AI Article Synopsis
- - A novel and efficient method for synthesizing the KRAS inhibitor MRTX849 was developed, which avoids the use of transition metals and protecting groups.
- - The synthesis involved introducing two chiral building blocks to the drug's core structure through two optimized sequential reactions, enhancing the process's effectiveness.
- - This new five-step method eliminated the need for chromatography and palladium catalysis, resulting in a significant increase in efficiency with a 45% overall yield from readily available materials.
Article Abstract
A concise, transition-metal and protection-free synthesis of (MRTX849), a novel KRAS inhibitor drug recently approved by the FDA, is reported. Introduction of two chiral building blocks to the tetrahydropyridopyrimidine core was accomplished via two sequential SAr 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 SAr displacement to introduce the chiral piperazine. This new, five-step, chromatography-free synthesis of 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942190 | PMC |
| http://dx.doi.org/10.1021/acs.orglett.2c04266 | DOI Listing |
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