Development of a Practical Telescoped Process to Prepare (P)-7-(2-Amino-6-fluorophenyl)-4-hydroxy-6-(trifluoromethyl)pyrido[3,4-d]pyrimidin-8(7H)-one: a Key Intermediate of KRASG12C Inhibitor GH35

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-09-13 DOI:10.1021/acs.oprd.4c0027910.1021/acs.oprd.4c00279

Gaolei Zuo, Haojie Xu, Yaobin Zhang, Zhi Liu, Jinyue Tu, Donghui Gou, Peng Fu, Haifeng Huang, Jianhua Ren, Yuanyuan Hu, Feng Liu*, Jie Jack Li* and Guiping Zhang*,

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引用次数: 0

Abstract

GH35 is a potent irreversible covalent inhibitor of KRAS^G12C that is currently undergoing phase I clinical trials for the treatment of patients with advanced solid tumors. Herein, we describe an efficient and cost-effective telescoped process to produce an atropisomeric intermediate, GH35-RSM, for the synthesis of GH35. Iterative optimization based on medicinal chemistry synthetic route resulted in significant improvement of several key reactions, such as two-step chiral resolution affording highly pure atropisomer (P)-methyl 1-(2-fluoro-6-nitrophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (5-P) in 99.9% e.e. and 35% yield and introduction of a nitrile group into (P)-3-amino-1-(2-amino-6-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4-carbonitrile (17) by use of an environment-friendly catalyst system identified by high throughput screening. The telescoped six-step process was robustly performed to provide hundreds of kilograms of GH35-RSM in plants to support clinical studies.

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开发制备(P)-7-(2-氨基-6-氟苯基)-4-羟基-6-(三氟甲基)吡啶并[3,4-d]嘧啶-8(7H)-酮的实用远程工艺：KRASG12C 抑制剂 GH35 的关键中间体

GH35 是一种 KRASG12C 的强效不可逆共价抑制剂，目前正在进行治疗晚期实体瘤患者的 I 期临床试验。在此，我们介绍了一种高效、经济的伸缩工艺，用于生产合成 GH35 的异构体中间体 GH35-RSM。基于药物化学合成路线的迭代优化显著改善了几个关键反应，例如通过两步手性解析得到了高纯度的异构体 (P)-1-(2-氟-6-硝基苯基)-2-氧代-6-(三氟甲基)-1,2-二氢吡啶-3-羧酸甲酯 (5-P)，纯度为 99.通过使用高通量筛选确定的环境友好型催化剂体系，以 99.9% 的等当量和 35% 的收率将一个腈基引入 (P)-3-氨基-1-(2-氨基-6-氟苯基)-2-氧代-6-(三氟甲基)-1,2-二氢吡啶-4-甲腈 (17)。六步伸缩工艺的实施非常成功，可在植物中提供数百公斤的 GH35-RSM，为临床研究提供支持。

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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.