Sodium Hydroxide → 4-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine

Participants

Reaction Steps

Two combined batches of 4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-amine (1.087 g, 2.503 mmol) was stirred in 6M sodium hydroxide (30 mL, 180 mmol) solution with 1-bromo-2-(2-bromoethoxy)ethane (1.5 mL, 12.03 mmol) and tetrabutylammonium iodide (0.092 g, 0.250 mmol) at 110° C. After stirring for 2.5 hr the mixture was cooled and the aqueous was decanted and the remaining sticky solid was dissolved in EtOAc. The organic was washed with H2O and brine and dried over MgSO4 and concentrated to leave a residue. The residue was loaded onto a 25 g Silica column and eluted with a EtOAc/Hex 15% to 40% over 15 column volumes. While loading onto the column, a significant amount of solid crystallized on the silica wafer. This material was scraped off and dried in-vacuo to provide 4-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (458 mg, 0.908 mmol, 36.3% yield) as a light orange solid. The material that was absorbed on the silica wafer was purified to provide additional material 4-(4-bromo-2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (300 mg, 0.595 mmol, 23.76% yield). The total yield desired product was 758 mg (60%). LC/MS: MS (ES+) m/e 503.9 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=7.83 Hz, 1H), 7.25-7.32 (d, J=1.77 Hz, 1H), 7.16 (t, J=7.83 Hz, 1H), 6.83-7.13 (m, 1H), 6.59 (d, J=7.58 Hz, 1H), 6.38 (d, J=1.77 Hz, 1H), 5.55 (s, 2H), 3.77-3.92 (m, 4H), 3.05-3.16 (m, 4H), 2.56 (s, 3H)

Provenance & Evidence