CRF Antagonists for the Treatment of Neurological Disorders

Abstract

BMS-764459 ( 1 ) and BMS-763534 ( 2 ) are CRF1 antagonists for the treatment of neurological disorders such as depression and anxiety. An efficient synthesis of 1 and 2 is described, which features an efficient palladium-catalyzed cyanation of a 5-chloropyrazinone where zinc acetate suppresses dehalogenation. This synthesis was applied to the preparation of >5 kg of 1 and 2 for clinical studies.