Methanesulfonic Acid → Phenylmethyl cis-2,3-dimethyl-1-piperazinecarboxylate

HRID 1366577Notes

Reaction equation

HRID 1366577 reaction equation
[CH3:1][C@H:2]1[C@@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][NH:3]1.CS(O)(=O)=O.C([O-])(=O)C.[K+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O.C(O)C>[CH3:1][C@H:2]1[C@@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][N:3]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]

Participants

7

Reactant 4

HCID 6395Methanesulfonic AcidHCID 10387Benzyl chloroformateHCID 517044Potassium Acetate2×HCID 13758650cis-2,3-Dimethylpiperazine

Product 1

HCID 66936549Phenylmethyl cis-2,3-dimethyl-1-piperazinecarboxylateYield 48.2%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
20 °C

Procedure

A 100 mL, three-necked round-bottom flask was charged with cis-2,3-dimethylpiperazine (Helvetica Chimica Acta, 1994, 77, 1057-64) (1.781 g, 15.6 mmol). The flask was cooled in an ice bath, and a solution of methanesulfonic acid (2.02 mL, 31.2 mmol) in 1.4 mL of water was added slowly, maintaining the temperature below 40° C. The solution was cooled to 20° C., and 2 mL of ethanol was added. The pH was adjusted to 4 with 60% aqueous potassium acetate, and then benzyl chloroformate (2.08 mL, 14.8 mmol in 1 mL of THF) and potassium acetate solutions were simultaneously added dropwise with adjustment of the rate to maintain the reaction solution at pH 4, with cooling to maintain the temperature at 25° C. After the mixture was stirred an additional hour, the organic solvents were removed and the remaining aqueous solution was washed with ethyl acetate. The ethyl acetate wash was extracted with 1 M HCl twice to recover the desired product. The acid extracts were combined with the original aqueous solution, and the pH was adjusted to 11 by the addition of 6 N NaOH, with cooling to maintain temperature below 40° C. The aqueous solution was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and concentrated in vacuo to provide phenylmethyl cis-2,3-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) as a yellow oil (1.77 g, 46%). LCMS: (M+H)+: 249.1.

Workup

  1. temperatureThe flask was cooled in an ice bath
  2. temperaturemaintaining the temperature below 40° C
  3. temperatureto maintain the reaction solution at pH 4
  4. temperaturewith cooling
  5. temperatureto maintain the temperature at 25° C
  6. customthe organic solvents were removed
  7. washthe remaining aqueous solution was washed with ethyl acetate
  8. washThe ethyl acetate wash
  9. extractionwas extracted with 1 M HCl twice
  10. customto recover the desired product
  11. additionthe pH was adjusted to 11 by the addition of 6 N NaOH
  12. temperaturewith cooling
  13. temperatureto maintain temperature below 40° C
  14. extractionThe aqueous solution was extracted with ethyl acetate
  15. dry with materialthe combined extracts were dried over magnesium sulfate
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-585c2cec80474862b4e931ba5d3e75ba
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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