Adagrasib’s Second-Generation Synthesis: Transitioning from Route Scouting to Optimization

This is the authors' abstract. We don't add key points for this paper.

Process optimization details are disclosed following the completion of process design for a second-generation manufacturing route of adagrasib. Key objectives for development included control of difficult-to-purge impurities in the key starting materials (KSMs), enhanced scalability of the KSM, improved pyrimidone formation of the core, increased robustness of oxidation, enhanced stability of the step 3 intermediate, removal of the halogenated solvent in the fourth step, and implementation of single crystallization of the final API. These improvements led to more efficient production of adagrasib and a further reduction in the cost of goods by approximately 50%.