Phosphorus oxychloride → 4-Chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline

HRID 1693005Notes

Reaction equation

HRID 1693005 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][C:17]1[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 136105219HCID 136105219, compound

Product 1

HCID 592128574-Chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a mechanically stirred suspension of 2-(2-methoxyphenyl)-7-methyl-3H-quinazolin-4-one (100 g, 0.37 mol) in 1 L toluene was added diisopropyl ethylamine (100 mL), followed by phosphorus oxychloride (69 g, 0.45 mol). The reaction was then heated to 80° C. for 4 h. The reaction mixture was distilled under reduced pressure to remove toluene, and the resulting residue was dissolved in 2.2 L CH2Cl2. Ice water was added, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution while maintaining the temperature below 20° C. The resulting organic layer was separated and the aqueous solution extracted with CH2Cl2, then the combined the organic layers were dried over sodium sulfate and distilled under reduced pressure. The crude product was dissolved 2:1 CH2Cl2/hexane, and the solution was passed through silica gel (2.5 kg, 60-120 mesh), followed by washing the silica bed with 2:1 CH2Cl2/hexane until the product eluted. The pure fractions were collected and combined, and the solvent was removed under reduced pressure. Hexane (500 mL) was added, and the mixture was stirred and filtered to give 4-chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline as a white to off-white solid (77 g, 72%). mp 161-164° C. 1H NMR (CDCl3) δ 2.6 (s, 3H), 3.9 (s, 3H), 6.9-7.2 (m, 2H), 7.4-7.6 (m, 2H), 7.7-8 (d, 2H), 8.2 (d, 1H) ppm; M/z (obs., [m+H]+)=285.

Workup

  1. distillationThe reaction mixture was distilled under reduced pressure
  2. customto remove toluene
  3. dissolutionthe resulting residue was dissolved in 2.2 L CH2Cl2
  4. additionIce water was added
  5. temperaturewhile maintaining the temperature below 20° C
  6. customThe resulting organic layer was separated
  7. extractionthe aqueous solution extracted with CH2Cl2
  8. dry with materialwere dried over sodium sulfate
  9. distillationdistilled under reduced pressure
  10. dissolutionThe crude product was dissolved 2:1 CH2Cl2/hexane
  11. washby washing the silica bed with 2:1 CH2Cl2/hexane until the product
  12. washeluted
  13. customThe pure fractions were collected
  14. customthe solvent was removed under reduced pressure
  15. additionHexane (500 mL) was added
  16. filtrationfiltered

Sources & evidence

ORD record
ord-2d2a6bfa96ac4f869c3402f8e489d301
Source dataset
uspto-grants-2012_04
Patent number
US08158637B2

Reaction notes

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