反应详情

温度

0 °C

3-(ethyloxy)-2-cyclohexen-1-one (1000 g, 1.0 eq, 1.0 wt) was dissolved in acetonitrile (5 L, 5 vol) at 0° C. and N-bromosuccinimide (1295 g, 1.02 eq, 1.295 wt) was added in four equal portions over 1 hour at <5° C. The mixture was stirred for 15 minutes at 0° C., warmed to 20° C. and stirred for a further 15 minutes at this temperature and sampled for completion by HPLC. Reaction was complete. 2-methylpropanimidamide (981 g, 1.1 eq, 0.981 wt) was added and the mixture stirred for 5 minutes at 20° C. Anhydrous sodium carbonate (1134 g, 1.5 eq, 1.134 wt) was charged to the vessel and the contents warmed to 65° C., stirred for a further 2 hours and sampled for completion by HPLC. Reaction was complete. Water (7 L, 7 vol) was added at 60° C. and the contents stirred for a further 15 minutes. 2-methyltetrahydrofuran (7 L, 7 vol) was added at 50° C. The suspension was cooled to 25° C., filtered and the inorganic solids washed with 2-methyltetrahydrofuran (2 L, 2 vol). The biphase was stirred for 5 minutes, settled and separated. The aqueous phase was back-extracted with 2-methyltetrahydrofuran (5 L, 5 vol). The combined organic phases were concentrated by atmospheric distillation to 5 L/5 vol. Toluene (10 L, 10 vol) was added, the mixture was concentrated by atmospheric distillation to 5 L/5 vol and cooled to 60° C. 5-6M hydrochloric acid in propan-2-ol (2 L, 1.3 eq, 2 vol) was added over 35 minutes at 60° C. Crystallisation was observed towards the end of the addition. The slurry was aged at 60° C. for 1 hour, cooled to 0° C. over 4 hours and stirred at this temperature for 10 hours 45 minutes. Solids were collected by vacuum filtration, washed with chilled (5° C.) toluene/propan-2-ol (2×2.5 L, 2:1 v/v, 2×2.5 vol), followed by tert-butylmethylether (2×2.5 L, 2×2.5 vol) and dried in vacuo at 50° C. for 5 hours. Yield of title compound obtained was 887 g, however this contained 13.2% w/w succinic acid and 4.2% w/w inorganics. Corrected yield was therefore 736 g/48% theory yield/74% w/w yield.

1. temperaturewarmed to 20° C.
2. stirringstirred for a further 15 minutes at this temperature
3. aliquotsampled for completion by HPLC
4. customReaction
5. stirringthe mixture stirred for 5 minutes at 20° C
6. temperaturethe contents warmed to 65° C.
7. stirringstirred for a further 2 hours
8. aliquotsampled for completion by HPLC
9. customReaction
10. stirringthe contents stirred for a further 15 minutes
11. temperatureThe suspension was cooled to 25° C.
12. filtrationfiltered
13. washthe inorganic solids washed with 2-methyltetrahydrofuran (2 L, 2 vol)
14. stirringThe biphase was stirred for 5 minutes
15. customseparated
16. extractionThe aqueous phase was back-extracted with 2-methyltetrahydrofuran (5 L, 5 vol)
17. concentrationThe combined organic phases were concentrated by atmospheric distillation to 5 L/5 vol. Toluene (10 L, 10 vol)
18. additionwas added
19. concentrationthe mixture was concentrated by atmospheric distillation to 5 L/5 vol
20. temperaturecooled to 60° C
21. customCrystallisation
22. additionwas observed towards the end of the addition
23. waitThe slurry was aged at 60° C. for 1 hour
24. temperaturecooled to 0° C. over 4 hours
25. stirringstirred at this temperature for 10 hours 45 minutes
26. filtrationSolids were collected by vacuum filtration
27. washwashed
28. temperaturewith chilled (5° C.) toluene/propan-2-ol (2×2.5 L, 2:1 v/v, 2×2.5 vol)
29. customdried in vacuo at 50° C. for 5 hours