反应详情

温度

150 °C

To a mixture of 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetic acid from Example 33 step A (1.05 g, 5.49 mmol) and 2-amino-3-nitrobenzoic acid (1 g, 5.49 mmol) in pyridine (15 mL) was added triphenyl phosphite (1.59 mL, 6.03 mmol), and the mixture heated in a microwave synthesizer at 150° C. for 10 min. The mixture was allowed to cool to rt, and then ethyl 3-aminopropanoate hydrochloride (945 mg, 6.03 mmol) was added. The mixture was heated in a microwave synthesizer at 190° C. for 4 min, and then concentrated under reduced pressure. THF (20 mL) and sodium ethoxide (21% in EtOH, 10 mL) were added and the mixture was heated at 50° C. for 0.5 h with stirring. The mixture was concentrated under reduced pressure and then partitioned between EtOAc and 4 N HCl. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified by silica gel chromatography eluting with 10-100% EtOAc/hexanes. The residue was triturated with Et2O and the solid was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-nitroquinazolin-4-ol (566 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.77 (t, J=7.91 Hz, 1H) 7.97-8.11 (m, 2H) 8.30-8.48 (m, 2H) 8.68 (s, 1H) 13.61 (br s, 1H).

1. temperatureto cool to rt
2. temperatureThe mixture was heated in a microwave synthesizer at 190° C. for 4 min
3. concentrationconcentrated under reduced pressure
4. additionTHF (20 mL) and sodium ethoxide (21% in EtOH, 10 mL) were added
5. temperaturethe mixture was heated at 50° C. for 0.5 h
6. concentrationThe mixture was concentrated under reduced pressure
7. custompartitioned between EtOAc and 4 N HCl
8. dry with materialThe organic layer was dried over sodium sulfate
9. concentrationconcentrated under reduced pressure
10. custompurified by silica gel chromatography
11. washeluting with 10-100% EtOAc/hexanes
12. customThe residue was triturated with Et2O
13. filtrationthe solid was collected by filtration