Piperazine → Vortioxetine hydrobromide

HRID 1909086Notes

Reaction equation

HRID 1909086 reaction equation
C1C=CC(P(C2[C:23]([C:24]3[C:33](P(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:32][CH:31]=[C:30]4[C:25]=3C=CC=[CH:29]4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[NH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.[Br:59]C1C=CC=CC=1I.C[C:68]1[CH:73]=[C:72](C)[CH:71]=[CH:70][C:69]=1[SH:75]>O.C1(C)C=CC=CC=1>[BrH:59].[CH3:23][C:24]1[CH:25]=[C:30]([CH3:29])[CH:31]=[CH:32][C:33]=1[S:75][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1

Participants

8

Reactant 5

HCID 4837PiperazineHCID 114151-Bromo-2-iodobenzeneHCID 836172,4-DimethylbenzenethiolHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxide

Product 1

HCID 56843850Vortioxetine hydrobromide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

Under a nitrogen atmosphere Pddba2 (211 mg, 0.367 mmol), BINAP (458 mg, 0.736 mmol), sodium tert-butoxide (26.0 g), piperazine (27.5 g) and toluene (185 mL) were stirred at room temperature for approx 30 minutes. To this mixture was added 1-bromo-2-iodobenzene (12 mL) and 2,4-dimethylthiophenol (12.3 mL) and the reaction mixture was stirred for approximately 60 minutes without heating. The reaction mixture was then heated at reflux for 5 hours, and then water (70 mL) was added followed by stirring for a further 5 minutes before the phases were separated (temperature above 60 C). The toluene phase was washed 2 times with a sodium chloride solution. To the warm toluene phase was added hydrobromic acid 48% (16.2 g), seeding crystals (HBr β-form) were added and the solution was cooled. 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine-HBr was isolated by filtration, and the filter cake was washed with toluene (160 mL) and water (190 mL). Analysis of a dried sample of filter cake showed 0.64% compound 1 and 70 ppm Pd. The wet filter cake was heated in isopropanol (345 mL) at reflux temperature and the hot solution was blank filtered. The clear solution was cooled to below room temperature, isopropanol solvate of 1-(2,4-dimethylphenylsulfanyl)phenyl]piperazine-HBr was isolated by filtration, washed with isopropanol (40 mL) and dried under vacuum at 40° C. Analysis showed compound 1 (0.05%) and 2 ppm Pd.

Workup

  1. temperaturewithout heating
  2. temperatureThe reaction mixture was then heated
  3. temperatureat reflux for 5 hours
  4. stirringby stirring for a further 5 minutes before the phases
  5. customwere separated (temperature above 60 C)
  6. washThe toluene phase was washed 2 times with a sodium chloride solution
  7. additionTo the warm toluene phase was added hydrobromic acid 48% (16.2 g)
  8. additionwere added
  9. temperaturethe solution was cooled

Sources & evidence

ORD record
ord-358da7fedbdb4b42931ab36722f66dde
Source dataset
uspto-grants-2013_12
Patent number
US08598348B2

Reaction notes

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