Cesium carbonate → 3-(6,7-Dimethoxyquinazolin-4-yloxy)-2-fluoroaniline

HRID 871637Notes

Reaction equation

HRID 871637 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1.CN(C=O)C.[NH2:17][C:18]1[C:19]([F:25])=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][N:28]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][C:33]=1[O:39][CH3:40])[N:30]=[CH:29][N:28]=[C:27]2[O:24][C:20]1[C:19]([F:25])=[C:18]([CH:23]=[CH:22][CH:21]=1)[NH2:17]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 27693644-Chloro-6,7-dimethoxyquinazolineHCID 198960373-Amino-2-fluorophenolHCID 21974620tetrahydrofuran N,N-dimethylformamide

Product 1

HCID 178195183-(6,7-Dimethoxyquinazolin-4-yloxy)-2-fluoroanilineYield 42.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred slurry of cesium carbonate (10.25 g, 31.47 mmol) in a 9:1 mixture of THF/DMF (100 mL) at rt, was added 3-amino-2-fluorophenol (2.00 g, 15.74 mmol) in one portion. After stirring for 30 min at rt, 4-chloro-6,7-dimethoxyquinazoline (3.54 g, 15.74 mmol) was added and the reaction mixture was heated at 50° C. for 18 h. The reaction was cooled to rt, then diluted with dichloromethane. The solution was washed with water, then brine, and dried over MgSO4. Filtration followed by concentration under reduced pressure gave a solid that was triturated with a mixture of 10% dichloromethane in ethyl acetate. Filtration afforded 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (2.10 g, 42%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 6.93 (dd, J=8.4, 8.4 Hz, 1H), 6.71 (dd, J=8.4, 8.4 Hz, 1H), 6.53 (m, 1H), 5.37 (brs, 2H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 316 (M+H)+.

Workup

  1. temperaturethe reaction mixture was heated at 50° C. for 18 h
  2. temperatureThe reaction was cooled to rt
  3. washThe solution was washed with water
  4. dry with materialbrine, and dried over MgSO4
  5. filtrationFiltration
  6. concentrationfollowed by concentration under reduced pressure
  7. customgave a solid
  8. customthat was triturated with a mixture of 10% dichloromethane in ethyl acetate
  9. filtrationFiltration

Sources & evidence

ORD record
ord-45010c1809c8415992c857eb2bbf3128
Source dataset
uspto-grants-2015_03
Patent number
US08969587B2

Reaction notes

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