反应详情

温度

6 °C

N-(5-Mercapto-indan-2-yl)-acetamide (330.0 g, 1.59 mol) was dissolved in a warm THF (1.65 L) at 50° C. The solution was then slowly added to LAH solution (1 M in THF) (2.385 L, 2.385 mol) at about 60-66° C. over 25 minutes to allow gentle reflux and slow gas evolution. After addition, the light yellow suspension was stirred under reflux for 4 hours. The reaction was cooled to about 5-7° C. in an ice-water bath. The reaction was quenched by the slow addition of methanol (203.7 g, 6.36 mol) under a nitrogen atmosphere and the reaction temperature was maintained below 25° C. by adjusting the addition rate. After quenching, the resulted green suspension was cooled to 5-7° C. and treated with tert-butyl 2-bromo-2-methylpropionate (354.7 g, 1.59 mol). The resulted mixture was warmed to room temperature while stirring and then maintained with stirring at room temperature for 2 hours. The reaction mixture was treated by the slow addition of H2O (90.6 mL) and 15% of aqueous NaOH (90.6 mL) sequentially. The resulted granular solid was removed by vacuum filtration through a 3 L coarse frit funnel lined with Celite filter aid. The filter cake was rinsed twice with THF (2×500 mL). The combined filtrate was concentrated in vacuo to remove about 70-80% of THF. The filter cake was suspended in EtOAc (2 L) and stirred for 30 minutes. The suspension was filtered through a 3 L coarse frit funnel. The filtrate was combined with the crude concentrated THF solution obtained above. The combined organic layer was washed with H2O (2 L). After separation of layers, the organic layer was concentrated in vacuo at 50° C. to remove the most of volatiles. The concentrated solution was diluted with anhydrous ethanol (800 mL) and re-concentrated to yield a purple oil. The crude product was used for the next step without further purification.

1. temperatureto allow gentle reflux
2. additionAfter addition
3. temperatureunder reflux for 4 hours
4. temperaturethe reaction temperature was maintained below 25° C.
5. customAfter quenching
6. temperaturethe resulted green suspension was cooled to 5-7° C.
7. temperatureThe resulted mixture was warmed to room temperature
8. stirringwhile stirring
9. temperaturemaintained
10. stirringwith stirring at room temperature for 2 hours
11. customThe resulted granular solid was removed by vacuum filtration through a 3 L coarse frit funnel
12. filtrationfilter aid
13. washThe filter cake was rinsed twice with THF (2×500 mL)
14. concentrationThe combined filtrate was concentrated in vacuo
15. customto remove about 70-80% of THF
16. stirringstirred for 30 minutes
17. filtrationThe suspension was filtered through a 3 L coarse frit funnel
18. customobtained above
19. washThe combined organic layer was washed with H2O (2 L)
20. customAfter separation of layers
21. concentrationthe organic layer was concentrated in vacuo at 50° C.
22. customto remove the most of volatiles
23. additionThe concentrated solution was diluted with anhydrous ethanol (800 mL)
24. concentrationre-concentrated
25. customto yield a purple oil
26. customThe crude product was used for the next step without further purification