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

08 May 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

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%.

Keywords

Weinreb amide
ketone synthesis
nucleophilic amination
lenacapavir

Supplementary materials

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Title
A new synthesis of the amine fragment: an important intermediate to the anti-HIV drug lenacapavir
Description
The supplementary materials include the details of GCMS, HPLC methods, the experimental procedures, characterization data, copies of NMR spectra.
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