Process Development of Bersacapavir, Part 1: Route Scouting Effort toward a Key Amide Intermediate

In this article, the route scouting effort toward a key secondary amide intermediate in the synthesis of bersacapavir is described. This study relies on the haloform reaction and the reactivity of trichloromethylketone. First, a more classical synthesis route was developed, based on the preparation of a carboxylic acid from the corresponding trichloromethylketone (conventional haloform reaction). The second, and preferred, approach utilized an innovative extension of the haloform reaction, allowing direct coupling between electron-poor aniline and trichloromethylketone. The desired amide intermediate was obtained in high yield and purity via a simple two-step synthesis using cheap and readily available starting materials.