Tetrahydrofuran → 6-(3-{[3-(1-Cyano-1-methylethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylic acid

HRID 1663694Notes

Reaction equation

HRID 1663694 reaction equation
[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:45]=[CH:46][CH:47]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([C:40]([O:42]CC)=[O:41])[N:39]=2)[N:36]=1>CN1CCCC1=O.C(OCC)(=O)C.CN(C)C=O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:26][C:27]1[CH:28]=[C:29]([CH:45]=[CH:46][CH:47]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([C:40]([OH:42])=[O:41])[N:39]=2)[N:36]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 65578Oxalyl chlorideHCID 571495383-(2-Cyanopropan-2-yl)benzoic acidHCID 57385786Ethyl 6-(3-aminophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate

Product 1

HCID 575054566-(3-{[3-(1-Cyano-1-methylethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazine-2-carboxylic acidYield 160.3%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

To a mixture of 3-(1-cyano-1-methylethyl)benzoic acid (454 mg, 2.40 mmol), tetrahydrofuran (10 mL) and N,N-dimethylformamide (0.01 mL) was added oxalyl chloride (366 mg, 2.88 mmol), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, tetrahydrofuran was added to the residue, and the mixture was azeotroped twice. The residue was dissolved in N-methylpyrrolidone (4 mL), added to a solution of ethyl 6-(3-aminophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate (350 mg, 1.17 mmol) in N-methylpyrrolidone (6 mL), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. To the residue were added 8N aqueous sodium hydroxide solution (4.0 mL) and methanol (10.0 mL), and the mixture was stirred at room temperature for 10 min. 6N Hydrochloric acid (5.0 mL) and water (60 mL) were added to the mixture, and the mixture was extracted with ethyl acetate (150 mL). The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to give the title compound (828 mg, 94%) as a white powder.

Workup

  1. customThe solvent was evaporated under reduced pressure, tetrahydrofuran
  2. additionwas added to the residue
  3. customthe mixture was azeotroped twice
  4. dissolutionThe residue was dissolved in N-methylpyrrolidone (4 mL)
  5. stirringthe mixture was stirred at room temperature for 2 hr
  6. washthe mixture was washed with saturated aqueous sodium hydrogencarbonate solution
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationfiltrated
  9. additionTo the residue were added 8N aqueous sodium hydroxide solution (4.0 mL) and methanol (10.0 mL)
  10. stirringthe mixture was stirred at room temperature for 10 min
  11. addition6N Hydrochloric acid (5.0 mL) and water (60 mL) were added to the mixture
  12. extractionthe mixture was extracted with ethyl acetate (150 mL)
  13. dry with materialThe extract was dried over anhydrous magnesium sulfate
  14. customthe solvent was evaporated under reduced pressure
  15. washThe residue was washed with hexane

Sources & evidence

ORD record
ord-63eecded4a0148b69f81da2fb595abc6
Source dataset
uspto-grants-2011_10
Patent number
US08034812B2

Reaction notes

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