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

被引：16

作者：

Chen, Cheng-yi ^{[1
]}

Lu, Zhichao ^{[1
]}

Scattolin, Thomas ^{[1
]}

Chen, Chengsheng ^{[1
]}

Gan, Yonghong ^{[1
]}

McLaughlin, Mark ^{[1
]}

机构：

[1] Mirati Therapeut, Chem Proc R&D, San Diego, CA 92121 USA

来源：

ORGANIC LETTERS | 2023年

关键词：

HYDROGEN-PEROXIDE; DECOMPOSITION; OXIDATION; KINETICS; SULFIDES;

D O I：

10.1021/acs.orglett.2c04266

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

A concise, transition-metal and protection-free synthesis of adagrasib (MRTX849), a novel KRASG12C inhibitor drug recently approved by the FDA, is reported. Introduction of two chiral building blocks to the tetrahydropyridopyrimidine core was accomplished via two sequential SNAr 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 SNAr 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.

引用

页码：944 / 949

页数：6