Cesium carbonate → HCID 59652012, compound

HRID 221839Notes

Reaction equation

HRID 221839 reaction equation
[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:17]([F:18])=[CH:16][C:15]([C:19]4[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=4)=[CH:14][C:13]=3[F:26])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:17]([F:18])=[CH:16][C:15]([C:19]4[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=4)=[CH:14][C:13]=3[F:26])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1

Participants

4

Reactant 2

HCID 10796Cesium carbonateHCID 24994436HCID 24994436, compound

Product 1

HCID 59652012HCID 59652012, compoundYield 29.9%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-3,5-difluoro-phenyl]-4,5-dihydro-2H-pyridazin-3-one (137 mg, 0.37 mmol) and cesium carbonate (232 mg, 0.71 mmol) in dimethyl sulfoxide (5 mL) was heated at 130° C. 45 min. The mixture was cooled to rt and partitioned between water and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude product. The crude product was purified by ISCO (40 g silica gel column) chromatography using 2% to 8% methanol in methylene chloride to 10% methanol containing 0.2% ammonium hydroxide in methylene chloride. The recovered product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated. The product was crystallized using a mixture of ethanol, ethyl acetate, ether and hexane to give 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-3,5-difluoro-phenyl]-2H-pyridazin-3-one (40 mg, 29%); Mp 195-197° C.; MS m/z 362 (M+H).

Workup

  1. custom45 min
  2. temperatureThe mixture was cooled to rt
  3. custompartitioned between water and methylene chloride
  4. extractionThe aqueous layer was extracted twice with methylene chloride
  5. washthe combined organics was washed with brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto provide a crude product
  10. customThe crude product was purified by ISCO (40 g silica gel column) chromatography
  11. dissolutionThe recovered product was dissolved in methylene chloride
  12. washwashed with saturated aqueous sodium bicarbonate solution, brine
  13. dry with materialdried (Na2SO4)
  14. filtrationfiltered
  15. concentrationconcentrated
  16. customThe product was crystallized
  17. additiona mixture of ethanol, ethyl acetate, ether and hexane

Sources & evidence

ORD record
ord-643ebbeabb82485fb0684791f0b6a6e1
Source dataset
uspto-grants-2012_06
Patent number
US08207168B2

Reaction notes

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