tert-Butyl piperazine-1-carboxylate → HCID 23658413、化合物

HRID 511883ノート

反応式

HRID 511883 の反応式
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

参加物

8

反応物 4

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

生成物 1

HCID 23658413HCID 23658413、化合物収率 64.7%

試薬・触媒・溶媒 3

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 887Methanol溶媒HCID 1140Toluene溶媒

反応条件

温度
80 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-cb3d00b874ae4b9691d22b71fc641f34
出典データセット
uspto-grants-2015_08
特許番号
US09101626B2

反応ノート

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