An Efficient, Direct Bis-ortho-chlorination of 4-(Difluoromethoxy)aniline and Its Application to the Synthesis of BMS-665053, a Potent and Selective Pyrazinone-Containing Corticotropin-Releasing Factor-1 Receptor Antagonist

An efficient scale-up synthesis of (S)-5-chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(difluoromethoxy)phenylamino)-pyrazin-2(1H)-one, 1 (BMS-665053), is described. This new process features a one-step direct bis-ortho-chlorination of 4-(difluoromethoxy)aniline with HCl and H2O2, and a palladium-catalyzed coupling of 2,6-dichloro-4-(difluoromethoxy)aniline 2 and (S)-3,5-dichloro-1-(1-cyclopropylethyl)pyrazin-2(1H)-one 3. The process was applied to the preparation of batches of 1 for preclinical toxicology studies.