Hydrochloric Acid → Ethyl 4-oxo-4-(4-pyridyl)butyrate

HRID 1070056Notes

Reaction equation

HRID 1070056 reaction equation
[C:1](N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1.[C:22]([O:25][C:26]([CH3:29])(C)C)(=[O:24])[CH3:23].C([N-]C(C)C)(C)C.[Li+].Cl.[H-].[Na+].BrCC(OCC)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[O:21]=[C:19]([C:16]1[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=1)[CH2:1][CH2:23][C:22]([O:25][CH2:26][CH3:29])=[O:24]

Participants

12

Reactant 8

HCID 313Hydrochloric Acid2×HCID 5922Isonicotinic AcidHCID 7748Ethyl bromoacetateHCID 10908tert-Butyl acetate2×HCID 24758Sodium hydrideHCID 682631,1'-CarbonyldiimidazoleHCID 516892Sodium BicarbonateHCID 2724682Lithium diisopropylamide

Product 1

HCID 10943675Ethyl 4-oxo-4-(4-pyridyl)butyrateYield 31%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×HCID 21226206Ethyl acetate hexaneSolvent

Procedure

Carbonyldiimidazole (7.25 g) was added to a solution of 4-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (80 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution of lithiated tert-butyl acetate prepared from tert-butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution, 65 ml) at −78° C. over 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain an oil from an ethyl acetate-hexane(2:3, v/v)-eluted fraction. This oil was dissolved in tetrahydrofuran (100 ml), and sodium hydride (60% in oil, 1.16 g) was added at 0° C., and then the reaction mixture was stirred for 10 minutes. Ethyl bromoacetate (2.88 ml) was added to the mixture, and the resultant was stirred at room temperature for 24 hours, 0.1N hydrochloric acid (300 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain an oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. This oil was dissolved in toluene (120 ml), and stirred with trifluoroaceic acid (5.64 ml) at 90° C. for 6 hours. An aqueous saturated solution of sodium bicarbonate was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl 4-oxo-4-(4-pyridyl)butyrate (2.61 g, yield 31%) from an ethyl acetate-hexane (2:1, v/v)-eluted fraction as a pale-brown oil.

Workup

  1. stirringAfter stirring for 15 minutes
  2. extractionextracted with ethyl acetate
  3. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customto obtain an oil from an ethyl acetate-hexane(2:3, v/v)-eluted fraction
  7. stirringthe reaction mixture was stirred for 10 minutes
  8. stirringthe resultant was stirred at room temperature for 24 hours
  9. extractionextracted with ethyl acetate
  10. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  11. dry with materialdried (MgSO4)
  12. concentrationconcentrated
  13. customto obtain an oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction
  14. extractionextracted with ethyl acetate
  15. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  16. dry with materialdried (MgSO4)
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-64ecc795830741fd82e6f334b1573d8a
Source dataset
uspto-grants-2001_06
Patent number
US06251926B1

Reaction notes

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