Manufacturing Process for 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, a Key Intermediate in the Synthesis of KRAS G12C Inhibitor Divarasib

The densely functionalized heterocycle 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (1) represents a key intermediate in the atroposelective synthesis of the potent KRAS G12C covalent inhibitor divarasib (GDC-6036). The first-generation manufacturing process of 1 comprised 9 steps, including tedious protecting group manipulations and a superstoichiometric copper-mediated trifluoromethylation of the corresponding iodopyridine using Chen's reagent. Additional process research and development enabled an improved, scalable second-generation route furnishing 1 in only 3 steps from the readily available and inexpensive starting material 2,6-dichloro-4-methylnicotinic acid (13) via a deoxofluorination, a chlorine-to-bromine halogen exchange, and a regioselective SNAr amination.