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
posted on 2024-01-04, 18:17authored byJoyce C. Leung, Yibo Xu, Suttipol Radomkit, Jaehee Lee, Wan Shin Kim, Jonathan T. Reeves, Weitong Dong, Hwanjong Jang, Xiaowen Hou, Jon C. Lorenz, Xiaole Shao, Denis Byrne, Joe Johnson, Anthony Brundage, Clement Valentin, Phouvieng Beyer, Susan V. DiMeo, Bo Qu, Ruoshi Li, Max Sarvestani, Jinhua J. Song
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.