Potassium Carbonate → Ethyl 4-oxobutanoate

HRID 1186868Notes

Reaction equation

HRID 1186868 reaction equation
[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7](C1C=C(F)C(OCCCCl)=C(F)C=1)=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+].C1(S([O-])(=O)=O)C=CC=CC=1>CC#N.[Na+].[I-]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH:7]=[O:8])[CH3:2]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 91526BenzenesulfonateHCID 596518884-[4-(3-Chloropropoxy)-3,5-difluorophenyl]-4-oxo-butyric acid ethyl ester

Product 1

HCID 82395Ethyl 4-oxobutanoateYield 204.7%

Reagents, catalysts & solvents 2

HCID 5238Sodium IodideCatalystHCID 6342AcetonitrileSolvent

Procedure

A mixture of 4-[4-(3-chloropropoxy)-3,5-difluorophenyl]-4-oxo-butyric acid ethyl ester (5 g, 14.9 mmol), K2CO3 (7.2 g, 52.1 mmol), NaI (220 mg, 1.4 mmol), and Benzenesulfonate; (R)-methylpyrrolidinium (8 g, 33 mmol) in CH3CN (110 mL) was heated under argon at 80° C. for 36 h. The reaction was concentrated and partitioned between saturated aqueous sodium bicarbonate 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 material (96% purity). The crude material was purified by ISCO (80 g silica gel column) chromatography using 2% to 9% methanol in methylene chloride to 10% methanol containing 0.1% ammonium hydroxide in methylene chloride. The isolated material was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated. The isolated material was crystallized with a mixture of methylene chloride, ether and hexane to obtain 4-{3,5-difluoro-4-[3-(R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-butyric acid ethyl ester (3.97 g, 70%, 99% purity), MS m/z=384 (M+H).

Workup

  1. concentrationThe reaction was concentrated
  2. custompartitioned between saturated aqueous sodium bicarbonate solution and methylene chloride
  3. extractionThe aqueous layer was extracted twice with methylene chloride
  4. washthe combined organics was washed with brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto provide a crude material (96% purity)
  9. customThe crude material was purified by ISCO (80 g silica gel column) chromatography
  10. dissolutionThe isolated material was dissolved in methylene chloride
  11. washwashed with saturated aqueous sodium bicarbonate solution, brine
  12. dry with materialdried (Na2SO4)
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThe isolated material was crystallized with a mixture of methylene chloride, ether and hexane

Sources & evidence

ORD record
ord-90fea238deb44bff9ab30b30dd0433b3
Source dataset
uspto-grants-2014_03
Patent number
US08673916B2

Reaction notes

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