Synthesis of Adagrasib (MRTX849), a Covalent KRAS(G12C) Inhibitor Drug for the Treatment of Cancer

[Image: see text] 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(N)Ar 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(N)Ar 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.