反应详情

温度

-50 °C

1.85 ml (12.97 mmol) of diisopropylamine, dried over KOH, in 6 ml of THF, rendered absolute using sodium, are introduced into a thoroughly heated 50 ml three-necked round-bottomed flask, equipped with a magnetic stirrer, thermometer and nitrogen delivery line, and cooled to −50° C. using an ethanol/dry-ice bath. 8.1 ml (12.97 mmol) of butyllithium (1.6M in hexane) are slowly added dropwise so that the internal temperature does not exceed −40° C. Heating to from −5 to 0° C. is carried out slowly, followed by stirring at that temperature for 30 min. Cooling to −65° C. is then carried out and 1.30 ml (12.94 mmol) of ethyl acetate are slowly added dropwise so that the internal temperature does not exceed −60° C. Stirring is subsequently carried out for 40 min. at −65° C. and then 1.20 g (3.28 mmol) of (E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-methylacrylamide, dissolved in 5 ml of THF, are added dropwise in the course of 25 min. and stirring is carried out for one hour at that temperature. The temperature is then increased to −5° C. in the course of 15 min. and stirring is carried out for 45 min. 8 ml of saturated ammonium chloride solution are added dropwise over a period of 3 min., in the course of which the temperature rises to 12° C. Stirring is then carried out for 15 min., 10 ml of toluene are added, the phases are separated and the aqueous phase is extracted three times with 20 ml of toluene. The combined organic phases are washed with saturated sodium chloride solution until neutral, dried over magnesium sulfate, filtered and concentrated by evaporation. Purification of the crude product by means of flash chromatography (hexane/ethyl acetate=9:1) yields a viscous orange resin which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.

1. additionare introduced into a thoroughly heated 50 ml three-necked round-bottomed flask
2. customequipped with a magnetic stirrer
3. customdoes not exceed −40° C
4. temperatureHeating to from −5 to 0° C.
5. temperatureCooling to −65° C.
6. customdoes not exceed −60° C
7. stirringStirring
8. waitis subsequently carried out for 40 min. at −65° C.
9. additionare added dropwise in the course of 25 min.
10. stirringstirring
11. waitis carried out for one hour at that temperature
12. temperatureThe temperature is then increased to −5° C. in the course of 15 min.
13. stirringstirring
14. waitis carried out for 45 min
15. customrises to 12° C
16. stirringStirring
17. waitis then carried out for 15 min.
18. customthe phases are separated
19. extractionthe aqueous phase is extracted three times with 20 ml of toluene
20. washThe combined organic phases are washed with saturated sodium chloride solution until neutral,
21. dry with materialdried over magnesium sulfate
22. filtrationfiltered
23. concentrationconcentrated by evaporation
24. customPurification of the crude product by means of flash chromatography (hexane/ethyl acetate=9:1)
25. customyields a viscous orange resin which