تفاعل #86686

معادلة التفاعل

7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane

potassium phosphate tribasic

N-Acetyl-L-cysteine

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

methanesulfonamide

→

title compound

N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

المذيبات

acetic acid

dimethylformamide

ethyl acetate

ظروف التفاعل

المعالجة

1. 1
   workup.ADDITIONwere charged to the 600-mL reactor
2. 2
   أخرىThe reactor was purged with argon for not less than 90 minutes
3. 3
   أخرى2-Methyltetrahydrofuran (100 mL) was purged with argon for not less than 30 minutes
4. 4
   أخرىThe reactor was tightly sealed
5. 5
   أخرىA 500-mL round bottom flask equipped with a magnetic stir bar
6. 6
   أخرىpurged with argon for not less than 30 minutes
7. 7
   workup.STIRRINGwith stirring
8. 8
   درجة الحرارةheated to 60° C
9. 9
   أخرىThe reactor was tightly sealed
10. 10
    درجة الحرارةthe contents were heated to 90° C.
11. 11
    workup.STIRRINGstirred at this temperature for 14 hours
12. 12
    درجة الحرارةThe reaction mixture was cooled to 35° C.
13. 13
    workup.ADDITION5% aqueous N-acetyl-L-cysteine solution (100 mL) was added
14. 14
    workup.ADDITIONthe contents were mixed for 1 hour at 35° C
15. 15
    ترشيحSolids were collected by filtration
16. 16
    غسيلwashed with water (2×25 mL) and ethyl acetate (3×80 mL)
17. 17
    أخرىwere dried under high vacuum for 2-4 hours
18. 18
    أخرىequipped with an overhead stirrer
19. 19
    درجة الحرارةthe contents were heated to 60° C.
20. 20
    workup.ADDITIONmixed for 1 hour
21. 21
    ترشيحThe mixture was filtered through an approximately 2-inch pad of diatomaceous earth
22. 22
    غسيلwashed with DMF (50 mL)
23. 23
    أخرىThe dark-brown/black-colored solid collected on the diatomaceous earth
24. 24
    workup.ADDITIONthe light yellow/clear filtrate was charged to a separate 1-L, three-neck, round-bottom flask
25. 25
    أخرىequipped with an overhead stirrer
26. 26
    workup.ADDITIONThe DMF solution was mixed
27. 27
    workup.ADDITIONmethanol (300 mL) was added over 8 hours
28. 28
    درجة الحرارةwhile maintaining the internal temperature at 25±5° C
29. 29
    ترشيحThe white solid was collected by filtration
30. 30
    غسيلwashed with methanol (150 mL)
31. 31
    أخرىdried in a vacuum oven at 50° C. for not less than 8 hours

الإجراء التجريبي

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).

المصدر