Piperazine → N-[2-(6-Methoxymethoxy-2,5,7,8-tetramethylchroman-2-yl)ethyl]piperazine

HRID 131060Notes

Reaction equation

HRID 131060 reaction equation
C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2([CH3:30])[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([CH3:29])[C:17]([CH3:28])=[C:18]([O:24][CH2:25][O:26][CH3:27])[C:19]=3[CH3:23])[O:14]2)(=O)=O)=CC=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCCCCC.C(OCC)(=O)C.C(Cl)(Cl)Cl.CO>C1(C)C=CC=CC=1>[CH3:27][O:26][CH2:25][O:24][C:18]1[C:19]([CH3:23])=[C:20]2[C:15](=[C:16]([CH3:29])[C:17]=1[CH3:28])[O:14][C:13]([CH2:12][CH2:11][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:30])[CH2:22][CH2:21]2

Participants

6

Reactant 4

HCID 4837Piperazine2×HCID 21226206Ethyl acetate hexaneHCID 21584188Chloroform methanolHCID 224173562-(6-Methoxymetoxy-2,5,7,8-tetramethylchroman-2-yl)ethyl p-toluenesulfonate2×

Product 1

HCID 69221526N-[2-(6-Methoxymethoxy-2,5,7,8-tetramethylchroman-2-yl)ethyl]piperazine

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

2-(6-Methoxymetoxy-2,5,7,8-tetramethylchroman-2-yl)ethyl p-toluenesulfonate (compound 4) (16.01 g, 35.7 mmol) was diluted in 200 mL of toluene, and piperazine (6.15 g, 71.4 mmol) was added to it, as shown in FIG. 5. The reaction solution was heated at reflux. TLC (silica gel 60 F254 plates; hexane:ethyl acetate (2:1) and chloroform:methanol (4:1)) indicated the reaction to be complete after 2.5 hours, and therefore, it was worked-up as follows: The reaction solution was cooled to room temperature (RT) which caused residual piperazine to precipitate out, and the piperazine was removed by filtration. The filter cake was rinsed with toluene, and this rinsing was combined with the filtrate. The filtrate was concentrated to an oil which weighed 15.79 g. The oil was diluted with chloroform (25 mL), and it was decanted onto a silica gel column (230-400 mesh, 60 Å) that had been prepared with chloroform:methanol (6:1) slurry. The flash column bed measured ˜5 cm×30 cm. The flash column was eluted with the following mobile phase systems: 1) CHCl3:MeOH (6:1); 3 L; -collected 40ט30 mL fractions, followed by 8ט100 mL fractions; 2) CHCl3:MeOH (2:1); 1.8 L; -collected 4×200 mL fractions, followed by 2×400 mL fractions; and 3) CHCl3:MeOH (1:1); 0.8 L; -collected 2×400 mL fractions. Based upon the TLC results of each fraction, appropriate fractions were combined and concentrated to a clear oil which weighed 10.70 g. The compound was characterized by NMR and MS as follows: 1) C-NMR (CDCl3): 12.25, 12.80, 13.68, 20.99, 24.42, 32.07, 36.59, 46.48, 54.42, 55.19, 57.88, 74.35, 99.89, 117.69, 123.28, 126,51, 128.45, 147.25, 148.16 ppm; 2) H-NMR (CDCl3): 1.23 (s, 3H), 1.78 (m, 5H), 2.05 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.39 (b, 4H), 2.48 (t, 2H), 2.57 (t, 2H), 286 (t, 4H), 3.59 (s, 3H), 4.82 (s, 2H) ppm; and 3) MS (ESI): 363.3 [M+H]+.

Workup

  1. temperatureThe reaction solution was heated
  2. temperatureat reflux
  3. customthe reaction
  4. customto precipitate out
  5. customthe piperazine was removed by filtration
  6. washThe filter cake was rinsed with toluene
  7. concentrationThe filtrate was concentrated to an oil which
  8. additionThe oil was diluted with chloroform (25 mL), and it
  9. customwas decanted onto a silica gel column (230-400 mesh, 60 Å) that
  10. customhad been prepared with chloroform:methanol (6:1) slurry
  11. washThe flash column was eluted with the following mobile phase systems
  12. customTLC results of each fraction, appropriate fractions
  13. concentrationconcentrated to a clear oil which

Sources & evidence

ORD record
ord-c58fc38a6d224b1992ea40ff155317f4
Source dataset
uspto-grants-2008_06
Patent number
US07384558B2

Reaction notes

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