反应详情

Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (3.5 mmol) and tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice bath and add sodium hydride (0.21 g, 60% in oil, 5.22 mmol). After 1 hour, add 5-chloropentan-2-one, ethylene ketal (0.79 mL, 5.22 mmol) and tetra-n-butylammonium bromide (112 mg, 0.35 mmol) and warm to ambient temperature. Heat to reflux. After 18 hours, cool, add sodium hydride (0.1 g) and 5-chloropentan-2-one, ethylene ketal (0.50 mL) and again heat to reflux. After 24 hours, cool in a dry-ice/acetone bath and add a saturated aqueous solution of ammonium chloride. Warm to ambient temperature and dilute the reaction mixture with a saturated aqueous solution of sodium bicarbonate. Concentrate in vacuo to remove most to the tetrahydrofuran and extract three times with ethyl acetate. Extract the combined organic layers with water and then brine, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.1% saturated aqueous ammonia solution to give (1-(4-oxopentyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine, ethylene ketal.

1. temperatureCool in an ice bath
2. temperatureHeat to reflux
3. waitAfter 18 hours
4. temperaturecool
5. temperatureagain heat to reflux
6. waitAfter 24 hours
7. temperaturecool in a dry-ice/acetone bath
8. temperatureWarm to ambient temperature
9. concentrationConcentrate in vacuo
10. customto remove most to the tetrahydrofuran
11. extractionextract three times with ethyl acetate
12. extractionExtract the combined organic layers with water
13. dry with materialbrine, dry the organic layer over Na2SO4
14. filtrationfilter
15. customevaporate in vacuo
16. customto give a residue