Sodium Carbonate → N-(2-fluoro-5-{[2-(glycoloylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

HRID 1668023

Reaction equation

HRID 1668023 reaction equation
[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([F:32])=[C:20]([NH:22][C:23]([C:25]5[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=5)=[O:24])[CH:21]=4)=[N:11][N:10]3[CH:33]=2)=[O:5])CC1.CO.Cl.C(OCC(O)=O)(=[O:39])C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CO.CN(C)C=O>[F:32][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]3[N:10]([CH:33]=[C:7]([NH:6][C:4](=[O:5])[CH2:1][OH:39])[N:8]=3)[N:11]=2)=[CH:21][C:20]=1[NH:22][C:23]([C:25]1[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=1)=[O:24]

Participants

11

Reactant 7

HCID 10340Sodium CarbonateHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 83766Acetoxyacetic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 21893726Hydrochloride methanolHCID 24767979N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

Product 1

HCID 57505573N-(2-fluoro-5-{[2-(glycoloylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamideYield 19%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (507 mg, 1.13 mmol) was added 10% hydrogen chloride methanol solution (30 mL), and the mixture was stirred at 50° C. for 23 hr. The solvent was evaporated under reduced pressure. To the residue were added acetoxyacetic acid (242 mg, 2.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (336 mg, 1.75 mmol), 1-hydroxybenzotriazole (167 mg, 1.24 mmol), N-ethyldiisopropylamine (0.60 mL, 3.51 mmol) and N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 62 hr. Methanol (10 mL), water (10 mL) and saturated aqueous sodium carbonate solution (2 mL) were added to the mixture, and the mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by NH silica gel column chromatography (ethyl acetate/hexane=0/100→100/0-methanol/ethyl acetate=2/98) and crystallized from ethanol to give the title compound (94 mg, 19%) as a white powder.

Workup

  1. customThe solvent was evaporated under reduced pressure
  2. stirringthe mixture was stirred at room temperature for 62 hr
  3. stirringthe mixture was stirred at room temperature for 2 hr
  4. concentrationconcentrated under reduced pressure
  5. additionA saturated aqueous sodium hydrogencarbonate solution was added to the residue
  6. extractionthe mixture was extracted with ethyl acetate
  7. washThe organic layer was washed with saturated brine
  8. dry with materialdried over anhydrous magnesium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was separated
  11. custompurified by NH silica gel column chromatography (ethyl acetate/hexane=0/100→100/0-methanol/ethyl acetate=2/98)
  12. customcrystallized from ethanol

Sources & evidence

ORD record
ord-b53c2973b5d54aaeaa0bcaf5ca21e8e9
Source dataset
uspto-grants-2011_10
Patent number
US08044049B2

Linked notes

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