反应详情

温度

80 °C

A 450-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.105 g, 0.115 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.133 g, 0.275 mmol) and milled potassium phosphate tribasic (5.35 g, 25.2 mmol). The flask was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (70 mL) was taken in a 100-mL round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 450-mL reactor using a cannula under argon atmosphere. The contents of the 450-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 250-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 (16.0 g, 22.9 mmol), methanesulfonamide (2.61 g, 27.5 mmol) and 2-methyltetrahydrofuran (155 mL), purged with argon for not less than 60 minutes. This solution was transferred to the 450-mL reactor that has been cooled to the room temperature using a cannula under argon atmosphere. The temperature of the 450-mL flask was raised to 90° C. and the contents were stirred for 14 hours. The reaction mixture was allowed to cool down to 70° C., diluted with ethyl acetate (190 mL) and stirred for 3 hours at 70° C., cooled to the room temperature, stirred for an additional 4 hours, filtered through a fine frit filter funnel and rinsed with ethyl acetate (90 mL) to obtain 29.4 g of light brown solid. A portion of this solid (13.04 g) was transferred to a 500-mL, 3-neck round bottom flask equipped with an overhead stirrer and a thermocouple. Tetrahydrofuran (175 mL) was added, followed by the addition of water 50 mL containing L-cysteine (0.63 g) and sodium chloride (5.5 g). The reaction mixture was stirred for 2 hours at 50° C. under a slight positive pressure of argon. The reaction mixture was transferred to a 500-mL separatory funnel and the aqueous layer was discarded. The organic layer was filtered through an approximately 2-inch pad of diatomaceous earth and rinsed with tetrahydrofuran (45 mL) to obtain a clear, light yellow solution. The organic layer was concentrated to a total weight of 45.59 g. A portion of this organic solution (41.58 g) was charged to a 250-mL, 3-neck round bottom flask fitted with an overhead stirrer. Ethyl acetate (80 mL) was added over 6 hours by a pump with constant stirring at room temperature. The product was collected by filtration, rinsed with ethyl acetate (20 mL) and dried in a vacuum oven for 2 hours to obtain 3.17 g of the title compound (>99.8 pure and 94.6% potent vs. standard).

1. customThe flask was purged with argon for not less than 90 minutes
2. custom2-Methyltetrahydrofuran (70 mL) was taken in a 100-mL round bottom flask
3. custompurged with argon for not less than 30 minutes
4. customA 250-mL, round bottom flask equipped with a magnetic stir bar
5. custompurged with argon for not less than 60 minutes
6. temperaturehas been cooled to the room temperature
7. temperatureThe temperature of the 450-mL flask was raised to 90° C.
8. stirringthe contents were stirred for 14 hours
9. temperatureto cool down to 70° C.
10. additiondiluted with ethyl acetate (190 mL)
11. stirringstirred for 3 hours at 70° C.
12. temperaturecooled to the room temperature
13. stirringstirred for an additional 4 hours
14. filtrationfiltered through a fine frit
15. filtrationfilter funnel
16. washrinsed with ethyl acetate (90 mL)
17. customto obtain 29.4 g of light brown solid
18. customequipped with an overhead stirrer
19. stirringThe reaction mixture was stirred for 2 hours at 50° C. under a slight positive pressure of argon
20. customThe reaction mixture was transferred to a 500-mL separatory funnel
21. filtrationThe organic layer was filtered through an approximately 2-inch pad of diatomaceous earth
22. washrinsed with tetrahydrofuran (45 mL)
23. customto obtain a clear, light yellow solution
24. concentrationThe organic layer was concentrated to a total weight of 45.59 g
25. additionA portion of this organic solution (41.58 g) was charged to a 250-mL, 3-neck round bottom flask
26. customfitted with an overhead stirrer
27. additionEthyl acetate (80 mL) was added over 6 hours by a pump
28. stirringwith constant stirring at room temperature
29. filtrationThe product was collected by filtration
30. washrinsed with ethyl acetate (20 mL)
31. customdried in a vacuum oven for 2 hours