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

HRID 1712976Notes

Reaction equation

HRID 1712976 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:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2Cl)[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:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:12][C:10]1[CH:9]=[CH:8][C:4]2[NH:5][CH2:6][CH2:7][O:2][C:3]=2[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonate2×HCID 230227816-(Benzyloxy)-4-chloro-7-methoxyquinolineHCID 533084593,4-Dihydro-2H-1,4-benzoxazin-7-ol hydrochloride2×

Product 1

HCID 577371437-(6-(benzyloxy)-7-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazineYield 83.6%

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 6-(benzyloxy)-4-chloro-7-methoxyquinoline (1.00 g, 3.34 mmol) in DMF (10.0 mL) was stirred at 80° C. for 18 h. An additional 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol hydrochloride (0.626 g, 3.34 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 80 g column, gradient elution with 0-5% methanol-dichloromethane) to afford an orange oil. Trituration with methanol and filtering the resulting suspension afforded 7-(6-(benzyloxy)-7-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.156 g, 83.6% yield) as an orange glass. MS (MH+) 415.1; Calculated 414 for C25H22N2O4.

Workup

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

Sources & evidence

ORD record
ord-5aab13d1ffad4e1abbd6f7105e5bbb82
Source dataset
uspto-grants-2010_09
Patent number
US07795254B2

Reaction notes

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