反应详情

温度

120 °C

To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.4 g, 0.88 mmol) and isobutyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (0.6 g, 1.86 mmol) in dioxane (4 mL) and water (0.5 ml) was added diisopropylethylamine (0.34 g, 2.64 mmol). The solution was sparged with N2(g) for ten minutes before the addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.072 g, 10 mol %). The resulting suspension was heated at 120° C. for 2 hours in a sealed tube on a CEM Explorer microwave synthesizer. On cooling to room temperature the mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (70 mL), brine (50 mL) then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (97:3 dichloromethane/methanol) then preparative reverse phase HPLC of the combined product containing fractions (0.1% aqueous ammonium acetate-acetonitrile) to afford 7-[4-(1H-imidazol-2-yl)phenyl]-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.058 g, 12% yield) as a white solid. 1H NMR (400 MHz, methanol-d4): 7.92 (d, 2H), 7.70 (d, 2H), 7.58-7.50 (m, 2H), 7.15 (s, 2H), 7.05 (d, 1H), 4.52 (s, 2H), 4.22 (t, 2H), 3.77 (d, 2H), 3.71 (t, 2H), 2.87 (t, 2H), 2.39 (m, 1H), 1.86 (d, 2H), 1.59 (m, 2H); MS (EI) for C25H25F3N4O2: 471 (MH+).

1. customThe solution was sparged with N2(g) for ten minutes before the addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.072 g, 10 mol %)
2. temperatureOn cooling to room temperature the mixture
3. additionwas diluted with ethyl acetate (100 mL)
4. washwashed with saturated sodium bicarbonate (70 mL), brine (50 mL)
5. dry with materialthen dried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. customThe resulting residue was purified by silica gel chromatography (97:3 dichloromethane/methanol)
9. additionpreparative reverse phase HPLC of the combined product containing fractions (0.1% aqueous ammonium acetate-acetonitrile)