反应详情

温度

105 °C

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxyquinazolin-4-ol (450 mg, 1.4 mmol) were added phosphoryl tribromide (3.14 g) and toluene (4 mL) followed by DIEA (0.488 mL, 2.8 mmol). The mixture was heated at 105° C. for 1 h. The mixture was allowed to cool and was partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (300 mg, 3.1 mmol) in DMF (4 mL) and the mixture was stirred at rt for 3 days. The crude mixture was purified by preparative HPLC (Varian C-18 reverse phase column, eluting with a gradient of solvent B=0.05% formic acid/ACN and solvent A=0.05% formic acid/H2O/5% ACN) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (170 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 3.95 (s, 3H) 5.91 (s, 1H) 7.38 (d, J=7.91 Hz, 1H) 7.56 (t, J=8.10 Hz, 1H) 7.93-8.06 (m, 2H) 8.19 (d, J=8.10 Hz, 1H) 8.66 (s, 1H) 10.53 (br s, 1H) 12.15 (br s, 1H); LC-MS (ESI) m/z 401 (M+H)+.

1. temperatureto cool
2. customwas partitioned between EtOAc and saturated aq sodium bicarbonate
3. dry with materialThe organic layer was dried over sodium sulfate
4. concentrationconcentrated under reduced pressure
5. customThe crude mixture was purified by preparative HPLC (Varian C-18 reverse phase column
6. washeluting with a gradient of solvent B=0.05% formic acid/ACN and solvent A=0.05% formic acid/H2O/5% ACN)