Hydrochloric Acid → Ethyl 4-oxo-4-(pyridin-3-yl)butanoate

HRID 1070055Notes

Reaction equation

HRID 1070055 reaction equation
[C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:21])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.[C:22]([O:25][C:26]([CH3:29])(C)C)(=[O:24])[CH3:23].C([N-]C(C)C)(C)C.[Li+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[O:21]=[C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:1][CH2:23][C:22]([O:25][CH2:26][CH3:29])=[O:24]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 938Nicotinic AcidHCID 10908tert-Butyl acetate2×HCID 682631,1'-CarbonyldiimidazoleHCID 516892Sodium BicarbonateHCID 2724682Lithium diisopropylamide

Product 1

HCID 4248889Ethyl 4-oxo-4-(pyridin-3-yl)butanoateYield 38%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

Carbonyldiimidazole (7.25 g) was added to a solution of nicotinic acid (5.00 g) in tetrahydrofuran (100 ml) at 0° C. After stirring at room temperature for 2 hours, the mixture was added dropwise to a solution lithiated tert-butyl acetate prepared from tert-butyl acetate (17.5 ml) and lithium diisopropylamide (2N tetrahydrofuran solution, 65 ml) −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 dissolved in tetrahydrofuran (100 ml), sodium hydride (60% in oil, 1.38 g) was added at 0° C. and stirred for 10 minutes. Ethyl bromoacetate (3.33 ml) was added to the mixture, and the reaction mixture was stirred at room temperature for 3 hours, 0.1N hydrochloric acid (350 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 (150 ml), and trifluoroaceic acid (7.68 ml) was added and then the resultant was stirred at 90° C. for 4 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-(3-pyridyl)butyrate (3.39 g, yield 38%) as a colorless oil from an ethyl acetate-hexane (2:1, v/v)-eluted fraction.

Workup

  1. additionthe mixture was added dropwise to a solution
  2. stirringAfter stirring for 15 minutes
  3. extractionextracted with ethyl acetate
  4. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in tetrahydrofuran (100 ml)
  8. additionsodium hydride (60% in oil, 1.38 g) was added at 0° C.
  9. stirringstirred for 10 minutes
  10. additionEthyl bromoacetate (3.33 ml) was added to the mixture
  11. stirringthe reaction mixture was stirred at room temperature for 3 hours
  12. addition0.1N hydrochloric acid (350 ml) was added
  13. extractionextracted with ethyl acetate
  14. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  15. dry with materialdried (MgSO4)
  16. concentrationconcentrated
  17. customto obtain an oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction
  18. stirringthe resultant was stirred at 90° C. for 4 hours
  19. extractionextracted with ethyl acetate
  20. washThe ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride
  21. dry with materialdried (MgSO4)
  22. concentrationconcentrated

Sources & evidence

ORD record
ord-dc46dcba786c488a8a92136e6f17e451
Source dataset
uspto-grants-2001_06
Patent number
US06251926B1

Reaction notes

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