Fit-for-Purpose Synthesis of a KRASG12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-07-22 DOI:10.1021/acs.oprd.4c00211

Carmela Molinaro, Nicholas Wong, Nicholas A. White, Lauren E. Sirois, Raphael Bigler, Quentin P. Bindschaedler, Steven Do, Sushant Malhotra, Francis Gosselin

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Abstract

An enabling, fit-for-purpose synthesis of stereochemically pure KRAS^G12C covalent inhibitor 1, a potential new treatment for cancer, is described. The synthetic route provided 1 in 13 steps from commercially available 2-fluoro-5-methylaniline (2), tert-butyl (S)-3-methylpiperazine-1-carboxylate (8) and (S)-(1-methylpyrrolidin-2-yl)methanol (10). A key transformation in this sequence was the diastereoselective 1,4-addition of an aryl boronate derived from 2 with rac-4-methylcyclohex-2-en-1-one (rac-4) in a Hayashi arylation that sets two relative stereocenters of the target molecule. This in turn inspired the development of an improved synthesis of (R)-4-methylcyclohex-2-en-1-one ((R)-4) via optimized methodology for the asymmetric monohydrogenation of 1,4-dienes, thus setting the stage for a fully asymmetric synthesis of inhibitor 1.

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通过非对映选择性 Hayashi 芳基化合成适合目的的 KRASG12C 共价抑制剂

本文描述了一种立体化学纯 KRASG12C 共价抑制剂 1（一种潜在的癌症新疗法）的可行、适用合成方法。该合成路线从市售的 2-氟-5-甲基苯胺 (2)、(S)-3-甲基哌嗪-1-羧酸叔丁酯 (8) 和 (S)-(1-甲基吡咯烷-2-基)甲醇 (10) 经过 13 个步骤制得 1。这一过程中的一个关键转变是，在林芳基化反应（Hayashi arylation）中，由 2 衍生出的硼酸芳基与 rac-4-methylcyclohex-2-en-1-one （rac-4）进行非对映选择性 1,4 加成，从而设定了目标分子的两个相对立体中心。这反过来又启发了通过优化 1,4 二烯的不对称单氢化方法改进 (R)-4- 甲基环己-2-烯-1-酮（(R)-4）的合成，从而为抑制剂 1 的完全不对称合成奠定了基础。

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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.

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