反应详情

温度

0 °C

Dissolve 2′,2′-difluoro-2′-deoxycytidine (10.0 g, 38.0 mmol) in anhydrous pyridine (100 mL) and cool to 0° C. while stirring under nitrogen. Add chlorotrimethylsilane (24.0 mL, 190.0 mmol) dropwise, maintaining an internal temperature <5° C. Continue stirring at 0° C. for 2 hours. In a separate flask, dissolve 2-propylpentanoic acid (6.0 g, 41.8 mmol) in anhydrous acetonitrile (100 mL). Add 1,1-carbonyldiimidazole (6.8 g, 41.8 mmol) in small portions over 30 minutes and stir for 2 hours. Add this acetonitrile solution dropwise to the pyridine solution at 0° C. and allow the reaction to come to ambient temperature. Heat the reaction at 45° C. overnight then cool to 30-35° C. and add 100 mL absolute ethanol and heat at 45° C. for 30 minutes. Add 50 mL water and heat at 45° C. for 5 hours then cool to ambient temperature and concentrate in vacuo. Partition the crude residue between ethyl acetate and water. Acidify to pH ˜2 with phosphoric acid and separate the organic layer. Back extract the aqueous layer with additional ethyl acetate. Combine the organic solutions and wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry over magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography (120 g) eluting with a gradient of 30% to 60% ethyl acetate in methylene chloride. Isolate desired product as a white crushable foam (11.2 g, 77% yield).

1. stirringContinue stirring at 0° C. for 2 hours
2. stirringstir for 2 hours
3. customthe reaction
4. customto come to ambient temperature
5. temperatureHeat
6. customthe reaction at 45° C. overnight
7. temperaturethen cool to 30-35° C.
8. temperatureheat at 45° C. for 30 minutes
9. temperatureheat at 45° C. for 5 hours
10. temperaturethen cool to ambient temperature
11. concentrationconcentrate in vacuo
12. customPartition the crude residue between ethyl acetate and water
13. customseparate the organic layer
14. extractionBack extract the aqueous layer with additional ethyl acetate
15. washwash with saturated sodium bicarbonate solution and saturated sodium chloride solution
16. dry with materialdry over magnesium sulfate
17. concentrationconcentrate in vacuo
18. customPurify by silica gel chromatography (120 g)
19. washeluting with a gradient of 30% to 60% ethyl acetate in methylene chloride