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

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 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 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 trifluoroacetic acid (7.68 ml) was added and then the resultant mixture 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.

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

ORD record

ord-73d8d35230eb44059ae4b9e61af17939

Source dataset

uspto-grants-2002_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06495581B1