Acetic Acid → 3-(2-Chlorophenyl)-6-fluoro-2-[(2-fluoroanilino)methyl]quinazolin-4-one

HRID 1169266Notes

Reaction equation

HRID 1169266 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[F:22]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 95842-FluoroanilineHCID 5003444Sodium cyanoborohydrideHCID 106858093-(2-Chlorophenyl)-6-fluoro-3,4-dihydroquinazolin-4-one-2-carboxaldehyde

Product 1

HCID 99088093-(2-Chlorophenyl)-6-fluoro-2-[(2-fluoroanilino)methyl]quinazolin-4-oneYield 76.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.10 g, 0.33 mmol), 2-fluoroaniline (0.064 mL, 0.66 mmol) and acetic acid (0.038 mL, 0.66 mmol) in methanol (10 mL) was stirred 1.5 hours at ambient temperature. Sodium cyanoborohydride (0.083 g, 1.32 mmol) was added and the reaction was stirred overnight. The reaction was diluted with water and concentrated to remove most of the methanol. The milky white liquid residue was treated with saturated aqueous bicarbonate and extracted with ethyl acetate. The organic layer was washed with aqueous bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20 g) eluting the product with 5% and then 10% ethyl acetate/hexane. In this fashion 0.10 g (76%) of 3-(2-chloro-phenyl)-6-fluoro-2-[(2-fluoro-phenylamino)-methyl]-3H-quinazolin-4-one was isolated as a yellow foam which had: 1H NMR δ 7.95 (dd, J=3, 8.5 Hz, 1H), 7.85 (dd, J=5, 9 Hz, 1H), 7.69 (dd, J=2, 7.5 Hz, 1H), 7.63-7.46 (m, 3H), 7.43-7.37 (m, 1H), 7.05-6.90 (m, 2H), 6.70-6.62 (m, 1H), 6.43 (dt, J=1, 9 Hz, 1H), 5.30 (br s, 1H), 3.91 (ABq, Δv1-3=27.5 Hz, J=17 Hz, 2H). Analysis calculated for C21H14ClF2N3O•0.25 H2O: C, 62.70; H, 3.63; N, 10.44. Found: C, 62.78; H, 3.51; N, 10.29.

Workup

  1. stirringthe reaction was stirred overnight
  2. concentrationconcentrated
  3. customto remove most of the methanol
  4. additionThe milky white liquid residue was treated with saturated aqueous bicarbonate
  5. extractionextracted with ethyl acetate
  6. washThe organic layer was washed with aqueous bicarbonate and brine
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated
  9. customchromatographed on silica gel (20 g)
  10. washeluting the product with 5%

Sources & evidence

ORD record
ord-d1d0ca0e886049dfbaf5a279fd488003
Source dataset
uspto-grants-2003_09
Patent number
US06627755B1

Reaction notes

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