A new synthesis of the amine fragment: an important intermediate to the anti-HIV drug lenacapavir

Abstract

Herein, we describe a new five-step approach to prepare 1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine, an important intermediate in the synthesis of lenacapavir. The key step in the sequence is the Weinreb amide-based ketone synthesis, which provides an alternative entry point to the core structural component. Starting from the inexpensive 2-(3,5-difluorophenyl)acetic acid, the Weinreb amide synthesis and the followed nucleophilic substitution afford the ketone in 47% yield. The subsequent functional group manipulation delivers the racemic amine which can be resolved with known mandelic acid resolution. This synthetic route has been demonstrated on decagram scale and affords the racemic amine in an overall isolated yield of 25%.