反应详情

温度

150 °C

To 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid from Example 33 step A (440 mg, 2.31 mmol) and 2-amino-3-bromobenzoic acid (0.5 g, 2.31 mmol) in pyridine (8 mL) was added triphenyl phosphite (0.667 mL, 2.54 mmol) and the mixture was heated in a microwave synthesizer at 150° C. for 10 min. The mixture was cooled to rt and then ethyl 3-aminopropanoate hydrochloride (396 mg, 2.54 mmol) was added and the mixture was heated in a microwave synthesizer at 180° C. for 3 min. The mixture was concentrated under reduced pressure. THF (10 mL) was added followed by sodium ethoxide (21% in EtOH, 3.2 mL) and the mixture was stirred at 50° C. for 2 h. An additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added and the mixture stirred at 50° C. for 4 h. The mixture was allowed to cool and was partitioned between EtOAc and 1 N HCl. The organic layer was washed (3×) with 1 N HCl, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with DCM and collected by filtration to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (444 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (t, J=7.91 Hz, 1H) 7.99-8.12 (m, 2H) 8.13-8.23 (m, 2H) 8.69 (d, J=2.45 Hz, 1H) 13.39 (br s, 1H).

1. temperatureThe mixture was cooled to rt
2. temperaturethe mixture was heated in a microwave synthesizer at 180° C. for 3 min
3. concentrationThe mixture was concentrated under reduced pressure
4. additionTHF (10 mL) was added
5. additionAn additional amount of sodium ethoxide (21% in EtOH, 1 mL) was added
6. stirringthe mixture stirred at 50° C. for 4 h
7. temperatureto cool
8. customwas partitioned between EtOAc and 1 N HCl
9. washThe organic layer was washed (3×) with 1 N HCl
10. dry with materialdried over sodium sulfate
11. concentrationconcentrated under reduced pressure
12. customThe residue was triturated with DCM
13. filtrationcollected by filtration