tert-Butyl piperazine-1-carboxylate → HCID 23658413, compound

HRID 2273690Notes

Reaction equation

HRID 2273690 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH3:16].C([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(OC(C)(C)C)=O.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.[C:76]([OH:83])(=[O:82])/[CH:77]=[CH:78]/[C:79]([OH:81])=[O:80]>C1(C)C=CC=CC=1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:76]([OH:83])(=[O:82])/[CH:77]=[CH:78]/[C:79]([OH:81])=[O:80].[CH3:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1

Participants

8

Reactant 4

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 444972Fumaric AcidHCID 634876Binap, (A+-)-HCID 583985481-[(2-Bromophenyl)thio]-2,4-dimethylbenzene

Product 1

HCID 23658413HCID 23658413, compoundYield 64.7%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 10 gram 1-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene (34 mmol) in 50 ml dry toluene was added 7 gram boc-piperazine (38 mmol), degassed with nitrogen for 5 minutes, added 312 mg Pd2 dba3 (2 mol-%) and 637 mg rac-BINAP (3 mol-%), degassed for another 5 minutes before adding 3.9 gram ButONa (41 mmol) and heated to 80° C. for 15 hours. The reaction mixture was cooled to RT and extracted twice with 20 ml 15% brine, dried over Na2SO4, added charcoal, refluxed for 15 minutes, filtered though celite and evaporated to 14.2 gram of brownish oil (4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-BOC-piperazine) having a purity of 95% determined by NMR. The crude oil was dissolved in 200 ml MeOH and 20 ml 6M HCl (aq.) and refluxed for 1 hour after which HPLC showed full deprotection. After cooling to RT the methanol was removed by vacuum on a rotary-evaporator, 20 ml conc. NaOH (pH was measured to 13-14) was added after which the mixture was stirred 15 minutes with 100 ml EtOAc. The organic phase was collected and extracted twice with 30 ml 15% brine, dried over Na2SO4 and added 5.2 g fumaric acid (44 mmol) in 30 ml MeOH. During heating to reflux a homogenous solution forms from which a rapid precipitation takes place either during further heating or upon cooling. The precipitate was collected, washed with 20 ml EtOAc and 20 ml acetone, dried in vacuum giving 9.3 gram of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine fumarate (22 mmol) as a white powder in 66% overall yield having a purity of 99.5% by LC-MS.

Workup

  1. customdegassed with nitrogen for 5 minutes
  2. customdegassed for another 5 minutes
  3. additionbefore adding 3.9 gram ButONa (41 mmol)
  4. temperatureThe reaction mixture was cooled to RT
  5. extractionextracted twice with 20 ml 15% brine
  6. dry with materialdried over Na2SO4
  7. additionadded charcoal
  8. temperaturerefluxed for 15 minutes
  9. filtrationfiltered though celite
  10. customevaporated to 14.2 gram of brownish oil (4-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-BOC-piperazine)
  11. dissolutionThe crude oil was dissolved in 200 ml MeOH
  12. temperature20 ml 6M HCl (aq.) and refluxed for 1 hour after which HPLC
  13. temperatureAfter cooling to RT the methanol
  14. customwas removed by vacuum on a rotary-evaporator, 20 ml conc. NaOH (pH was measured to 13-14)
  15. additionwas added after which the mixture
  16. customThe organic phase was collected
  17. extractionextracted twice with 30 ml 15% brine
  18. dry with materialdried over Na2SO4
  19. temperatureDuring heating
  20. temperatureto reflux a homogenous solution forms from which
  21. customa rapid precipitation
  22. temperatureduring further heating
  23. temperatureupon cooling
  24. customThe precipitate was collected
  25. washwashed with 20 ml EtOAc and 20 ml acetone
  26. customdried in vacuum

Sources & evidence

ORD record
ord-7befbcec32874aa6a07e5da2865a9147
Source dataset
uspto-grants-2015_09
Patent number
US09125908B2

Reaction notes

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