反应详情

温度

2.5 °C

55.8 g (250 mmol) of (S)-2-benzyloxycarbonylaminopropionic acid (obtainable from the corresponding aminocarboxylic acid by protection of the amino function with a benzyloxycarbonyl derivative; Bodansky et al., loc. cit.) were dissolved in 560 ml of ethyl acetate (Fluka) while stirring and under argon, cooled to 0 to 5° C. and treated with 31.0 ml (250 mmol) of pivaloyl chloride (Fluka). 35.0 ml of triethylamine (Fluka) were added dropwise to the light yellowish solution within 30 minutes, with the temperature being held at 0 to 5° C. A white suspension formed. The white precipitate was filtered off through a pre-cooled glass filter (G3) and the filter cake was washed with 140 ml of cold ethyl acetate (0 to 5° C., Fluka). To the combined filtrates, a clear, colourless liquid which contained the anhydride, were added 55.9 g (250 mmol) of ethyl (piperidin-4-yloxy)-acetate hydrochloride (obtainable from the corresponding tert.-butyl compound (Alig et al., loc. cit.) by trans-esterification with ethanol/hydrochloric acid) and 66.6 g (250 mmol) of Na3PO4.3H2O. The white suspension was treated at 5 to 10° C. 500 ml of deionised water within 30 seconds under argon and while stirring vigorously, with the temperature rising to 20° C. The colourless two-phase system was stirred vigorously at 20 to 25° C. for one hour. Subsequently, the aqueous phase was separated and the organic phase was washed with 1M sodium bicarbonate solution and then with 1N aqueous ammonia solution. The organic phase was dried over about 50 g of sodium sulphate, filtered and the filter cake was washed with about 100 ml of ethyl acetate. The combined filtrates were evaporated in a rotary evaporator and the oily residue was taken up with 100 ml of ethanol. The clear solution was evaporated at 50°/20 mbar to give 90.2 g (92 wt. %) of ethyl (S)-[1-(2-benzyloxycarbonylaminopropionyl)-piperidin-4-yloxy]-acetate as a clear, colourless oil.

1. custombeing held at 0 to 5° C
2. customA white suspension formed
3. filtrationThe white precipitate was filtered off through a pre-cooled glass
4. filtrationfilter (G3)
5. washthe filter cake was washed with 140 ml of cold ethyl acetate (0 to 5° C., Fluka)
6. additionThe white suspension was treated at 5 to 10° C
7. stirringwhile stirring vigorously, with the temperature
8. customrising to 20° C
9. stirringThe colourless two-phase system was stirred vigorously at 20 to 25° C. for one hour
10. customSubsequently, the aqueous phase was separated
11. washthe organic phase was washed with 1M sodium bicarbonate solution
12. dry with materialThe organic phase was dried over about 50 g of sodium sulphate
13. filtrationfiltered
14. washthe filter cake was washed with about 100 ml of ethyl acetate
15. customThe combined filtrates were evaporated in a rotary evaporator
16. customThe clear solution was evaporated at 50°/20 mbar