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

HRID 631590Notes

Reaction equation

HRID 631590 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[O:14][C:12]1[CH:13]=[C:8]([CH:9]=[CH:10][C:11]=1[F:15])[NH2:7]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 27693644-Chloro-6,7-dimethoxyquinazolineHCID 226414135-Amino-2-fluorophenol

Product 1

HCID 668768273-(6,7-Dimethoxyquinazolin-4-yloxy)-4-fluoroanilineYield 67.3%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Procedure

To a stirred slurry of cesium carbonate (9.53 g, 29 mmol) in a mixture of THF/DMF (9/1, 200 mL) at rt, was added 5-amino-2-fluorophenol (2.10 g, 14.6 mmol) in one portion. After stirring for 30 min at rt, 4-chloro-6,7-dimethoxyquinazoline (3.61 g, 16 mmol) was added and the reaction mixture was heated at 50° C. for 30 h. The reaction was cooled to rt, then diluted with ethyl acetate. The solution was washed with 1 N sodium hydroxide solution, then brine, and dried over MgSO4. Filtration followed by concentration under reduced pressure gave a solid that was triturated with methanol. Filtration afforded 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline (3.10 g, 67%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.05 (dd, J=9.2, 9.2 Hz, 1H), 6.47-6.56 (m, 2H), 5.19 (brs, 2H), 4.00 (s, 3H), 3.99 (s, 3H); LC-MS (ESI) m/z 316 (M+H)+.

Workup

  1. temperaturethe reaction mixture was heated at 50° C. for 30 h
  2. temperatureThe reaction was cooled to rt
  3. washThe solution was washed with 1 N sodium hydroxide solution
  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 methanol
  9. filtrationFiltration

Sources & evidence

ORD record
ord-845f1fd6f0a041c0a9c425859a10ea95
Source dataset
uspto-grants-2016_04
Patent number
US09320739B2

Reaction notes

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