反应详情

25 g 3,5-difluoroisonicotinic acid (157.141 mmol, 1 eq.) and 37,245 g 2-fluoro-4-iodoaniline (157.141 mmol. 1 eq.) were dissolved in 1275.5 mL of dry THF and put under a nitrogen atmosphere. The mixture was cooled with an ice bath to +3° C., upon which 471.422 mL lithium hexamethyldisilazide (LiHMDS) solution (1M in THF; 471.422 mmol, 3. eq.) were added slowly. Upon completion of addition of the base, the reaction mixtures was allowed to warm to rt and stirring was continued for 18 h. The reaction mixture was concentrated in Vacuo and then partitioned between aq. sodium hydroxide solution (2N, 800 ml) and dichloromethane. The separated organic phase was washed twice with sodium hydroxide solution (2N, 300 ml each). The combined aqueouse layers were cooled to 0° C. and treated with HCl (conc., 222 ml) until ph=2 was reached. The resulting yellow suspension was stirred for 18 h at room temperature and then the precipitate was filtered off to yield 5.15 g (13.01 mmol, 8%) of the analytically pure target compound as a tanish solid. The organic filtrate formed a suspension as well. This precipitate was filtered off as well and rinsed twice with dichloromethane. The precipitate was suspended in water (400 ml), cooled to 0° C. and treated with HCl (conc., 20 ml) until ph=1 was reached. The resulting yellow suspension was stirred for 18 h at room temperature and then the precipitate was filtered off to yield 28.27 g (71.41 mmol, 45%) of the analytically pure target compound as a yellowish solid.

1. additionwere added slowly
2. additionUpon completion of addition of the base
3. customthe reaction mixtures
4. concentrationThe reaction mixture was concentrated in Vacuo
5. custompartitioned between aq. sodium hydroxide solution (2N, 800 ml) and dichloromethane
6. washThe separated organic phase was washed twice with sodium hydroxide solution (2N, 300 ml each)
7. temperatureThe combined aqueouse layers were cooled to 0° C.
8. additiontreated with HCl (conc., 222 ml) until ph=2
9. stirringThe resulting yellow suspension was stirred for 18 h at room temperature
10. filtrationthe precipitate was filtered off
11. customto yield 5.15 g (13.01 mmol, 8%) of the analytically pure target compound as a tanish solid
12. customThe organic filtrate formed a suspension as well
13. filtrationThis precipitate was filtered off as well and
14. washrinsed twice with dichloromethane
15. temperaturecooled to 0° C.
16. additiontreated with HCl (conc., 20 ml) until ph=1
17. stirringThe resulting yellow suspension was stirred for 18 h at room temperature
18. filtrationthe precipitate was filtered off
19. customto yield 28.27 g (71.41 mmol, 45%) of the analytically pure target compound as a yellowish solid