Dimethylformamide → N-(3-fluoro-4-(6-(pyrrolidine-1-carboxamido)pyrimidin-4-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

HRID 415909Notes

Reaction equation

HRID 415909 reaction equation
[OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=O)[C:6](=[O:13])[N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C=O)C.[NH2:27][C:28]1[CH:48]=[CH:47][C:31]([O:32][C:33]2[N:38]=[CH:37][N:36]=[C:35]([NH:39][C:40]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:41])[CH:34]=2)=[C:30]([F:49])[CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O.ClCCl.CO>[F:49][C:30]1[CH:29]=[C:28]([NH:27][C:10]([C:7]2[C:6](=[O:13])[N:5]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]([CH2:3][C:2]([OH:1])([CH3:20])[CH3:21])[C:8]=2[CH3:9])=[O:12])[CH:48]=[CH:47][C:31]=1[O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40]([N:42]2[CH2:43][CH2:44][CH2:45][CH2:46]2)=[O:41])[N:36]=[CH:37][N:38]=1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 231534594-(4-Amino-2-fluorophenoxy)-6-[(pyrrolidin-1-yl)carbonylamino]pyrimidineHCID 533934301-(2-Hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazole-4-carboxylic Acid

Product 1

HCID 11963221N-(3-fluoro-4-(6-(pyrrolidine-1-carboxamido)pyrimidin-4-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamideYield 70.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 21226129Dichloromethane methanolSolvent

Procedure

1-(2-hydroxy-2-methylpropyl)5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.230 g, 0.792 mmol) was dissolved in dichloromethane (10 ml). Then DMF (0.5 ml) was added to the mixture while stirring. Then N-(6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-1-carboxamide (0.277 g, 0.871 mmol), along with TEA (0.33 ml, 2.38 mmol) was added to the mixture and stirred 5 minutes at ambient temperature. Then HATU (0.301 g, 0.792 mmol) was added into the mixture in one portion. The resulting mixture was allowed to stir under inert atmosphere for 3 hours. The reaction was monitored by LC/MS, which confirmed completion. The mixture was diluted with dichloromethane and water and with 4:1 dichloromethane/methanol (3×20 ml). Combined organic layer was dried over sodium sulfate, filtered, and concentrated in-vacuo. The crude was purified by chromatography (Amino-Propyl silica gel column, in a gradient of 1-5% MeOH/dichloromethane to give an oil. The oil was recrystallized from dichloromethane/hexanes to give the desired product N-(3-fluoro-4-(6-(pyrrolidine-1-carboxamido)pyrimidin-4-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.330 g, 0.56 mmol, 70% yield) as a white solid. MS (ESI pos. ion) m/z: 590 (MH+). Calc'd exact mass for C30H32FN7O5: 589. 1HNMR (300 MHz, CDCl3): 1.05 (s, 6H), 1.91 (s, 4H), 2.21 (s, 1H), 2.78 (s, 3H), 3.40 (s, 4H), 3.78 (s, 2H), 7.01-7.22 (m, 4H), 7.31-7.48 (m, 2H), 7.59 (s, 1H), 7.79 (dd, J=12.42, 2.19 Hz, 1H), 8.26 (s, 1H), 10.75 (s, 1H).

Workup

  1. stirringstirred 5 minutes at ambient temperature
  2. stirringto stir under inert atmosphere for 3 hours
  3. dry with materialCombined organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in-vacuo
  6. customThe crude was purified by chromatography (Amino-Propyl silica gel column
  7. customin a gradient of 1-5% MeOH/dichloromethane to give an oil
  8. customThe oil was recrystallized from dichloromethane/hexanes

Sources & evidence

ORD record
ord-904336959cab4df9aef6a352ea9f15b2
Source dataset
uspto-grants-2012_01
Patent number
US08088794B2

Reaction notes

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