Successful Development and Scale-up of a Palladium-Catalysed Animation Process in the Manufacture of ZM549865

摘要

Key steps in the synthesis of ZM549865(a 5-HT receptor antagonist)are the palladium-catalysed animation of ethyl 8-bromo-6-fluoro-4-oxo-4H-2-chromenecarboxylate and subsequent hydrolysis of the ester group.The development of a simple,robust process capable of making multikilogram amounts of the required intermediate is described.Performing the amination step at 125 deg C instead of 80 deg C and optimising the hydrolysis conditions led to an increase in overall yield from 44% to about 70% as well as reducing the reaction time from days to hours.The chromone ring was initially constructed by reaction of 2-bromo-4-fluorophenol with dimethyl acetylene-dicarboxylate followed by cyclisation.A potentially cheaper route was developed that involved formation of a substituted acetophenone via the Fries rearrangement,followed by condensation with diethyl oxalate and cyclisation.