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
Joyce 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 and Jinhua J. Song,
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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.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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