1-Bromo-2-iodobenzene → Vortioxetine hydrobromide

HRID 2273679Notes

Reaction equation

HRID 2273679 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[SH:17].C([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(OC(C)(C)C)=O>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[BrH:1].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[S:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1

Participants

6

Reactant 3

HCID 114151-Bromo-2-iodobenzeneHCID 836172,4-DimethylbenzenethiolHCID 143452tert-Butyl piperazine-1-carboxylate

Product 1

HCID 56843850Vortioxetine hydrobromideYield 36%

Reagents, catalysts & solvents 2

HCID 634876Binap, (A+-)-CatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

102 g 2-bromo-iodobenzene (362 mmol) and 50 g 2,4-dimethylthiophenol (362 mmol) are dissolved in 1000 ml toluene. To this solution was added 81 g BOC-piperazine (434 mmol) followed by 2.08 g Pddba2 (1 mol %) and 4.51 g rac-BINAP (2 mol %). The mixture was purged with nitrogen for 5 minutes before adding a slurry of 87 g NaOBut (905 mmol) in 300 ml toluene. The suspension was heated to 100° C. under nitrogen overnight. A GCMS analysis showed full conversion into the intermediate product (1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene) and the temperature was increased to reflux (120° C.) for another 24 hours. A HPLC analysis showed full conversion into the intermediate (1-BOC-4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine). The reaction mixture was cooled on ice for one hour before filtering the mixture. The filter cake is washed with 2×200 ml toluene and to the combined filtrates was added 80 ml 48-wt % HBr (aq.) followed by heating to reflux for 18 hours after which full deprotection was detected by HPLC. The mixture was cooled on ice for 2 hours and filtrated. The brownish solid was dissolved in 1000 ml boiling H2O for 1 hour together with activated charcoal (25 g), filtered while hot and left to cool. The precipitate was collected by filtration and drying in vacuum at 40° C. overnight produced 49 g of 4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (36%) as a white solid.

Workup

  1. customThe mixture was purged with nitrogen for 5 minutes
  2. additionbefore adding a slurry of 87 g
  3. temperaturethe temperature was increased
  4. temperatureto reflux (120° C.) for another 24 hours
  5. temperatureThe reaction mixture was cooled on ice for one hour
  6. filtrationbefore filtering the mixture
  7. washThe filter cake is washed with 2×200 ml toluene and to the combined filtrates
  8. additionwas added 80 ml 48-wt % HBr (aq.)
  9. temperatureby heating
  10. temperatureto reflux for 18 hours after which full deprotection
  11. temperatureThe mixture was cooled on ice for 2 hours
  12. filtrationfiltrated
  13. dissolutionThe brownish solid was dissolved in 1000 ml
  14. customfor 1 hour
  15. filtrationfiltered while hot and
  16. waitleft
  17. temperatureto cool
  18. filtrationThe precipitate was collected by filtration
  19. customdrying in vacuum at 40° C. overnight

Sources & evidence

ORD record
ord-4421f62923f9494583855ae57d303d96
Source dataset
uspto-grants-2015_09
Patent number
US09125909B2

Reaction notes

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