Piperazine → 1-(2,6-Difluorobenzoyl)piperazine

HRID 1993649Notes

Reaction equation

HRID 1993649 reaction equation
[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10](Cl)=[O:11]>C(O)(=O)C>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:11]

Participants

4

Reactant 2

HCID 4837PiperazineHCID 874382,6-Difluorobenzoyl chloride

Product 1

HCID 183627501-(2,6-Difluorobenzoyl)piperazine

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent2×

Conditions

Temperature
40 °C

Procedure

Charge acetic acid (5 L) to a 22 L flask. Place the reaction in an ice-water bath. Add piperazine (355.00 g, 2.0 equiv; 4.06 moles) in portions with stirring, and increase temperature to ˜40° C. Add another 5 L of acetic acid. Stir until mixture becomes a solution. Adjust cooling bath to ˜13° C. Add 2,6-difluorobenzoyl chloride (355.00 g, 1.00 equiv; 2.01 moles; 253.39 mL) drop wise over a 2 hours period, while maintaining reaction temperature at approximately 13-15° C. Stir overnight. Concentrate under reduced pressure and dissolve residue in 2 L of ice water. Cool flask in an ice water bath. Add 5 N NaOH to adjust pH to 7.5 while maintaining the reaction temperature below 30° C. Filter at ˜10° C. Extract product from filtrate with dichloromethane (4×2 L). Remove solvent under reduced pressure. Dissolve the solid in 1.5 L of methanol at room temperature and filter. Concentrate the methanol solution, then solvent exchange with toluene 2.0 L, afforded pure product. Filter to obtain (2,6-difluorophenyl)-piperazin-1-yl-methanone. Concentrate filtrate and filter again to obtain additional product (total 400 g).

Workup

  1. customthe reaction in an ice-water bath
  2. temperatureAdjust cooling bath to ˜13° C
  3. temperaturewhile maintaining
  4. customreaction temperature at approximately 13-15° C
  5. stirringStir overnight
  6. concentrationConcentrate under reduced pressure
  7. dissolutiondissolve residue in 2 L of ice water
  8. temperatureCool flask in an ice water bath
  9. additionAdd 5 N NaOH
  10. temperaturewhile maintaining the reaction temperature below 30° C
  11. filtrationFilter at ˜10° C
  12. dissolutionDissolve the solid in 1.5 L of methanol at room temperature
  13. filtrationfilter
  14. concentrationConcentrate the methanol solution
  15. customsolvent exchange with toluene 2.0 L, afforded pure product
  16. filtrationFilter

Sources & evidence

ORD record
ord-6ab525b9107245e69355633ef3a3c3cc
Source dataset
uspto-grants-2010_01
Patent number
US07652015B2

Reaction notes

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