Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS^G12C Inhibitor

Abstract

A commercial process to manufacture sotorasib (AMG 510), a first-in-class KRASG12C inhibitor, is described. Development efforts focused on rendering a fit-for-purpose early-phase route into a viable long-term commercial process through the reduction of side reactions to improve yield and product quality, as well as reducing cycle times of crystallization processes by improving particle properties and filtration times. These improvements were key to ensuring clinical supply and commercial launch. The final route consists of five synthetic operations from starting material M-1, including a telescoped two-step sequence, and a final form-setting crystallization.