Oxalyl chloride → N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamide

HRID 1663787Notes

Reaction equation

HRID 1663787 reaction equation
[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[F:41])[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[N:31]=2)[N:28]=1>CN(C)C=O.O1CCCC1.[OH-].[Na+]>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:40]([F:41])=[C:19]([NH:18][C:8]([C:6]5[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:20]=4)=[N:28][N:27]3[CH:29]=2)=[O:34])[CH2:36][CH2:37]1

Participants

7

Reactant 3

HCID 65578Oxalyl chlorideHCID 10758811-Ethyl-3-methyl-1H-pyrazole-4-carboxylic acidHCID 57505446N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide

Product 1

HCID 24767983N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1-ethyl-3-methyl-1H-pyrazole-4-carboxamideYield 52%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 8028TetrahydrofuranSolventHCID 14798Sodium HydroxideSolvent

Procedure

To a solution of 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 13.0 mmol) and N,N-dimethylformamide (3 drops) in tetrahydrofuran (30 mL) was added oxalyl chloride (2.23 mL, 26.0 mmol) with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (20 mL) with stirring under ice-cooling, N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (3.27 g, 10.0 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution (50 ml) and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1, 80 mL, 40 mL×2). The organic layer was washed with water (10 mL×3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and crystallized from ethyl acetate to give the title compound (2.39 g, yield 52%) as a white solid. melting point 199° C.

Workup

  1. temperaturecooling
  2. stirringthe mixture was stirred at room temperature for 3 hr
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. dissolutionThe residue was dissolved in N,N-dimethylacetamide (20 mL)
  5. stirringwith stirring under ice-
  6. temperaturecooling
  7. stirringthe mixture was stirred at room temperature for 18 hr
  8. extractionextracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1, 80 mL, 40 mL×2)
  9. washThe organic layer was washed with water (10 mL×3)
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30)
  12. customcrystallized from ethyl acetate

Sources & evidence

ORD record
ord-fd777767434b46a989d801e03872f3ef
Source dataset
uspto-grants-2011_10
Patent number
US08034812B2

Reaction notes

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