Methanesulfonic Acid → Ethyl trans-2,5-dimethyl-1-piperazinecarboxylate

HRID 379604

Reaction equation

HRID 379604 reaction equation
[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.CS(O)(=O)=O.C([O-])(=O)C.[K+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O.O1CCCC1.C(O)C>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]

Participants

8

Reactant 4

HCID 6395Methanesulfonic AcidHCID 10928Ethyl chloroformate3×HCID 2206722,5-Dimethylpiperazine, trans-HCID 517044Potassium Acetate4×

Product 1

HCID 10607598Ethyl trans-2,5-dimethyl-1-piperazinecarboxylateYield 74.2%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-8de108a265954d4f8c28f9fdd4ad9d63
Source dataset
uspto-grants-2001_10
Patent number
US06300332B1

Linked notes

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