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

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Reaction Steps

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.

Provenance & Evidence