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.

The process to manufacture sotorasib (AMG 510) employs a Suzuki–Miyaura reaction as a key step in the synthetic sequence. Detailed kinetic and mechanistic investigations into this process were utilized to identify the active catalytic species and rate-determining step, rationalizing current procedural requirements and process limitations. This knowledge was applied to demonstrate that simple alteration of the base (from KOAc to K2CO3) provided significant process improvements by shifting the rate-determining step and transmetalation pathways. Kinetic modeling was utilized for parameter optimization and resulted in significant reductions in both the Pd catalyst loading and equivalents of boronic acid as well as removing the requirement for slow reagent dosing. This report highlights the distinct mechanistic pathways that may occur upon alteration of the base in Suzuki–Miyaura coupling reactions.