Synthesis of the NK1 Receptor Antagonist GW597599. Part 1: 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 synthetic route devised from the medicinal chemistry one, used several hazardous reagents, gave low yields, and produced high levels of wastes. By targeted process of research and development, application of novel techniques, and extensive route scouting, a novel synthetic route for GW597599 has been developed. This paper reports the optimisation work of the first stage in the chemical synthesis of GW597599: the development of a pilot-plant suitable process for the synthesis of the arylpiperazine derivative 7 in an optically pure fashion. In particular, the process definition allowed eliminating the initial need for cryogenic conditions and copper catalysis in Grignard chemistry. It also allowed replacing a classical resolution step with a more efficient dynamic kinetic resolution, substantially enhancing the overall yield and throughput.