Dimethyl Sulfate → 1-Benzyl 4-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate

HRID 1260461Notes

Reaction equation

HRID 1260461 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH3:27])=[O:25]

Participants

5

Reactant 3

HCID 6497Dimethyl SulfateHCID 11430Potassium CarbonateHCID 2756777N-4-Boc-N-1-Cbz-2-piperazine carboxylic acid

Product 1

HCID 44519651-Benzyl 4-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylateYield 90%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Procedure

This step was carried out using the procedure described in Tetrahedron Letters 30 (39), 1989, 5193-5196. A 0.5 M solution of A1 in acetone was treated with K2CO3 (1.3 eq.) and Me2SO4 (1.2 eq.) and the mixture was refluxed 6 h. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. The residue was dissolved in Et2O and washed with sat. aq. NaHCO3 solution, and brine, then dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with 20-100% EtOAc/petroleum ether to give the title compound in 90% yield. 1H NMR (300 MHz, CDCl3, 300K) δ 7.35 (5H, m), 5.17 (2H, m), 4.77-4.50 (2H, m), 4.10-3.85 (1H, m), 3.74 (1.5H, s), 3.64 (1.5H, s), 3.30 (1H, m), 3.10 (1H, dd, J 13.6, 4.4), 2.86 (1H, m), 1.45 (9H, s). MS (ES+) C19H26N2O6 requires 378, found: 401 (M+Na)+.

Workup

  1. temperaturethe mixture was refluxed 6 h
  2. filtrationThe reaction mixture was filtered
  3. concentrationfiltrate was concentrated under reduced pressure
  4. dissolutionThe residue was dissolved in Et2O
  5. washwashed with sat. aq. NaHCO3 solution, and brine
  6. customdried
  7. customevaporated
  8. customThe residue was purified by column chromatography on silica gel
  9. washeluting with 20-100% EtOAc/petroleum ether

Sources & evidence

ORD record
ord-61b7b81c5b434c809d8d035d9bdc5b69
Source dataset
uspto-grants-2013_06
Patent number
US08470823B2

Reaction notes

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