Multkilogram enantioselective synthesis of a HCV polymerase inhibitor

摘要

The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient construction of the eight-membered dihydroindolobenzoxazocine ring and enantioselective installation of the secondary amine stereocenter are required. This presentation will describe our process development1 of a Mitsunobu protocol to achieve the latter goal which uses diphenylphosphoryl azide at ambient temperature to invert a scalemic secondary alcohol. The hazard evaluation performed to establish the safety of this protocol and allow pilot-plant introduction at >8.o kg scale will be discussed. The overall synthesis of 1 will also be described as well as alternative enantioselective approaches to 1.