Hindered Biaryl Bond Construction and Subsequent Diastereomeric Crystallization to Produce an Atropisomeric Covalent KRASG12C Inhibitor ARS-2102

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2022-12-28 DOI:10.1021/acs.oprd.2c00335

Xiaogen Yang, Zhiwen Li, Wenwen Xu, Guanming Zhu, Xiantong Feng, Jun Zhang, Hongbin Zhao, Yuyin Chen, Jianshe Kong, Wanping Mai, Lian-Sheng Li, Daniel J. Pippel, Pingda Ren* and Xiaohu Deng*,

引用次数: 1

Abstract

A scaleup route for a first-generation covalent KRAS^G12C inhibitor ARS-2102 was devised, featuring an “early cross-coupling” strategy to construct the tetra-substituted atropisomeric biaryl scaffold. An iterative diastereomeric recrystallization enabled an effective chiral resolution of key intermediate 24. A global deprotection followed by chemoselective functionalization afforded ARS-2102 in excellent yield and diastereomeric enrichment. This chromatography-free sequence was successfully executed on kilogram scale.

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阻碍双芳基键构建和随后的非对映体结晶制备atrosom异构共价KRASG12C抑制剂ARS-2102

设计了第一代共价KRASG12C抑制剂ARS-2102的放大途径，采用“早期交叉偶联”策略构建四取代的atrop异构联芳基支架。迭代非对映体再结晶使关键中间体24的有效手性分辨成为可能。在化学选择性功能化之后的整体去保护使ARS-2102具有优异的产量和非对映异构体富集。该无色谱序列在公斤级上成功执行。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

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.