Doravirine

A robust kilogram scale synthesis of doravirine was recently reported:^{[9][10][11][12]}

A reaction catalyzed with cyclooctadiene iridium methoxide dimer and bis(pinacolato)diboron followed by treatment with ozone converted 1-chloro-3-iodobenzene [625-99-0] (1) to 3-chloro-5-iodophenol [861347-86-6] (2). A SNAr reaction with 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine [628692-22-8] (3) led to diaryl ether, 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine [1338226-06-4] (4). Basic hydrolysis followed by recrystallization gave rise to 2-pyridinol, PC58460051 (5). Introduction of the nitrile functional group using copper cyanide in NMP was achieved under relatively mild conditions. Keeping the temperature under 110 °C was critical for suppressing undesired bis-cyanation products, and that the iodide was chosen over the analogous bromide to further help ensure selectivity for the desired mono-nitrile product, PC58460048 (6). Alkylation with 5-(Chloromethyl)-2,4-dihydro-4-methyl-3H-1,2,4-triazol-3-one [1338226-21-3] (7) was possible under mild conditions to give 2-pyridone [1338226-05-3] (8). Temperature controlled alkylation with iodomethane and potassium carbonate completed the synthesis of doravirine (9).