Process Development of Bersacapavir, Part 2. Early Game Route Selection: Catalytic versus Stoichiometric Haloform-Type Amidation

During the chemical development of bersacapavir API, special attention was paid to the key step of the early game synthesis: the extended haloform-type amidation. This manuscript describes the effort of the team toward the development of a catalytic version of that transformation thanks to the use of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and its unique reactivity. Guided by fine solubility studies, the catalytic procedure was optimized, streamlined, and scaled up. A very high yield and purity were achieved with significant process mass intensity (PMI) improvement in comparison to the previous process utilizing an excess of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).