Thionyl Chloride → N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,4-dimethyl-1H-pyrazole-3-carboxamide

HRID 1663828Notes

Reaction equation

HRID 1663828 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[N:3]1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[F:38])[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[N:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN(C)C(=O)C>[CH:32]1([C:30]([NH:29][C:27]2[N:28]=[C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]4[CH:35]=[CH:36][C:37]([F:38])=[C:16]([NH:15][C:8]([C:4]5[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:10])[CH:17]=4)=[N:25][N:24]3[CH:26]=2)=[O:31])[CH2:33][CH2:34]1

Participants

8

Reactant 4

HCID 24386Thionyl ChlorideHCID 516892Sodium BicarbonateHCID 53256851,4-Dimethyl-1H-pyrazole-3-carboxylic acidHCID 57505446N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

Product 1

HCID 57505564N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,4-dimethyl-1H-pyrazole-3-carboxamideYield 63%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 8028TetrahydrofuranSolventHCID 31374DimethylacetamideSolvent

Procedure

To a suspension of 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (151 mg, 1.08 mmol) in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide (1 drop) and thionyl chloride (0.08 mL, 1.1 mmol), and the mixture was stirred at room temperature for 50 min. The reaction mixture was concentrated under reduced pressure and dissolved in N,N-dimethylacetamide (2.0 mL). On the other hand, to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol) in N,N-dimethylacetamide (6.0 mL) was added dropwise the above-mentioned solution under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Under ice-cooling, aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) and recrystallized from tetrahydrofuran/ethanol to give the title compound (283 mg, 63%) as pale-yellow crystals.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. dissolutiondissolved in N,N-dimethylacetamide (2.0 mL)
  3. temperaturecooling
  4. stirringthe mixture was stirred at room temperature for 2 hr
  5. temperatureUnder ice-cooling
  6. extractionthe mixture was extracted with ethyl acetate
  7. washThe extract was washed with saturated brine
  8. dry with materialdried over anhydrous magnesium sulfate
  9. filtrationfiltrated
  10. customThe solvent was evaporated under reduced pressure
  11. customthe residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=80/20→100/0)
  12. customrecrystallized from tetrahydrofuran/ethanol

Sources & evidence

ORD record
ord-2a2afa19696c40e2acdd329a62d16841
Source dataset
uspto-grants-2011_10
Patent number
US08034812B2

Reaction notes

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