反应详情

温度

92.5 °C

To a 100-mL three-neck round bottom flask equipped with an overhead stirrer, thermocouple, and condenser with gas inlet for nitrogen, was charged with KOt-Bu (95%, 8.3 g, 70.40 mmol, 4.0 eq) and 2-methyltetrahydrofuran (36 mL) followed by morpholine (18.5 mL, 210.6 mmol, 12.0 eq). The mixture was heated to 90-95° C. and then a solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (4.46 g, 210.6 mmol) in 2-methyltetrahydrofuran (9 mL) was added dropwise via a syringe pump over a period of one hour. Following addition of the amine, the transfer vessel was rinsed with 2-methyltetrahydrofuran (5 mL). The rinse was added to the reaction mixture, which was stirred at reflux for one hour. HPLC analysis indicated the reaction was complete. The slurry was then cooled to 60° C. and water (15 mL) was added, which dissolved the solids. The organic and aqueous phases were separated at 40-50° C. The aqueous phase was extracted with 2-methyltetrahydrofuran (20 mL) at 50° C. The organic layers were combined and concentrated under reduced pressure to afford crude product (9.0 g) which contained residual morpholine. The crude product was heated in hot toluene (30 mL). Some undissolved solids remained and the hot solution was decanted into a clean receiver. The toluene solution was cooled, resulting in crystallization of solids. The solution was further cooled in a refrigerator at 2-8° C. for one hour. The solids were filtered, washed with toluene (10 mL), and dried to afford the title compound as a tan solid (2.85 g).

1. customTo a 100-mL three-neck round bottom flask equipped with an overhead stirrer
2. washthe transfer vessel was rinsed with 2-methyltetrahydrofuran (5 mL)
3. additionThe rinse was added to the reaction mixture, which
4. temperatureat reflux for one hour
5. temperatureThe slurry was then cooled to 60° C.
6. additionwater (15 mL) was added
7. dissolutionwhich dissolved the solids
8. customThe organic and aqueous phases were separated at 40-50° C
9. extractionThe aqueous phase was extracted with 2-methyltetrahydrofuran (20 mL) at 50° C
10. concentrationconcentrated under reduced pressure
11. customto afford crude product (9.0 g) which
12. customthe hot solution was decanted into a clean receiver
13. temperatureThe toluene solution was cooled
14. customresulting in crystallization of solids
15. temperatureThe solution was further cooled in a refrigerator at 2-8° C. for one hour
16. filtrationThe solids were filtered
17. washwashed with toluene (10 mL)
18. customdried