Phosphorus oxychloride → 4-Chloro-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazoline

HRID 749190Notes

Reaction equation

HRID 749190 reaction equation
[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:4]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:33])=O>ClCCl>[Cl:33][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 1355106997-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one

Product 1

HCID 113812714-Chloro-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazolineYield 75%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of 7-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one (3.00 g, 10.4 mmol) and diisopropyl ethylamine (5 ml) in dichloromethane (300 ml) was stirred at ambient temperature under an atmosphere of nitrogen. Phosphoryl chloride (10 ml) was added, and the resultant orange solution was heated at reflux for 20 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. Residual phosphoryl chloride was then removed by azeotrope with toluene to give the crude product as an orange oil. Purification by chromatography on silica gel, eluting with 5% triethylamine in dichloromethane, gave an orange solid, which was further purified by trituration under acetonitrile, and then dried in vacuo to yield 4-chloro-5-(N-methylpiperidin-4-yloxy)-7-methoxyquinazoline (2.4 g, 75% yield) as a pale yellow amorphous solid:

Workup

  1. temperaturethe resultant orange solution was heated
  2. temperatureat reflux for 20 hours
  3. concentrationconcentrated in vacuo
  4. customResidual phosphoryl chloride was then removed by azeotrope with toluene
  5. customto give the crude product as an orange oil
  6. customPurification by chromatography on silica gel
  7. washeluting with 5% triethylamine in dichloromethane
  8. customgave an orange solid, which
  9. customwas further purified by trituration under acetonitrile
  10. customdried in vacuo

Sources & evidence

ORD record
ord-57e5603cef4f4582ad692ca272519896
Source dataset
uspto-grants-2008_07
Patent number
US07402585B2

Reaction notes

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