Process Development of Bersacapavir, Part 3: Safety and Late-Stage Development Considerations Linked to Chloroform Generated in Haloform-Type Amidation

This manuscript describes the chemical process development for the synthesis of a crucial amide intermediate and the improvements that were achieved over previous processes. Careful studies guided by distillation modeling revealed an advantage of put-and-take operation compared to continuous volume and led to the discrete distillation values to successfully capture CHCl3 in the distillate, which can then be disposed of separately. Optimization of the workup conditions and crystallization resulted in higher yields and simplified waste treatment. The process is robust and has been successfully scaled up in multiple production campaigns.