Development of\na Practical Telescoped Process to Prepare\n(<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\nof KRAS<sup>G1

GH35 is a potent irreversible covalent inhibitor of KRAS<sup>G12C</sup> that is currently undergoing phase I clinical trials for\nthe treatment\nof patients with advanced solid tumors. Herein, we describe an efficient\nand cost-effective telescoped process to produce an atropisomeric\nintermediate, GH35-RSM, for the synthesis of GH35. Iterative optimization\nbased on medicinal chemistry synthetic route resulted in significant\nimprovement of several key reactions, such as two-step chiral resolution\naffording highly pure atropisomer (<i>P</i>)-methyl 1-(2-fluoro-6-nitrophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate\n(5-<i>P</i>) in 99.9% <i>e</i>.<i>e</i>. and 35% yield and introduction of a nitrile group into (<i>P</i>)-3-amino-1-(2-amino-6-fluorophenyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-4-carbonitrile\n(17) by use of an environment-friendly catalyst system identified\nby high throughput screening. The telescoped six-step process was\nrobustly performed to provide hundreds of kilograms of GH35-RSM in\nplants to support clinical studies.