1-Methylpiperazine → Benzyl 2-(4-methylpiperazin-1-yl)-2-phenylacetate

HRID 2407554Notes

Reaction equation

HRID 2407554 reaction equation
[C:1]1([CH:7](OS(C2C=CC(C)=CC=2)(=O)=O)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:32][CH2:31]1

Participants

5

Reactant 3

HCID 531671-MethylpiperazineHCID 81531DiisopropylethylamineHCID 86618475Benzyl 2-phenyl-2-(tosyloxy)acetate

Product 1

HCID 66648860Benzyl 2-(4-methylpiperazin-1-yl)-2-phenylacetateYield 93.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g, 15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) and N,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65° C. for 7 hours. The reaction was allowed to cool to ambient temperature and the volatile component was removed in vacuo. The residue was partitioned between ethylacetate and water, and the organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel, ethyl acetate) to provide benzyl 2-(4-methylpiperazin-1-yl)-2-phenylacetate as an orangish-brown viscous oil (4.56 g). Chiral HPLC analysis (Chiralcel OD-H) indicated that the sample is a mixture of enantiomers in a 38.2 to 58.7 ratio. The separation of the enantiomers were effected as follow: the product was dissolved in 120 mL of ethanol/heptane (1:1) and injected (5 mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID×50 cm L, 20 μm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at 220 nm. Enantiomer-1 (1.474 g) and enantiomer-2 (2.2149 g) were retrieved as viscous oil. 1H NMR (CDCl3, δ=7.26, 500 MHz) 7.44-7.40 (m, 2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d, J=12.5, 1H), 5.08 (d, J=12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H). RT=2.10 (Cond. III); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C20H25N2O2: 325.19; found 325.20.

Workup

  1. customthe volatile component was removed in vacuo
  2. customThe residue was partitioned between ethylacetate and water
  3. washthe organic layer was washed with water and brine
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe resulting crude material was purified by flash chromatography (silica gel, ethyl acetate)

Sources & evidence

ORD record
ord-4257324c43524bb8a6d45d71c36a544c
Source dataset
uspto-grants-2014_08
Patent number
US08809548B2

Reaction notes

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