反应详情

温度

20 °C

A 12 L, 3-necked round bottom flask was charged with trans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had been recrystallized fiom toluene to mp=115-119° C., and 600 mL of water. The flask was cooled in an ice bath and a solution of methanesulfonic acid (1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring and cooling to maintain the temperature below 40° C. The solution was cooled to 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel was filled with 60% aqueous potassium acetate from a 2 L reservoir of the solution, and potassium acetate was added to the reaction flask to adjust the pH to 4.0. A second addition funnel was charged with a solution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL of tetrahydrofuran. The ethyl chloroformate and potassium acetate solutions were simultaneously added dropwise at a rate to maintain the reaction solution at pH 4.0±0.1, with cooling as necessary to maintain temperature at 25° C. After addition of the ethyl chloroformate was complete, the reaction was stirred for 1 hour with continued addition of potassium acetate solution to maintain a pH of 4.0. The organic solvents were removed by distillation under vacuum. The remaining aqueous solution was washed with 1500 mL of ethyl acetate to remove any bis-carbamate impurity. The ethyl acetate wash was extracted with two 500 mL portions of 1 M hydrochloric acid to recover desired product. The acid extracts were combined with the original aqueous solution and the pH was adjusted to 11 by addition of 10 M sodium hydroxide, with cooling to maintain temperature below 40° C. The aqueous solution was extracted with two 1500 mL portions of ethyl acetate, the combined extracts were dried over magnesium sulfate, and the solvent was removed to give 927 g (74%) ethyl trans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.

1. customhad been recrystallized fiom toluene to mp=115-119° C., and 600 mL of water
2. temperatureThe flask was cooled in an ice bath
3. temperaturecooling
4. temperatureto maintain the temperature below 40° C
5. additionA 500 mL addition funnel
6. additionwas added to the reaction flask
7. temperatureto maintain the reaction solution at pH 4.0±0.1
8. temperaturewith cooling as necessary
9. temperatureto maintain temperature at 25° C
10. temperatureto maintain a pH of 4.0
11. customThe organic solvents were removed by distillation under vacuum
12. washThe remaining aqueous solution was washed with 1500 mL of ethyl acetate
13. customto remove any bis-carbamate impurity
14. washThe ethyl acetate wash
15. extractionwas extracted with two 500 mL portions of 1 M hydrochloric acid
16. customto recover desired product
17. additionthe pH was adjusted to 11 by addition of 10 M sodium hydroxide
18. temperaturewith cooling
19. temperatureto maintain temperature below 40° C
20. extractionThe aqueous solution was extracted with two 1500 mL portions of ethyl acetate
21. dry with materialthe combined extracts were dried over magnesium sulfate
22. customthe solvent was removed