Synthesis of the NK1 Receptor Antagonist GW597599. Part 2: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine

Abstract

GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields, and produced high levels of wastes. Through a targeted process of research and development, application of novel techniques, and extensive route scouting, a synthetic route for GW597599 has been developed. This paper reports the optimisation work of the second stage in the chemical synthesis of GW597599: the development of a pilot-plant-suitable process for the manufacturing of an optically pure arylpiperazine derivative. In particular, the new process eliminates the need to purchase and store dangerous and expensive borane by generating it in situ and also the need for a chlorinated solvent, thereby improving the safety of the process and substantially reducing the overall waste. The final yield and throughput will be significantly enhanced.