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Trifluoroacetic acid → (2r,5s)-n-(2-Acetyl-4-pyridyl)-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carboxamide

HRID 1838266
Notes
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Reaction equation

HRID 1838266 reaction equation
FC(F)(F)C(O)=O.C(O[C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[O:23])[CH3:22])[CH:16]=1)(C)(C)C.ClC(OC1C=CC=CC=1)=O.[CH3:35][C@H:36]1[CH2:41][NH:40][C@H:39]([CH3:42])[CH2:38][N:37]1[C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[C:45]([C:51]([F:54])([F:53])[F:52])[CH:44]=1>N1C=CC=CC=1.O.C(Cl)(Cl)Cl>[C:21]([C:17]1[CH:16]=[C:15]([NH:14][C:13]([N:40]2[CH2:41][C@H:36]([CH3:35])[N:37]([C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[C:45]([C:51]([F:53])([F:52])[F:54])[CH:44]=3)[CH2:38][C@H:39]2[CH3:42])=[O:24])[CH:20]=[CH:19][N:18]=1)(=[O:23])[CH3:22]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 15891Phenyl chloroformateHCID 11391932trans-4-(2,5-Dimethylpiperazin-1-yl)-2-trifluoromethylbenzonitrileHCID 69108642tert-Butyl (2-acetylpyridin-4-yl)carbamate

Product 1

HCID 69108626(2r,5s)-n-(2-Acetyl-4-pyridyl)-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carboxamide
Yield 46.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1049PyridineSolvent2×HCID 6212ChloroformSolvent

Procedure

While stirring with ice-cooling, 12.5 ml of trifluoroacetic acid was added to 12.5 ml of chloroform solution containing 1.41 g of 2-acetyl-4-pyridinylcarbamic acid t-butyl ester. The mixture was immediately warmed up to room temperature and stirred for 2 hours and 40 minutes. The solvent was evaporated under reduced pressure to obtain a crude amine. This compound was dissolved in 25 ml of pyridine, and the solution was mixed with 0.83 ml of phenyl chloroformate while stirring with ice-cooling and then immediately warmed up to room temperature. After 8 hours and 30 minutes, this was mixed with 10 ml of pyridine solution containing 1.4 g of (2S,5R)-4-(2,5-dimethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile and heated under reflux for 1 hour. The reaction mixture cooled to room temperature was mixed with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography to obtain 1.03 g of the title compound from methanol-chloroform (1:99, v/v) eluate.

Workup

  1. temperaturecooling
  2. stirringstirred for 2 hours and 40 minutes
  3. customThe solvent was evaporated under reduced pressure
  4. customto obtain a crude amine
  5. stirringwhile stirring with ice-
  6. temperaturecooling
  7. temperatureimmediately warmed up to room temperature
  8. temperatureheated
  9. temperatureunder reflux for 1 hour
  10. temperatureThe reaction mixture cooled to room temperature
  11. extractionextracted with chloroform
  12. washThe organic layer was washed with saturated brine
  13. dry with materialdried over anhydrous sodium sulfate
  14. customthe solvent was evaporated under reduced pressure
  15. customThe residue was purified by a silica gel column chromatography

Sources & evidence

ORD record
ord-10c8687f646a4311aa64dab58e98542f
Source dataset
uspto-grants-2004_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06673799B1

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes