Development of a Scalable Synthesis toward a KRAS G12C Inhibitor Building Block Bearing an All-Carbon Quaternary Stereocenter, Part 1: From Discovery Route to Kilogram-Scale Production

Abstract

Synthesis of molecules containing all-carbon quaternary stereocenters has been a longstanding challenge in organic chemistry. In one of our discovery oncology programs, a key chiral building block bearing an all-carbon quaternary chiral center was of particular interest and was later identified as a core structure for a KRAS G12C inhibitor. Herein, the development of a safer and practical route to the key building block 1 is described. By replacing processes involving the use of an energetic reagent and extensive chromatographic purifications, a scalable process utilizing chemical resolution was developed to access the chiral building block in kilogram quantities, enabling timely delivery of API for preclinical and clinical studies.

Development of a Scalable Synthesis toward a KRAS G12C Inhibitor Building Block Bearing an All-Carbon Quaternary Stereocenter, Part 2: Asymmetric Synthesis via Shi Epoxidation

“…The first-generation chemical development route mostly derived from a modified discovery synthesis of 1 as illustrated in Scheme . After the C-methylation of β-keto ester 2 , enzymatic resolution with PLE established the chiral center.…”