反应详情

温度

100 °C

To a solution of tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (1 g, 2.4 mmol) in DMSO/MeOH (4:1, 20 mL), were added benzaldehyde (0.32 mL, 3.2 mmol) and sodium dithionite (2.0 g, 9.5 mmol). The mixture was heated at 100° C. for 22 h and 1M-NaOH was added to the mixture with cooling in an ice bath until the pH becomes 9. The mixture was diluted with THF (50 mL) then Boc2O (1.5 g) was added and mixed stirred for 2 h at rt. The mixture was filtered through celite and the water phase was extracted with ethyl acetate (×2). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. After evaporation, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100) to give tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate (520 mg) as a white solid (46%). To a suspension of tert-butyl {1-[4-(5-chloro-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.1 mmol) in toluene/ethanol/saturated NaHCO3 (3/3/0.3 mL), were added 3-(4-morphoryl)phenylboronic acid (65 mg, 0.22 mmol) and Pd(PPh3)4 (12 mg, 0.01 mmol). The mixture was heated at 100° C. for 13.5 h. After evaporation under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100) to give the titled compound (69 mg) as a white solid. 1H-NMR (CDCl3) δ: 8.17 (1H, d, J=8.6 Hz), 7.78 (1H, d, J=8.6 Hz), 7.62 (3H, d, J=7.4 Hz), 7.54 (3H, t, J=8.0 Hz), 7.42 (2H, td, J=5.6, 3.2 Hz), 7.40-7.37 (1H, m), 7.36-7.31 (3H, m), 6.94 (1H, dd, J=8.0, 1.7 Hz), 3.89 (4H, t, J=4.6 Hz), 3.22 (4H, t, J=4.9 Hz), 2.65-2.32 (4H, m), 2.20-2.11 (1H, m), 1.93-1.90 (1H, m), 1.47-1.19 (9H, m); LC/MS: 602 [M+H]+.

1. temperaturewith cooling in an ice bath until the pH
2. additionmixed
3. filtrationThe mixture was filtered through celite
4. extractionthe water phase was extracted with ethyl acetate (×2)
5. washThe combined organic phase was washed with brine
6. dry with materialdried over anhydrous Na2SO4
7. customAfter evaporation
8. customthe residue was purified by silica gel column chromatography (hexane/ethyl acetate, 4:1 to 0:100)