Development of a Practical Telescoped Process to Prepare (<i>P</i>)-7-(2-Amino-6-fluorophenyl)-4-hydroxy-6-(trifluoromethyl)pyrido[3,4-<i>d</i>]pyrimidin-8(7<i>H</i>)-one: a Key Intermediate of KRAS^G12C Inhibitor GH35

GH35 is a potent irreversible covalent inhibitor of KRASG12C that is currently undergoing phase I clinical trials for the treatment of patients with advanced solid tumors. Herein, we describe an efficient and cost-effective telescoped process to produce an atropisomeric intermediate, GH35-RSM, for the synthesis of GH35. Iterative optimization based on medicinal chemistry synthetic route resulted in significant improvement of several key reactions, such as two-step chiral resolution affording highly pure atropisomer (P)-methyl 1-(2-fluoro-6-nitrophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (5-P) in 99.9% e.e. and 35% yield and introduction of a nitrile group into (P)-3-amino-1-(2-amino-6-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4-carbonitrile (17) by use of an environment-friendly catalyst system identified by high throughput screening. The telescoped six-step process was robustly performed to provide hundreds of kilograms of GH35-RSM in plants to support clinical studies.