Acetic Acid → 3-(2-Chloro-phenyl)-6-fluoro-2-[(2-fluoro-benzylamino)-methyl]-3H-quinazolin-4-one

HRID 1169263Notes

Reaction equation

HRID 1169263 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:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[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:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[F:22]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 666492-FluorobenzylamineHCID 5049666Sodium triacetoxyborohydrideHCID 106858093-(2-Chlorophenyl)-6-fluoro-3,4-dihydroquinazolin-4-one-2-carboxaldehyde

Product 1

HCID 103098713-(2-Chloro-phenyl)-6-fluoro-2-[(2-fluoro-benzylamino)-methyl]-3H-quinazolin-4-one

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.20 g, 0.66 mmol), 2-fluorobenzylamine (0.038 mL, 0.33 mmol), and acetic acid (0.19 mL, 3.3 mmol) in dichloroethane (10 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.350 g, 1.65 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature and stirred 16 hours. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (30 g) with elution proceeding as follows: 30% ethyl acetate/hexane (100 mL), nil; (50 mL), unweighed impurity; (100 mL), nil; (125 mL), unweighed impurity; (150 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; (450 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-2-[(2-fluoro-benzylamino)-methyl]-3H-quinazolin-4-one as a pale pink solid which had: mp 140° C.; 1H NMR δ 7.89 (dd, J=3, 8 Hz, 1H), 7.76 (dd, J=4, 9 Hz, 1H), 7.58 (dd, J=2, 8 Hz, 1H), 7.53-7.41 (m, 4H), 7.35-7.30 (m, 2H), 7.07 (t, J=8 Hz, 1H), 6.99 (t, J=10 Hz, 1H), 3.89 (ABq, Δv1-3=21 Hz, J=13 Hz, 2H), 3.46 (ABq, Δv1-3=31 Hz, J=17 Hz, 2H); APCI MS m/z=412 (P+1).

Workup

  1. temperatureto warm to ambient temperature
  2. stirringstirred 16 hours
  3. customThe reaction was quenched by addition of saturated aqueous bicarbonate
  4. stirringcontinued stirring for 30 minutes
  5. customThe phases were separated
  6. extractionthe aqueous layer was extracted with methylene chloride
  7. washThe combined organic phase was washed with brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated
  10. customchromatographed on silica gel (30 g) with elution proceeding

Sources & evidence

ORD record
ord-d222b0f339b947bdb574482a1103368a
Source dataset
uspto-grants-2003_09
Patent number
US06627755B1

Reaction notes

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