反应详情

To a solution of diisopropylamine (8.76 g) in tetrahydrofuran (230 mL) was added 1.6 mol/L n-butyllithium hexane solution (51 mL) at −78° C., and the mixture was stirred for 1 hr. 2-Fluoropyridine (11.2 g) was added dropwise thereto, and the mixture was stirred for 2 hr. To the resultant pale-yellow suspension was slowly added dropwise a solution of tert-butyl 3,3-difluoro-4-{[(4-methylphenyl)sulfonyl]oxy}-2-oxopyrrolidine-1-carboxylate (22.6 g) in tetrahydrofuran (50 mL), and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was heated to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained mixture was dissolved in dichloromethane (30 mL), trifluoroacetic acid (100 mL) was added dropwise under ice-cooling, and the mixture was stirred for 4 hr while allowing the mixture to warm to room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and a saturated aqueous sodium hydrogen carbonate solution was added until the mixture became neutral. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→3:1) to give the title compound as a colorless solid (yield 10.9 g, 51%).

1. stirringthe mixture was stirred for 2 hr
2. stirringthe mixture was stirred for 1 hr
3. concentrationconcentrated under reduced pressure
4. additionThe residue was diluted with ethyl acetate
5. washwashed with water
6. extractionThe separated aqueous layer was extracted again with ethyl acetate
7. washCombined organic layers were washed with saturated brine
8. dry with materialdried over anhydrous magnesium sulfate
9. concentrationconcentrated under reduced pressure
10. dissolutionThe obtained mixture was dissolved in dichloromethane (30 mL)
11. additiontrifluoroacetic acid (100 mL) was added dropwise under ice-
12. temperaturecooling
13. stirringthe mixture was stirred for 4 hr
14. temperatureto warm to room temperature
15. concentrationThe reaction mixture was concentrated under reduced pressure
16. additiondiluted with ethyl acetate
17. additiona saturated aqueous sodium hydrogen carbonate solution was added until the mixture
18. extractionThe separated aqueous layer was extracted again with ethyl acetate
19. washCombined organic layers were washed with saturated brine
20. dry with materialdried over magnesium sulfate
21. concentrationconcentrated under reduced pressure
22. customThe residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→3:1)