Development of Adagrasib’s Commercial Manufacturing Route

A commercial route to adagrasib ( 1 ) was developed to support clinical and commercial needs. Yield was improved to 32% over six chemical steps. A doubly regioselective S N Ar reduced consumption of a chiral intermediate, reaction optimization led to parts per million palladium catalysis, and a new method to deprotect Cbz-groups were developed to mitigate risk associated with benzyl iodide.