Phosphorus oxychloride → HCID 178486695, compound

HRID 640016Notes

Reaction equation

HRID 640016 reaction equation
P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]2)=[C:10]([O:19][CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:9]=1.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[CH:44]=[N:45][N:46]([CH2:48][C:49]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:53]=2[F:59])=[O:50])[CH:47]=1>ClCCCl.O>[F:59][C:53]1[C:54]([F:58])=[CH:55][CH:56]=[CH:57][C:52]=1[NH:51][C:49](=[O:50])[CH2:48][N:46]1[CH:47]=[C:43]([NH:42][CH:12]2[C:11]3[C:16](=[CH:17][C:8]([O:7][CH3:6])=[CH:9][C:10]=3[O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[N:15]=[CH:14][NH:13]2)[CH:44]=[N:45]1

Participants

7

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 160679542-(4-amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamideHCID 136383491tert-butyl (2R)-2-{[(7-methoxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate

Product 1

HCID 178486695HCID 178486695, compoundYield 44.5%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

Phosphoryl chloride (0.27 ml, 2.94 mmol) was added to a solution of tert-butyl (2R)-2-{[(7-methoxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (0.550 g, 1.47 mmol) and di-iso-propylethylamine (1.02 ml, 5.88 mmol) in 1,2-dichloroethane (20 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 (10 ml) and then 2-(4-amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (0.370 g, 1.47 mmol) was added and the mixture was 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 and then filtered and the residue purified by silica gel chromatography eluting with a 0 to 10% mixture methanol in dichloromethane to give tert-butyl (2R)-2-[({4-[(1-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]-7-methoxy-3,4-dihydroquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.400 g, 44% yield over 3 steps):

Workup

  1. customThe mixture was evaporated under reduced pressure
  2. temperaturethe mixture was 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 methanol in dichloromethane

Sources & evidence

ORD record
ord-0405ae47de234d3c940d4a3ccaf531f9
Source dataset
uspto-grants-2010_04
Patent number
US07691867B2

Reaction notes

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