p-Toluenesulfonic acid → Tert-butyl 4-((2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate

HRID 419747Notes

Reaction equation

HRID 419747 reaction equation
[NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.[C:26]([O:30][C:31]([N:33]1[CH2:41][CH2:40][CH:36]([C:37](O)=[O:38])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCCP(=O)=O.CN1CCOCC1>CCOC(C)=O.O.C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:41][CH2:40][CH:36]([C:37](=[O:38])[NH:1][CH2:2][C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]

Participants

9

Reactant 5

HCID 6101p-Toluenesulfonic acidHCID 79724-MethylmorpholineHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 133658842-Amino-1-[3-(trifluoromethyl)phenyl]ethanoneHCID 16167369Propylphosphoric anhydride

Product 1

HCID 57751897Tert-butyl 4-((2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylateYield 79%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
2.5 °C

Procedure

Charge (2-Amino-1-(3-trifluoromethyl-phenyl)-ethanone)-, p-toluene sulfonate (1:1) (913 g, 2.43 mol) and 1-tert-Butoxycarbonylisonipecotic acid (623 g, 2.73 mol, 1.12 eq) along with THF (2.75 L) and EtOAc (5.5 L) and cool to 0-5° C. Add 1.2 equivalents of propylphosphonic anhydride (T3P) (1.2 eq, 2.91 mol, 1.512 L of a 50% solution in EtOAc) and maintain the reaction temperature at 0-5° C. during addition. Stir for 10 min, then add N-methylmorpholine (566 g, 5.6 mol, 2.3 eq) holding the temperature below 5° C. during addition. Warm the reaction to room temperature and after 10 hours, cool in an ice bath and add water (7.3 L). Separate the layers and wash the aqueous layer with EtOAc (2.75 L). Combine the organic layers and wash with 0.5M aqueous sodium bicarbonate solution (2.75 L). Wash the organic layer with saturated aqueous sodium chloride (2.75 L), then treat the resulting organic layer with sodium sulfate and filter. Remove the solvent via distillation down to ˜4.6 L. Add back heptane (11 L) while removing solvent via distillation until the final volume reaches ˜11 L. Cool to 50° C. and seed. Hold the resulting slurry at 50° C. for 3 h, then cool the slurry to room temperature and stir for 2 h. Filter the solids and wash the cake, first with 10% EtOAc in heptane (2 L) then with heptane (2 L). After drying in a vacuum oven at 60° C. for 3 h, 800 g (79%) of 4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester is obtained as a white solid.

Workup

  1. temperaturemaintain the reaction temperature at 0-5° C.
  2. additionduring addition
  3. customthe temperature below 5° C.
  4. additionduring addition
  5. temperatureWarm
  6. customthe reaction to room temperature
  7. waitafter 10 hours
  8. temperaturecool in an ice bath
  9. customSeparate the layers
  10. washwash the aqueous layer with EtOAc (2.75 L)
  11. washCombine the organic layers and wash with 0.5M aqueous sodium bicarbonate solution (2.75 L)
  12. washWash the organic layer with saturated aqueous sodium chloride (2.75 L)
  13. additiontreat the resulting organic layer with sodium sulfate
  14. filtrationfilter
  15. customRemove the solvent
  16. distillationvia distillation down to ˜4.6 L
  17. additionAdd back heptane (11 L)
  18. customwhile removing solvent
  19. distillationvia distillation until the final volume
  20. temperatureCool to 50° C.
  21. customat 50° C.
  22. customfor 3 h
  23. temperaturecool the slurry to room temperature
  24. stirringstir for 2 h
  25. filtrationFilter the solids
  26. washwash the cake
  27. customAfter drying in a vacuum oven at 60° C. for 3 h

Sources & evidence

ORD record
ord-593d2b464cee44868120ddbc44ae838d
Source dataset
uspto-grants-2012_01
Patent number
US08093383B2

Reaction notes

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