A New Synthesis of Enantiopure Amine Fragment: An Important Intermediate to the Anti-HIV Drug Lenacapavir

Herein, we describe a new seven-step approach to prepare (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine ((S)-4) from the inexpensive 2-(3,5-difluorophenyl)acetic acid. The key steps in the sequence include (1) the Weinreb amide-based ketone synthesis to provide an entry point to the core structure; (2) simple functional group transformations to afford the racemic amine 4-rac; and (3) dynamic kinetic resolution (DKR) to access the chiral amine (S)-4. This seven-step process delivered the enantiopure amine (S)-4 in an overall isolated yield of approximately 15%. The process was demonstrated on a decagram scale, and the process requires no chromatographic purifications. Single-crystal X-ray crystallography measurements verified the chiral amine structure and absolute configuration.