反应详情

温度

-26 °C

To a solution of INT 5 (360 g, 1.941 mol) and 3-bromoaniline (509 g, 2.957 mol) in toluene (3.5 L) was added p-toluenesulfonic acid monohydrate (18.8 g, 0.099 mol). The mixture, equipped with a Dean stark trap, was refluxed overnight. After 1.5 hours, 300 mL of turbid toluene was removed from the Dean stark trap. After 5 hours 150 mL of turbid toluene was removed from the Dean stark trap and dry toluene and molecular sieves 4 Å (20 g) were added. On the next day, more molecular sieves 4 Å (60 g) were added and the reaction mixture was refluxed for an additional 4 hours. The molecular sieves were filtered off and the filtrate was concentrated. The crude imine and (S)—N-(5-fluoro-2-hydroxybenzyl)-2-methylpropane-2-sulfinamide (68.5 g, 0.279 mol, prepared according to: Pei, Dong; Wang, Zhouyu; Wei, Siyu; Zhang, Yu; Sun, Jian. Org. Lett. (2006), 8 (25), 5913-5915.) were dissolved in CH2Cl2 (6.6 L) and the mixture was cooled to −26° C. Trichlorosilane (302 g, 2.233 mol) was added dropwise within 20 minutes and the resulting mixture was stirred overnight keeping the temperature between −25° C. and −22° C. The mixture was poured onto saturated aqueous NaHCO3 (7 L) and extracted with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc). The resulting product was further purified by formation of the HCl salt and washing it with Et2O. The resulting solid was dissolved in hot EtOH and cooled to room temperature while stirring. The resulting solid was filtered off and dried in vacuum. The salt was then liberated to give INT 6.

1. customThe mixture, equipped with a Dean stark trap
2. temperaturewas refluxed overnight
3. custom300 mL of turbid toluene was removed from the Dean stark trap
4. customAfter 5 hours 150 mL of turbid toluene was removed from the Dean stark trap and dry toluene and molecular sieves 4 Å (20 g)
5. additionwere added
6. additionOn the next day, more molecular sieves 4 Å (60 g) were added
7. temperaturethe reaction mixture was refluxed for an additional 4 hours
8. filtrationThe molecular sieves were filtered off
9. concentrationthe filtrate was concentrated
10. customthe temperature between −25° C. and −22° C
11. extractionextracted with EtOAc
12. washThe combined organic layers were washed with brine
13. dry with materialdried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated
16. customThe residue was purified by chromatography on silica gel (cyclohexane/EtOAc)
17. customThe resulting product was further purified by formation of the HCl salt
18. washwashing it with Et2O
19. dissolutionThe resulting solid was dissolved in hot EtOH
20. temperaturecooled to room temperature
21. stirringwhile stirring
22. filtrationThe resulting solid was filtered off
23. customdried in vacuum
24. customto give INT 6