Cesium carbonate → 7-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine

HRID 1712973Notes

Reaction equation

HRID 1712973 reaction equation
Cl.[O:2]1[CH2:7][CH2:6][NH:5][C:4]2[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:3]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](Cl)=[CH:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([O:12][C:10]3[CH:9]=[CH:8][C:4]4[NH:5][CH2:6][CH2:7][O:2][C:3]=4[CH:11]=3)=[CH:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonate2×HCID 226465627-(Benzyloxy)-4-chloro-6-methoxyquinolineHCID 533084593,4-Dihydro-2H-1,4-benzoxazin-7-ol hydrochloride3×

Product 1

HCID 577371497-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazineYield 40.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol), cesium carbonate (4.35 g, 13.3 mmol), and 7-(benzyloxy)-4-chloro-6-methoxyquinoline (1.000 g, 3.34 mmol) in DMF (10.0 mL) was stirred at 80° C. After 17 h, additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 mmol) was added, and the mixture stirred at 80° C. for 20 h. Additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.6259 g, 3.336 mmol) and cesium carbonate (4.35 g, 13.3 mmol) were added, and the mixture stirred at 80° C. for 3 days. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange-brown oil. This material was purified twice via column chromatography (RediSep 120 g column, gradient elution with 0-5% methanol-dichloromethane) to afford an orange oil. Trituration with methanol and filtering the resulting suspension afforded 7-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.560 g, 40.5% yield) as a tan solid. MS (MH+) 415.1; Calculated 414 for C25H22N2O4.

Workup

  1. stirringthe mixture stirred at 80° C. for 3 days
  2. customThe reaction mixture was partitioned between dichloromethane and water
  3. customThe aqueous phase was separated
  4. extractionextracted with dichloromethane
  5. washThe combined organic phases were washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto afford an orange-brown oil
  10. customThis material was purified twice via column chromatography (RediSep 120 g column, gradient elution with 0-5% methanol-dichloromethane)
  11. customto afford an orange oil
  12. filtrationTrituration with methanol and filtering the resulting suspension

Sources & evidence

ORD record
ord-2c5ab2b8afab4f9d89d7912537cb8901
Source dataset
uspto-grants-2010_09
Patent number
US07795254B2

Reaction notes

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