Phosphorus oxychloride → N-(2,3-difluorophenyl)-2-{4-[(7-hydroxy-5-isopropoxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide

HRID 639983Notes

Reaction equation

HRID 639983 reaction equation
P(Cl)(Cl)(Cl)=O.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[C:12]([O:21][CH:22]([CH3:24])[CH3:23])[CH:11]=1)(=O)C.C(N(C(C)C)CC)(C)C.[NH2:34][C:35]1[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=2[F:51])=[O:42])[CH:39]=1>ClCCCl.O>[F:51][C:45]1[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=1[NH:43][C:41](=[O:42])[CH2:40][N:38]1[CH:39]=[C:35]([NH:34][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[CH:11][C:12]=3[O:21][CH:22]([CH3:23])[CH3:24])[N:17]=[CH:16][N:15]=2)[CH:36]=[N:37]1

Participants

7

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 160679542-(4-amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamideHCID 1355107057-Acetoxy-5-isopropoxy-3,4-dihydroquinazolin-4-one

Product 1

HCID 136383489N-(2,3-difluorophenyl)-2-{4-[(7-hydroxy-5-isopropoxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamideYield 60%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

Phosphoryl chloride (3.7 ml, 40 mmol) was added to a solution of 5-isopropoxy-4-oxo-3,4-dihydroquinazolin-7-yl acetate (2.6 g, 10 mmol) and di-iso-propylethylamine (14 ml, 80 mmol) in 1,2-dichloroethane (75 ml) and the reaction was heated at 80° C. for 1 hour. The mixture was evaporated under reduced pressure and the residue suspended in dimethylacetamide (30 ml). 2-(4-Amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (2.5 g, 10 mmol) was added and the mixture was then heated at 90° C. for 1 hour. The mixture was evaporated under reduced pressure and the residue stirred in a 7N solution of ammonia in methanol (100 ml) at ambient temperature for 2 hours. The mixture was evaporated under reduced pressure to leave a yellow solid which was stirred in water (50 ml) for 1 hour, then filtered and the residue purified by silica gel chromatography eluting with a 0 to 10% mixture of methanol in dichloromethane to give N-(2,3-difluorophenyl)-2-{4-[(7-hydroxy-5-isopropoxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (2.7 g, 60% yield):

Workup

  1. customThe mixture was evaporated under reduced pressure
  2. temperaturethe mixture was then heated at 90° C. for 1 hour
  3. customThe mixture was evaporated under reduced pressure
  4. customThe mixture was evaporated under reduced pressure
  5. customto leave a yellow solid which
  6. filtrationfiltered
  7. customthe residue purified by silica gel chromatography
  8. washeluting with a 0 to 10% mixture of methanol in dichloromethane

Sources & evidence

ORD record
ord-dbf6f1c1973f4a1899b213b5bff33d39
Source dataset
uspto-grants-2010_04
Patent number
US07691867B2

Reaction notes

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