Process Development Overcomes a Challenging Pd-Catalyzed C-N Coupling for the Synthesis of RORc Inhibitor GDC-0022

Process development for a multi-kilogram-scale synthesis of GDC-0022, an inhibitor of retinoic acid receptor-related orphan receptor gamma (RORc), is described. Delivery of the active pharmaceutical ingredient (API) relied on diastereoselective preparation of a six-membered sultam building block, as well as execution of its benzylation under heterogeneous conditions. Investigation and optimization of a challenging late-stage palladium-catalyzed C-N coupling of a bicyclic amine were likewise central to synthetic efforts. Understanding of this key reaction, as well as the development of API salt forms and isolations, ultimately enabled a successful reaction at 8.0 kg scale, utilizing 1.0 mol % XantPhos-Pd-G2 as precatalyst and, in turn, preparation of >5.0 kg of GDC-0022 tosylate salt for preclinical needs.