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), 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (0.238 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., 5% aqueous N-acetyl-L-cysteine solution (100 mL) was added and the contents were mixed for 1 hour at 35° C. Solids were collected by filtration, washed with water (2×25 mL) and ethyl acetate (3×80 mL) and were 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 an approximately 2-inch pad of diatomaceous earth and washed with DMF (50 mL). The dark-brown/black-colored solid collected on the 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 (15.6 g, 88% 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. addition5% aqueous N-acetyl-L-cysteine solution (100 mL) was added
14. additionthe contents were mixed for 1 hour at 35° C
15. filtrationSolids were collected by filtration
16. washwashed with water (2×25 mL) and ethyl acetate (3×80 mL)
17. customwere dried under high vacuum for 2-4 hours
18. customequipped with an overhead stirrer
19. temperaturethe contents were heated to 60° C.
20. additionmixed for 1 hour
21. filtrationThe mixture was filtered through an approximately 2-inch pad of diatomaceous earth
22. washwashed with DMF (50 mL)
23. customThe dark-brown/black-colored solid collected on the diatomaceous earth
24. additionthe light yellow/clear filtrate was charged to a separate 1-L, three-neck, round-bottom flask
25. customequipped with an overhead stirrer
26. additionThe DMF solution was mixed
27. additionmethanol (300 mL) was added over 8 hours
28. temperaturewhile maintaining the internal temperature at 25±5° C
29. filtrationThe white solid was collected by filtration
30. washwashed with methanol (150 mL)
31. customdried in a vacuum oven at 50° C. for not less than 8 hours