A Convergent Synthesis of HPK1 Inhibitor GNE-6893 via Palladium-Catalyzed Functionalization of a Tetrasubstituted Isoquinoline

A scalable convergent synthesis of GNE-6893 (1) involving Pd-catalyzed Suzuki–Miyaura cross-coupling and C–N coupling as key steps is reported. The production of the final active pharmaceutical ingredient (API) was achieved in 33% overall yield and 98 A% HPLC purity by a one-pot process of global deprotection, pH adjustment, crystallization, and isolation. Green chemistry practices were implemented in the process development of GNE-6893 (1) by utilizing a biocatalytic resolution to produce (3R,4S)-4-methyltetrahydrofuran-3-ol and replacing toxic triphosgene with a safer alternative, disuccinimidyl carbonate (DSC), to construct the carbamate penultimate intermediate to API.