反应详情

温度

0 °C

trans-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (25.00 g, 107.2 mmol) was dissolved in THF (1100 mL). To this solution was added 2-chloroacetic acid (15.19 g, 160.8 mmol) and PPh3 (42.16 g, 160.8 mmol). The solution was cooled to 0° C. and DEAD (25.31 mL, 160.8 mmol) was added as a THF solution (250 mL). The reaction mixture was protected from light and stirred overnight as it slowly increased to ambient temperature. The THF was removed in vacuo and replaced with EtOAc. The solution was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product was dissolved in dioxane (500 mL), and water was added (250 mL). A 1N NaOH solution was added until the pH reached ˜10 (200 mL). The mixture was stirred for 1 hour and then quenched with 1N KHSO4 (250 mL). The mixture was extracted with EtOAc (3×250 mL) and the combined organic phases were washed with saturated aqueous NaHCO3, dried over Na2CO3, filtered and concentrated to a white paste. The paste was then slurried in 50% Et2O/hexanes (200 mL) and filtered through qualitative paper. The resulting white solid was washed with 50% Et2O/hexanes (3×200 mL) and the filtrate was concentrated. The crude residue was purified by column chromatography (10 to 40% Acetone/hexanes) to provide the product (22.4 g, 89%) as a thick colorless oil.

1. temperatureslowly increased to ambient temperature
2. customThe THF was removed in vacuo
3. washThe solution was washed with saturated aqueous NaHCO3
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. dissolutionThe crude product was dissolved in dioxane (500 mL)
8. additionwater was added (250 mL)
9. additionA 1N NaOH solution was added until the pH
10. stirringThe mixture was stirred for 1 hour
11. customquenched with 1N KHSO4 (250 mL)
12. extractionThe mixture was extracted with EtOAc (3×250 mL)
13. washthe combined organic phases were washed with saturated aqueous NaHCO3
14. dry with materialdried over Na2CO3
15. filtrationfiltered
16. concentrationconcentrated to a white paste
17. filtrationfiltered through qualitative paper
18. washThe resulting white solid was washed with 50% Et2O/hexanes (3×200 mL)
19. concentrationthe filtrate was concentrated
20. customThe crude residue was purified by column chromatography (10 to 40% Acetone/hexanes)