反应详情

温度

80 °C

A 600-mL, stainless steel, Parr® reactor was equipped with an overhead stirrer, thermocouple and a heating mantle. Tris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.179 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.208 g, 0.429 mmol) and milled potassium phosphate tribasic (8.36 g, 39.4 mmol) were charged to the 600-mL reactor. The reactor was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (100 mL) was purged with argon for not less than 30 minutes and was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 80° C. and stirred at this temperature for 30 minutes. A 500-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (25 g, 35.8 mmol), methanesulfonamide (4.09 g, 42.9 mmol) and ethyl acetate (200 mL), purged with argon for not less than 30 minutes with stirring and heated to 60° C. A clear solution was observed. This solution was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 90° C. and stirred at this temperature for 14 hours. The reaction mixture was cooled to 35° C., solids were collected by filtration, washed with ethyl acetate (300 mL) and dried under high vacuum for 2-4 hours. The solids were then transferred to a 1-L, three-neck, round-bottom flask equipped with an overhead stirrer and a thermocouple. N-Acetyl-L-cysteine (0.58 g, 3.5 mmol), dimethylformamide (DMF) (100 mL) and glacial acetic acid (0.85 g) were charged to the 1-L flask; the contents were heated to 60° C. and mixed for 1 hour. The mixture was filtered through approximately 2-inch pad of diatomaceous earth and washed with DMF (50 mL). The dark-brown/black-colored solid collected on diatomaceous earth was discarded and the light yellow/clear filtrate was charged to a separate 1-L, three-neck, round-bottom flask equipped with an overhead stirrer, a thermocouple and a syringe pump. The DMF solution was mixed and methanol (300 mL) was added over 8 hours, while maintaining the internal temperature at 25±5° C. The white solid was collected by filtration washed with methanol (150 mL) and dried in a vacuum oven at 50° C. for not less than 8 hours. The title compound was isolated as a white solid (15.8 g, 89% yield).

1. additionwere charged to the 600-mL reactor
2. customThe reactor was purged with argon for not less than 90 minutes
3. custom2-Methyltetrahydrofuran (100 mL) was purged with argon for not less than 30 minutes
4. customThe reactor was tightly sealed
5. customA 500-mL round bottom flask equipped with a magnetic stir bar
6. custompurged with argon for not less than 30 minutes
7. stirringwith stirring
8. temperatureheated to 60° C
9. customThe reactor was tightly sealed
10. temperaturethe contents were heated to 90° C.
11. stirringstirred at this temperature for 14 hours
12. temperatureThe reaction mixture was cooled to 35° C.
13. filtrationsolids were collected by filtration
14. washwashed with ethyl acetate (300 mL)
15. customdried under high vacuum for 2-4 hours
16. customequipped with an overhead stirrer
17. temperaturethe contents were heated to 60° C.
18. additionmixed for 1 hour
19. filtrationThe mixture was filtered through approximately 2-inch pad of diatomaceous earth
20. washwashed with DMF (50 mL)
21. customThe dark-brown/black-colored solid collected on diatomaceous earth
22. additionthe light yellow/clear filtrate was charged to a separate 1-L, three-neck, round-bottom flask
23. customequipped with an overhead stirrer
24. additionThe DMF solution was mixed
25. additionmethanol (300 mL) was added over 8 hours
26. temperaturewhile maintaining the internal temperature at 25±5° C
27. filtrationThe white solid was collected by filtration
28. washwashed with methanol (150 mL)
29. customdried in a vacuum oven at 50° C. for not less than 8 hours