Stereocontrolled First Generation Synthesis of RIPK1 Inhibitor GDC-8264

We report an efficient, stereocontrolled, and chromatography-free first-generation manufacturing process for GDC-8264 (1), a RIPK1 inhibitor. Key steps include a diastereoselective reductive amination, a triazole condensation, an alcohol deoxyfluorination, and a late-stage Weinreb ketone formation. The 12-step process successfully produced >3.5 kg of GDC-8264 (1) in 19% overall yield with 99.2 A % HPLC purity, >99% ee, and >99.9:0.1 dr to support early stage clinical studies.