Hydrochloric Acid → 1-(2-Tert-butyl-4-methylphenyl)piperazine dihydrochloride

HRID 534823Notes

Reaction equation

HRID 534823 reaction equation
[Li][CH2:2]CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=1.CI.[ClH:32].C(OC(=O)C)C.Cl>C1COCC1.C(OCC)(=O)C.O>[ClH:32].[ClH:32].[C:26]([C:9]1[CH:8]=[C:7]([CH3:2])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)([CH3:27])([CH3:28])[CH3:29]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 6328Methyl iodideHCID 21866389Hydrogen chloride-ethyl acetateHCID 66751044Tert-butyl 4-(4-bromo-2-tert-butylphenyl)piperazine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 667508371-(2-Tert-butyl-4-methylphenyl)piperazine dihydrochlorideYield 47%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of n-BuLi (1.6 M in n-hexane, 5.7 mL, 9.1 mmol) in THF (30 mL) was added a solution of tert-butyl 4-(4-bromo-2-tert-butylphenyl)piperazine-1-carboxylate (Example 85, 3.0 g, 7.55 mmol) in THF (10 mL) at −80° C. After stirred for 30 minutes at that temperature, it was added methyl iodide (1.61 g, 11.3 mmol) and allowed to be warmed to room temperature. After 16 h, it was added water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over MgSO4, and the solvent was evaporated under reduced pressure to get crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=97:3 to 90:10) to provide a white solid. It was added 4 M hydrochloric acid in ethyl acetate solution (7.5 mL). After 16 h, it was concentrated under reduced pressure to give a pale yellow powder, which was re-crystallized from methanol, ethyl acetate and hexane to provide a white powder. It was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm] to give a white solid. It was added 4 M hydrochloric acid ethyl acetate solution (7.5 mL). The solvent was removed under reduced pressure to give 1-(2-tert-butyl-4-methylphenyl)piperazine dihydrochloride (1.08 g, 47%) as a white powder.

Workup

  1. waitAfter 16 h
  2. extractionextracted with ethyl acetate
  3. washThe organic layer was washed with brine
  4. dry with materialdried over MgSO4
  5. customthe solvent was evaporated under reduced pressure
  6. customto get crude product
  7. customThe product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=97:3 to 90:10)
  8. customto provide a white solid
  9. waitAfter 16 h
  10. concentrationit was concentrated under reduced pressure
  11. customto give a pale yellow powder, which
  12. customwas re-crystallized from methanol, ethyl acetate and hexane
  13. customto provide a white powder
  14. customIt was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm]
  15. customto give a white solid
  16. customThe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-3876e013c0854fba9b9b709e5380c60b
Source dataset
uspto-grants-2014_10
Patent number
US08853215B2

Reaction notes

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