Water → 7-Fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(3H)-one

HRID 1873645Notes

Reaction equation

HRID 1873645 reaction equation
CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.F[C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[C:17](=[O:26])[NH:18][CH:19]=[N:20]2.O>C1COCC1>[F:25][C:23]1[CH:22]=[C:21]2[C:16]([C:17](=[O:26])[NH:18][CH:19]=[N:20]2)=[C:15]([O:7][CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:24]=1

Participants

6

Reactant 4

HCID 962WaterHCID 74956Tetrahydro-4H-pyran-4-olHCID 23665647Potassium tert-butoxide3×HCID 1355106875,7-Difluoro-3,4-dihydroquinazolin-4-one

Product 1

HCID 1357420957-Fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(3H)-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-bf0545c0c182429c805865e7b288c366
Source dataset
uspto-grants-2012_11
Patent number
US08304417B2

Reaction notes

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