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
posted on 2023-12-29, 21:16authored byJeff Shen, Nicholas A. White, Qingping Tian, Lauren E. Sirois, Haiming Zhang, Francis Gosselin
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.