反应详情

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.

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