1-Methylpiperazine → Tert-butyl 3-(4-methylpiperazin-1-yl)propanoate

HRID 2190946Notes

Reaction equation

HRID 2190946 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:3]1

Participants

5

Reactant 2

HCID 531671-MethylpiperazineHCID 256128tert-Butyl 3-bromopropionate

Product 1

HCID 66915321Tert-butyl 3-(4-methylpiperazin-1-yl)propanoateYield 99.8%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
25 °C

Procedure

4-methyl piperazine (7.68 mL, 70 mmol, 4 equiv) was added to a stirred solution of tert-butyl 3-bromopropionate (3.0 mL, 18 mmol) in ethyl acetate (15 mL) at 0° C. The solution was stirred at 25° C. for 1 h with evolution of a white precipitate, then heated on an oil bath to 55° C. for 2 h. TLC analysis (20% EtOAc in Hexanes, Rf=0.9 (starting material), 0.1 (product)) indicated complete consumption of the bromide reagent. The reaction was diluted with EtOAc (100 mL) and transferred to a separatory funnel, and the organic phase was washed with water (100 mL), NaHCO3 (sat'd, 2×100 mL), and brine (100 mL), dried over MgSO4 and concentrated to give a slightly yellow oil. The oil was dissolved in methylene chloride (20 mL), loaded on to a pre-equilibrated plug of silica gel (20% EtOAc in Hexanes, 150 mL SiO2) and the desired product was eluted from the silica with increasingly polar eluent (EtOAc in hexanes, starting at 20%, 200 mL volumes increasing in 15% increments to 100%). Fractions containing the desired material were concentrated to give tert-butyl 3-(4-methylpiperazin-1-yl)propanoate (4.1 g, quantitative). 1H NMR (400 MHz, CDCl3) δ (ppm)=3.45 (d, J=3 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.47 (br s, 6H), 2.38 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 1.42 (s, 9H).

Workup

  1. temperatureheated on an oil bath to 55° C. for 2 h
  2. customconsumption of the bromide reagent
  3. additionThe reaction was diluted with EtOAc (100 mL)
  4. customtransferred to a separatory funnel
  5. washthe organic phase was washed with water (100 mL), NaHCO3 (sat'd, 2×100 mL), and brine (100 mL)
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. customto give a slightly yellow oil
  9. washthe desired product was eluted from the silica
  10. temperaturewith increasingly polar
  11. temperatureeluent (EtOAc in hexanes, starting at 20%, 200 mL volumes increasing in 15% increments to 100%)
  12. additionFractions containing the desired material
  13. concentrationwere concentrated

Sources & evidence

ORD record
ord-f5de7284d7a746ff9625c63d5742cff2
Source dataset
uspto-grants-2012_12
Patent number
US08324410B2

Reaction notes

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