反应详情

温度

-78 °C

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine from Example 43 step B (150 mg, 0.375 mmol) in DCM (10 mL) at −78° C. under argon was added boron tribromide (1M in DCM, 3.75 mL, 3.75 mmol). The mixture was stirred at −78° C. for 20 min, and then allowed to warm slowly to rt. Additional boron tribromide (1M in DCM, 4 mL, 4 mmol) was added and the mixture was stirred at rt for 6 days. MeOH was added slowly and then the mixture was concentrated under reduced pressure to afford a mixture of brominated products. The mixture was partially purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O). To the recovered product were added a 1:1 mixture of THF/MeOH (8 mL) and palladium hydroxide (20% on carbon, 50 mg) and the mixture was heated under an atmosphere of hydrogen at 50° C. for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure, and then purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-ol (3 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 5.91 (s, 1H) 7.25 (d, J=7.54 Hz, 1H) 7.45 (t, J=8.10 Hz, 1H) 7.89-8.19 (m, 3H) 8.66 (s, 1H) 9.80 (br s, 1H) 10.52 (br s, 1H) 12.16 (br s, 1H). LC-MS (ESI) m/z 387 (M+H)+.

1. temperatureto warm slowly to rt
2. stirringthe mixture was stirred at rt for 6 days
3. concentrationthe mixture was concentrated under reduced pressure
4. customto afford
5. additiona mixture of brominated products
6. customThe mixture was partially purified by preparative HPLC (Varian C-18 reverse phase column
7. washeluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O)
8. additionTo the recovered product were added
9. additiona 1:1 mixture of THF/MeOH (8 mL) and palladium hydroxide (20% on carbon, 50 mg)
10. temperaturethe mixture was heated under an atmosphere of hydrogen at 50° C. for 1 h
11. filtrationThe mixture was filtered
12. concentrationthe filtrate was concentrated under reduced pressure
13. custompurified by preparative HPLC (Varian C-18 reverse phase column
14. washeluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O)