Morpholine → N-(4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,3-difluorophenoxy)pyridin-2-yl)morpholine-4-carboxamide

HRID 870424Notes

Reaction equation

HRID 870424 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([F:32])[C:10]=2[F:33])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:41](Cl)(=O)[O:42]C1C=CC=CC=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C1COCC1>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:42])[CH:7]=3)=[C:10]([F:33])[C:11]=2[F:32])=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1

Participants

6

Reactant 4

HCID 8083MorpholineHCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 73053610N-(4-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

Product 1

HCID 73053697N-(4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,3-difluorophenoxy)pyridin-2-yl)morpholine-4-carboxamideYield 52.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (224 mg, 0.50 mmol) in THF (3 mL) was added Et3N (0.138 mL, 0.99 mmol), followed by adding phenyl carbonochloridate (0.125 mL, 1.00 mmol) dropwise. The reaction mixture was stirred at rt for 2 hours, then morpholine (0.4 mL, 5.00 mmol) was added. The mixture was stirred at rt for 36 hours, then quenched with saturated NH4Cl aqueous solution (20 mL) and CH2Cl2 (20 mL). The resulted mixture was stirred at rt for 10 minutes and extracted with CH2Cl2 (20 mL×3). The combined organic phases were washed with brine (20 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=20/1) to give the title compound as an orange solid (148 mg, 52.5%).

Workup

  1. stirringThe mixture was stirred at rt for 36 hours
  2. customquenched with saturated NH4Cl aqueous solution (20 mL) and CH2Cl2 (20 mL)
  3. stirringThe resulted mixture was stirred at rt for 10 minutes
  4. extractionextracted with CH2Cl2 (20 mL×3)
  5. washThe combined organic phases were washed with brine (20 mL×3)
  6. dry with materialdried over anhydrous Na2SO4
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=20/1)

Sources & evidence

ORD record
ord-7efa50731daa436596664fe50a100360
Source dataset
uspto-grants-2015_03
Patent number
US08969388B1

Reaction notes

Loading…