反应详情

温度

100 °C

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(methylsulfonyl)quinazolin-4-ol (100 mg, 0.27 mmol) were added phosphoryl tribromide (1.25 g) and toluene (0.5 mL) and DIEA (0.094 mL, 0.54 mmol), and the mixture was heated at 100° C. for 20 min. The mixture was cooled and 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 (67 mg, 0.69 mmol) in DMF (3 mL) and the mixture was stirred at rt for 0.5 h. The crude mixture was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(methylsulfonyl)quinazolin-4-amine (72 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 3.47 (s, 3H) 6.14 (s, 1H) 7.83 (t, J=7.91 Hz, 1H) 7.97-8.09 (m, 2H) 8.44 (d, J=7.35 Hz, 1H) 8.68 (s, 1H) 9.03 (d, J=8.10 Hz, 1H) 11.11 (s, 1H) 12.24-12.36 (m, 1H); LC-MS (ESI) m/z 449 (M+H)+.

1. temperatureThe mixture was cooled
2. custompartitioned 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 (Phenomenex C-18 reverse phase column
6. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)