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,Organic Process Research & Development

当前位置： X-MOL 学术 › Org. Process Res. Dev. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

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
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-09-13 , DOI: 10.1021/acs.oprd.4c00279
Gaolei Zuo ₁ , Haojie Xu _{1,

2,

3} , Yaobin Zhang ₁ , Zhi Liu ₁ , Jinyue Tu ₁ , Donghui Gou ₁ , Peng Fu ₄ , Haifeng Huang ₅ , Jianhua Ren ₅ , Yuanyuan Hu ₅ , Feng Liu _{2,

3} , Jie Jack Li ₁ , Guiping Zhang ₁

Affiliation

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.

中文翻译：

制备（P）-7-（2-氨基-6-氟苯基）-4-羟基-6-（三氟甲基）嘧啶-8（7H）-酮的实用望远镜工艺的开发：KRASG12C抑制剂 GH35 的关键中间体

GH35 是一种有效的不可逆 KRAS^G12C 共价抑制剂，目前正在进行 I 期临床试验，用于治疗晚期实体瘤患者。在本文中，我们描述了一种高效且具有成本效益的望远镜工艺，用于生产用于合成 GH35 的空斜异构体中间体 GH35-RSM。基于药物化学合成路线的迭代优化导致几个关键反应的显著改进，例如两步手性分离，在 99.9% e 中提供高纯度的阿托溴异构体（P）-甲基 1-（2-氟-6-硝基苯基）-2-氧代-6-（三氟甲基）-1,2-二氢吡啶-3-羧酸盐（5-P）。e. 使用通过高通量筛选鉴定的环保催化剂系统，将腈基引入（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-碳腈（17）中。望远镜式六步工艺稳健执行，在植物中提供数百公斤的 GH35-RSM 以支持临床研究。

更新日期：2024-09-13

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南