Selective Metalation of Functionalized Quinazolines to Enable Discovery and Advancement of Covalent KRAS Inhibitors

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2022-10-13 DOI:10.1021/acs.oprd.2c00242

Brett D. Allison*, Xiaohu Deng, Lian-Sheng Li, Jimmy Liang, Neelakandha S. Mani, Pingda Ren and Zachary S. Sales,

引用次数: 1

Abstract

The quinazoline compound ARS-1620 is a recently discovered, mutant-specific covalent inhibitor of KRAS^G12C. Route scouting in support of multigram ARS-1620 batches led to a new synthetic approach that relies on metalation of substituted quinazolines at C7. The exquisite selectivity seen in this metalation formed the basis for a scalable route to kilogram quantities of compounds in this family. It also accelerated medicinal chemistry efforts as critical intermediates became readily available in large quantities.

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功能化喹唑啉的选择性金属化以促进共价KRAS抑制剂的发现和进展

喹唑啉化合物ARS-1620是最近发现的一种突变特异性KRASG12C共价抑制剂。支持多图ARS-1620批次的路线侦察导致了一种新的合成方法，该方法依赖于C7取代喹唑啉的金属化。在这种金属化过程中所看到的精致选择性，为该家族中公斤级化合物的可扩展途径奠定了基础。它还加速了药物化学的努力，因为关键的中间体变得容易大量获得。

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.