Sodium Carbonate → di-tert-butyl (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylate

HRID 1091382Notes

Reaction equation

HRID 1091382 reaction equation
Cl.[NH2:2]O.[C:4](=[O:7])([O-])[O-].[Na+].[Na+].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:14][CH:13]=1)#[N:11].C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.O.C1(C)C=CC=CC=1>[O:7]1[CH:4]=[N:2][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C@H:18]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:16][CH:17]=2)=[N:11]1

Participants

9

Reactant 5

HCID 10340Sodium CarbonateHCID 31214Ethyl orthoformateHCID 443297Hydroxyamine hydrochlorideHCID 521998p-Toluenesulfonic acid monohydrateHCID 66594602di-tert-butyl (2S)-2-(4-cyanophenyl)piperazine-1,4-dicarboxylate

Product 1

HCID 66594852di-tert-butyl (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylateYield 70%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

Hydroxylamine hydrochloride (1.3 g, 20.2 mmol) and sodium carbonate (3.4 g, 32.1 mmol) were added to a solution of di-tert-butyl (2S)-2-(4-cyanophenyl)piperazine-1,4-dicarboxylate (2.5 g, 6.45 mmol) in ethanol (15 ml) and water (15 ml) at the room temperature and the solution was stirred at 80° C. for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Triethyl orthoformate (9.6 g, 64.8 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) were added to a solution of the residue in toluene (25 ml) and stirred at 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish di-tert-butyl (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)-piperazine-1,4-dicarboxylate (1.94 g, 70%) as a colorless oil. Hydrogen chloride in ethyl acetate (4N) was added to a solution of di-tert-butyl (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylate (1.94 g, 4.51 mmol) in methanol and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure to give white solid, which was washed with ethyl acetate to afford (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)piperazine dihydrochloride (1.3 g, 95%) as white crystals.

Workup

  1. customThe mixture was partitioned between water and chloroform
  2. washThe organic layer was washed with brine
  3. dry with materialdried over magnesium sulfate
  4. concentrationconcentrated in vacuo
  5. stirringstirred at 90° C. for 2 hours
  6. customThe mixture was partitioned between water and ethyl acetate
  7. washThe organic layer was washed with brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by silica gel column chromatography
  11. washeluting 10-20% ethyl acetate in hexane

Sources & evidence

ORD record
ord-9bd65606c7f740ecaba7e80d2d777b5e
Source dataset
uspto-grants-2012_03
Patent number
US08129377B2

Reaction notes

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