Mechanistic Investigation of a Domino N–H and C–H Borylation in the Manufacture of AMG 193

The manufacturing process of AMG193 employs iridium-catalyzed C–H borylation as a key step. In contrast to the literature precedent, irreproducibility during scale-up of this process prompted investigations that determined that N-boryl functionalization with HBpin inhibits C–H activation. An iridium-catalyzed tandem N–H/C–H borylation procedure was developed instead. Kinetic analysis indicated that N–H activation by iridium occurs at a faster rate than C–H activation. Additionally, catalyst deactivation pathways were diagnosed through these studies, which enabled a significant reduction in iridium loading. This report highlights the use of in situ reaction monitoring (ReactIR and NMR) to make rational improvements to this borylation process. Our mechanistic findings enabled a 10-fold reduction in the Ir catalyst and removed the requirement for HBpin protection of the aminopyridine substrate prior to C–H borylation.