1-Hydroxybenzotriazole → HCID 57505574, compound

HRID 1663837

Reaction equation

HRID 1663837 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.[ClH:36].[CH3:37][N:38]1[CH2:43][CH2:42][N:41](CC(O)=O)[CH2:40][CH2:39]1.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+]>CN(C)C=O>[ClH:36].[ClH:36].[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][N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[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

9

Reactant 7

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2762732(4-Methylpiperazin-1-yl)acetic acidHCID 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 57505574HCID 57505574, compoundYield 6%

Reagents, catalysts & solvents 1

HCID 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 (1.05 mg, 2.33 mmol) was added 10% hydrogen chloride methanol solution (120 mL), and the mixture was stirred at 50° C. for 44 hr. The solvent was evaporated under reduced pressure. To a half of the residue were added (4-methylpiperazin-1-yl)acetic acid (205 mg, 1.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg, 1.48 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 11 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, 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 purified by silica gel column chromatography (ethyl acetate/hexane=0/100→70/30) and the objective fraction was concentrated under reduced pressure. The residue was dissolved in methanol and treated with a 4N hydrogen chloride ethyl acetate solution to give the title compound (43 mg, 6%) as a white powder.

Workup

  1. customThe solvent was evaporated under reduced pressure
  2. stirringthe mixture was stirred at room temperature for 11 hr
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe organic layer was washed with saturated brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→70/30)
  8. concentrationthe objective fraction was concentrated under reduced pressure
  9. dissolutionThe residue was dissolved in methanol
  10. additiontreated with a 4N hydrogen chloride ethyl acetate solution

Sources & evidence

ORD record
ord-78e67444a123440a944b160829cdf5a9
Source dataset
uspto-grants-2011_10
Patent number
US08034812B2

Linked notes

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