Development of a Stereoselective Route for Kilogram-Scale Synthesis of STING Agonist BMS-986301

Abstract Following the discovery of a chiral P(V) reagent to enable diastereoselective synthesis of stereogenic thiophosphoramidates, we have developed a scalable synthesis to deliver kilogram quantities of the STING agonist BMS-986301. The route not only reduced the number of steps compared to the enabling route but also avoided the use of hazardous reagents. Further development enabled the use of crystallizations to isolate intermediates, effectively eliminating six chromatographic purifications. This resulted in an eightfold improvement in yield and 90% reduction in process mass intensity (PMI). The route was successfully implemented in a pilot-plant campaign to deliver 1.65 kg of BMS-986301 (1) and was therefore deemed suitable as a long-term option for commercial synthesis.