Methanesulfonic Acid → N-(3-Bromophenyl)-4-(difluoromethyl)pyrimidin-2-amine

Participants

Reaction Conditions

Reaction Steps

2-Chloro-4-(difluoromethyl)pyrimidine (69 wt % in DCM, 24.2 g, 101 mmol) was diluted with 1,4-dioxane (200 mL) to which was added 3-bromoaniline (14.9 mL, 137 mmol) followed by methanesulfonic acid (8.89 mL, 137 mmol). The resulting mixture was heated to an internal temperature of 95° C. where it was stirred for 10 h at which point the reaction mixture was cooled to room temperature and diluted with dichloromethane and water. NaOH (1N) was added until the pH of the aq layer was ˜7, the layers were separated and the aqueous layer was extracted a second time with additional of dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. To facilitate purification, the crude residue was diluted with dichloromethane (200 mL) and DMAP (0.84 g, 6.84 mmol) followed by acetic anhydride (3.87 mL, 41.1 mmol) were added. After stirring for 30 min all excess 3-bromoaniline had been acetylated, silica gel was added and the mixture concentrated under reduced pressure and the desired product isolated by purification by column chromatography on silida (0 to 100% EtOAc/Hex) to afford N-(3-bromophenyl)-4-(difluoromethyl)pyrimidin-2-amine as a white solid, MS ESI calcd. for C11H9BrF2N3 [M+H]+ 300. found 300. 1H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.71 (d, J=4.9 Hz, 1H), 8.06 (s, 1H), 7.70 (dd, J=8.2, 1.3 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.09 (d, J=4.9 Hz, 1H), 6.85 (t, J=54.4 Hz, 1H).

Provenance & Evidence