反应详情

温度

95 °C

A mixture of 4-(4-bromo-2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (1.01 g, 2.035 mmol), bis(pinacolato)diboron (1.550 g, 6.10 mmol), Pd2(dba)3 (0.093 g, 0.102 mmol), X-Phos (0.097 g, 0.203 mmol) and potassium acetate (0.599 g, 6.10 mmol) in 1,4-Dioxane (20 mL) in a 40 mL scintillation vial was heated for 1 hr at 95° C. When cooled, the reaction contents were poured into 1N HCl (3 ml) and H2O (3 mL) mixture, swirled and then extracted with EtOAc, dried over MgSO4 and concentrated in-vacuo. The residue was dissolved in MeOH and the material was purified by reverse phase chromatography eluting with a gradient 30% CH3CN to 60% CH3CN over 10 minutes. The fractions containing clean desired compound were combined and concentrated in vacuo to provide the desired product (178 mg, 0.386 mmol, 18.96% yield) as an off-white solid. Additional fractions, containing less pure desired product—contaminated with des-boronylated product as determined by LC/MS—were combined and the CH3CN was removed in-vacuo leaving the material in H2O. Upon standing a white solid fell out of the resulting solution. The white solid was collected by filtration, dried in a vacuum oven to yield (2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid (296 mg, 0.642 mmol, 31.5% yield). The total yield of desired product was (474 mg, 1.03 mmol, 50.5% yield). MS (ES+) m/e: 461.2, 462.3 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67 (d, J=7.83 Hz, 1H), 7.47-7.60 (m, 1H), 7.27 (s, 1H), 7.10 (d, J=2.27 Hz, 1H), 6.63 (d, J=7.83 Hz, 1H), 5.85 (s, 2H), 3.72-3.85 (m, 4H), 3.57 (s, 1H), 3.10-3.24 (m, 4H), 2.62 (s, 3H), 1.45 (d, J=7.07 Hz, 6H).

1. temperatureWhen cooled
2. customthe reaction contents
3. extractionextracted with EtOAc
4. dry with materialdried over MgSO4
5. concentrationconcentrated in-vacuo
6. dissolutionThe residue was dissolved in MeOH
7. customthe material was purified by reverse phase chromatography
8. washeluting with a gradient 30% CH3CN to 60% CH3CN over 10 minutes
9. additionThe fractions containing clean desired compound
10. concentrationconcentrated in vacuo