反应详情

温度

37 °C

To a stirring solution of 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (104 mg, 358 μmol) and diisopropylethylamine (62 μl, 358 μmol) in DMF (1 mL) was added HATU (136 mg, 358 μmol) and stirred at 37° C. under nitrogen for 15 min. To this was added 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (98 mg, 344 mmol) and stirred overnight at 37° C. The reaction mixture was diluted with dichloromethane (10 mL) and washed with 1M NaOH (20 mL), and extracted with dichloromethane (3×5 mL). Combined organics layer was washed with brine and then dried with MgSO4. Residual DMF was removed with repeated azeotroping with toluene (4×5 mL) under reduced pressure. The residue was purified on 12 g silica (10>30% of 6% 2 M NH3 in MeOH/DCM). Final material was lyophilized from 50% ACN/water to give the title compound (155 mg, 74% yield) as a white fluffy solid. MS (ESI pos. ion) m/z: 587 (MH+). Calc'd exact mass for C32H31FN4O6 587. 1H NMR (400 MHz, CHLOROFORM-d) 10.88 (1 H, s), 8.47 (1 H, d, J=5.3 Hz), 7.92 (1 H, dd, J=12.5, 2.0 Hz), 7.59 (1 H, s), 7.54 (2 H, t, J=7.7 Hz), 7.40-7.49 (2 H, m), 7.30 (3 H, d, J=7.8 Hz), 7.17 (1 H, t, J=8.7 Hz), 6.45 (1 H, d, J=5.3 Hz), 4.06 (3 H, s), 4.05 (3 H, s), 3.88 (2 H, s), 2.89 (3 H, s), 2.01 (1 H, s), 1.15(6 H, s)

1. stirringstirred overnight at 37° C
2. washwashed with 1M NaOH (20 mL)
3. extractionextracted with dichloromethane (3×5 mL)
4. washCombined organics layer was washed with brine
5. dry with materialdried with MgSO4
6. customResidual DMF was removed
7. customwith repeated azeotroping with toluene (4×5 mL) under reduced pressure
8. customThe residue was purified on 12 g silica (10>30% of 6% 2 M NH3 in MeOH/DCM)