Development of an Improved Process To Prepare a Key Intermediate in the Manufacture of Sotorasib

Sotorasib is a first-in-class KRASG12C inhibitor with a unique carbon–nitrogen atropisomer. Described herein is the development of an improved second-generation process to manufacture a key sotorasib intermediate, rac-4. Notable improvements to the second-generation process include the development of a three-step fully telescoped sequence in acetonitrile and the use of phosgene as an isocyanating agent, which allowed for dichloromethane, aqueous extractive work-ups, and distillations to be completely removed from the process. Compared to the first-generation process, these process improvements led to a 97% reduction in organic solvent usage and a 71% reduction in wastewater generation and still maintains a 75% yield and >99.5% purity of rac-4 in the overall process.