Synthesis of Adagrasib (MRTX849), a Covalent KRASG12C Inhibitor Drug for the Treatment of Cancer,Organic Letters

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Synthesis of Adagrasib (MRTX849), a Covalent KRASG12C Inhibitor Drug for the Treatment of Cancer
Organic Letters ( IF 4.9 ) Pub Date : 2023-02-01 , DOI: 10.1021/acs.orglett.2c04266
Cheng-Yi Chen ₁ , Zhichao Lu ₁ , Thomas Scattolin ₁ , Chengsheng Chen ₁ , Yonghong Gan ₁ , Mark McLaughlin ₁

Affiliation

A concise, transition-metal and protection-free synthesis of adagrasib (MRTX849), a novel KRAS^G12C inhibitor drug recently approved by the FDA, is reported. Introduction of two chiral building blocks to the tetrahydropyridopyrimidine core was accomplished via two sequential S_NAr reactions. Extensive reaction optimization led to a robust, transition-metal-free oxidation of the sulfide intermediate. A judicious choice of the leaving group with favorable steric and electronic characteristics at the 4-OH position of the tetrahydropyridopyrimidine core enabled a facile S_NAr displacement to introduce the chiral piperazine. This new, five-step, chromatography-free synthesis of adagrasib from readily available starting materials obviated the palladium catalysis and protecting group manipulations in the current commercial route and significantly improved the efficiency of the process in 45% overall yield.

中文翻译：

Adagrasib (MRTX849) 的合成，一种用于治疗癌症的共价 KRASG12C 抑制剂药物

报道了最近获得 FDA 批准的新型 KRAS ^{G12C抑制剂药物}adagrasib (MRTX849)的简明、过渡金属和无保护合成。将两个手性结构单元引入四氢吡啶并嘧啶核是通过两个连续的 S _N Ar 反应完成的。广泛的反应优化导致硫化物中间体的稳健、无过渡金属氧化。在四氢吡啶并嘧啶核的 4-OH 位置明智地选择具有良好空间和电子特性的离去基团，可以轻松进行 S _N Ar 置换，从而引入手性哌嗪。这种新的、五步、无层析的adagrasib合成从现成的起始材料中提取，避免了当前商业路线中的钯催化和保护基团操作，并显着提高了工艺效率，总收率为 45%。

更新日期：2023-02-01

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