Multigram-scale synthesis of GS-4997, an inhibitor of apoptosis signal-regulating kinase 1

This paper describes the development of a practical, efficient and reproducible preparation of ASK1 inhibitor GS-4997 (Selonsertib). Our efforts were committed to designing and developing a novel synthetic strategy. The novel route involved high-yielding preparation of 5-(4-cyclopropyl-1 H -imidazole-1-yl)-2-fluoro-4-methylbenzoic acid ( 5 ) through adjusting reaction sequence, and the one-pot procedure for the synthesis of 6-(4-isopropyl-4 H -1,2,4-triazol-3-yl) pyridin-2-amine ( 7 ). The developed process provided an overall yield of 45.8%, which enabled us to rapidly synthesize multi-gram quantities of GS-4997 in 99.3% purity. Graphical Abstract