反应详情

温度

105 °C

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethyl)quinazolin-4-ol (121 mg, 0.34 mmol) were added phosphoryl tribromide (890 mg) and toluene (1 mL) followed by DIEA (0.117 mL, 0.67 mmol). The mixture was heated at 105° C. for 1 h. 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 (150 mg, 1.5 mmol) in DMF (4 mL) and the mixture was stirred at rt for 1.5 h. The crude mixture was purified by preparative HPLC (Varian diphenyl 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-(trifluoromethyl)quinazolin-4-amine (30 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.03 (s, 1H) 7.77 (t, J=7.91 Hz, 1H) 7.96-8.06 (m, 2H) 8.27 (d, J=7.53 Hz, 1H) 8.67 (s, 1H) 8.97 (d, J=8.29 Hz, 1H) 11.00 (br s, 1H) 12.18 (br s, 1 H); LC-MS (ESI) m/z 439 (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 (Varian diphenyl reverse phase column
6. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)