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 from 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 with adjustment of 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 1M 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 from 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 1M 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