1-羟基苯并三唑(HOBT) → HCID 57505574，化合物

HRID 1663837

反应方程式

HRID 1663837 反应方程式
[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]

参与物

9

反应物 7

HCID 757711-羟基苯并三唑(HOBT)HCID 81531N,N-二异丙基乙胺HCID 516892碳酸氢钠HCID 27239391-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐HCID 27627324-甲基-1-哌嗪乙酸HCID 21893726Hydrochloride methanolHCID 24767979N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-fluorophenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide

产物 1

HCID 57505574HCID 57505574，化合物收率 6%

试剂、催化剂与溶剂 1

HCID 6228N,N-二甲基甲酰胺溶剂

反应条件

温度
50 °C

实验过程

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.

后处理

  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

来源与证据

ORD记录
ord-78e67444a123440a944b160829cdf5a9
来源数据集
uspto-grants-2011_10
专利号
US08034812B2

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