反应详情

A solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see Preparation A(vi) above; 10 g, 34 mmol) in water (25 mL) was added slowly to a solution of sodium bicarbonate (10 g, 119 mmol) in water 10 mL). More water (5 mL) was added and the mixture was stirred at room temperature for 10 minutes. A solution of 2-(tert-butyloxycarbonylamino)ethyl tosylate (see step (a) above; 11.92 g, 37 mmol) in toluene (40 mL) was added. This mixture was then heated at 65–70° C. for 7 hours before stirring at room temperature overnight. The reaction was reheated to 50° C. and the phases were separated. The aqueous layer was extracted with toluene (40 mL) at 50° C. The combined organic layers were washed with saturated sodium bicarbonate (25 mL). The solvents were evaporated under reduced pressure to yield a mixture of oil and solid (13 g, >100%). Ethyl acetate (50 mL) and citric acid (10%, 25 mL) were added to a portion of the oily solid (5 g, 138 mmol). The aqueous layer was separated and the organic layer washed again with citric acid (10%, 20 mL). The aqueous layers were combined and treated with solid sodium bicarbonate until neutral. The aqueous phase was extracted with ethyl acetate (2×50 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure to give the sub-title compound as a colourless semi-solid, which solidified fully when stored in the refrigerator (4.68 g, 93%).

1. temperatureThis mixture was then heated at 65–70° C. for 7 hours
2. stirringbefore stirring at room temperature overnight
3. customwas reheated to 50° C.
4. customthe phases were separated
5. extractionThe aqueous layer was extracted with toluene (40 mL) at 50° C
6. washThe combined organic layers were washed with saturated sodium bicarbonate (25 mL)
7. customThe solvents were evaporated under reduced pressure
8. customto yield
9. customThe aqueous layer was separated
10. washthe organic layer washed again with citric acid (10%, 20 mL)
11. additiontreated with solid sodium bicarbonate until neutral
12. extractionThe aqueous phase was extracted with ethyl acetate (2×50 mL)
13. dry with materialdried over magnesium sulfate
14. filtrationfiltered
15. customThe filtrate was evaporated to dryness under reduced pressure