反应详情

Potassium tert-butoxide (6.15 g) was added to a solution of 4-hydroxytetrahydropyran (2.94 g) in THF (40 ml) and the mixture was stirred at ambient temperature for 15 minutes. The resultant mixture was added to a stirred solution of 5,7-difluoro-3,4-dihydroquinazolin-4-one (5 g) in THF (60 ml) that was being heated to reflux. A further portion of THF (20 ml) was added and the reaction mixture was heated to reflux for 30 minutes. A second portion of potassium tert-butoxide (6.15 g) was added and the reaction mixture was heated to reflux for 40 minutes. A third portion of potassium tert-butoxide (1.52 g) was added and the reaction mixture was heated to reflux for 20 minutes. The reaction mixture was allowed to cool to ambient temperature. Water (50 ml) was added and the bulk of the organic solvent was evaporated. The residue was acidified to pH<2 by the dropwise addition of 2M aqueous hydrochloric acid. The resultant slurry was stirred for 15 minutes. The mixture was filtered and the isolated solid was washed with water (20 ml) and dried overnight in vacuo at 40° C. There was thus obtained 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (5.96 g; 96% HPLC purity using Method A, retention time 3.34 minutes); NMR Spectrum: (DMSOd6) 1.6-1.75 (m, 2H), 1.9-2.0 (m, 2H), 3.5-3.6 (m, 2H), 3.85-3.95 (m, 2H), 4.8 (m, 1H), 6.9 (m, 1H), 7.05 (m, 1H), 8.0 (s, 1H).

1. temperaturewas being heated to reflux
2. temperaturethe reaction mixture was heated
3. temperatureto reflux for 30 minutes
4. temperaturethe reaction mixture was heated
5. temperatureto reflux for 40 minutes
6. temperaturethe reaction mixture was heated
7. temperatureto reflux for 20 minutes
8. temperatureto cool to ambient temperature
9. customthe bulk of the organic solvent was evaporated
10. additionThe residue was acidified to pH<2 by the dropwise addition of 2M aqueous hydrochloric acid
11. stirringThe resultant slurry was stirred for 15 minutes
12. filtrationThe mixture was filtered
13. washthe isolated solid was washed with water (20 ml)
14. customdried overnight in vacuo at 40° C