Acetic Acid → HCID 24994436, compound

HRID 221838Notes

Reaction equation

HRID 221838 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)[CH:5]=[C:6]([F:15])[C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C(O)(=O)C>CN(C=O)C.CO>[CH:23]1([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[C:2]([F:1])=[CH:3][C:4]([C:16]4[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=4)=[CH:5][C:6]=3[F:15])[CH2:10][CH2:11]2)[CH2:26][CH2:25][CH2:24]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 14496CyclobutanoneHCID 5003444Sodium cyanoborohydrideHCID 59651988HCID 59651988, compound

Product 1

HCID 24994436HCID 24994436, compoundYield 27.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of 6-[3,5-difluoro-4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (350 mg, 1.1 mmol) in a mixture of DMF (2 mL) and MeOH (9 mL) was stirred under argon. Cyclobutanone (0.38 mL, 5 mmol), sodium cyanoborohydride (0.53 g, 8.45 mmol) and acetic acid (0.4 mL, 7 mmol) were added sequentially and stirred at 60° C. for 3 h. The reaction mixture was concentrated at reduced pressure and partitioned between aqueous 1M sodium carbonate solution 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) chromatography using 2 to 5% 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 to furnish a pure product. The pure product was crystallized with a mixture of methylene chloride, ethanol, ether and hexane to obtain 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-3,5-difluoro-phenyl]-4,5-dihydro-2H-pyridazin-3-one (110 mg, yield), mp 162-164° C.; MS m/z 364 (M+H)

Workup

  1. stirringstirred at 60° C. for 3 h
  2. concentrationThe reaction mixture was concentrated at reduced pressure
  3. custompartitioned between aqueous 1M sodium carbonate solution 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) 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. customto furnish a pure product
  17. customThe pure product was crystallized with a mixture of methylene chloride, ethanol, ether and hexane

Sources & evidence

ORD record
ord-a46caf3b1f974d35a091eb825709de32
Source dataset
uspto-grants-2012_06
Patent number
US08207168B2

Reaction notes

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