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.
A commercial
route to adagrasib (1) was developed
to support clinical and commercial needs. Yield was improved to 32%
over six chemical steps. A doubly regioselective SNAr reduced
consumption of a chiral intermediate, reaction optimization led to
parts per million palladium catalysis, and a new method to deprotect
Cbz-groups were developed to mitigate risk associated with benzyl
iodide.
A commercial route to MRTX849 (adagrasib) was developed to support clinical and commercial needs. Yield was improved to 32% over six chemical steps. A doubly regioselective SNAr reduced consumption of an expensive chiral intermediate, reaction optimization led to parts per million palladium catalysis, and a new method to deprotect Cbz-groups were developed to mitigate risk associated with benzyl iodide.
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