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

Key steps in the synthesis of ZM549865 (a 5-HT receptor antagonist) are the palladium-catalysed amination 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 degreesC instead of 80 degreesC 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 acetylenedicarboxylate 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.