反应详情

3,4-Pyridine dicarboxylic acid anhydride (95.7 g, 0.67 mol) and AlCl3 (367.3 g, 2.67 mol) were simultaneously, but separately, added in five portions (one every 15') to boiling 1,4-difluorobenzene (650 mL, 90° C.). After about 1 hour from the last addition, the majority of the 1,4-difluorobenzene was removed by distillation at normal pressure until a thick mass was obtained. The temperature was lowered to 80° C. and nitrobenzene (150 mL) was added in order to dissolve the residual mass. While still hot, the resulting solution was cautiously quenched into ice-cooled and stirred water (1000 g of ice and 530 g of demineralized water) (i.e., slowly drop the solution into the ice water). Then concentrated HCl (37%, 160 mL) was added to the poured mixture at 0°-5° C. and stirring was continued for about 3 hours. A greasy beige precipitate (about 150 g wet) was collected by filtration while the aqueous layer was separated from nitrobenzene and extracted with AcOEt (6×500 mL). Nitrobenzene layer was diluted with petroleum ether (400 mL) and the resulting little amount of precipitate was collected by filtration (about 2 g). Combined extracts were concentrated under vacuum, and the residual crude solid (about 45 g), together with the previously collected precipitates, was suspended into a mixture of AcOEt/petroleum ether (1/1) (600 mL). After about 2 hours at room temperature the suspension was filtered and dried in vacuum to give the mixture of 4-(2',5'-difluorobenzoyl)nicotinic acid and 3-(2',5'-difluorobenzoyl)isonicotinic acid (147.3 g, 84% yield) as a pale beige solid.

1. additionseparately, added in five portions (one every 15')
2. additionAfter about 1 hour from the last addition
3. customthe majority of the 1,4-difluorobenzene was removed by distillation at normal pressure until a thick mass
4. customwas obtained
5. customwas lowered to 80° C.
6. dissolutionto dissolve the residual mass
7. customWhile still hot, the resulting solution was cautiously quenched into ice-
8. temperaturecooled
9. additionThen concentrated HCl (37%, 160 mL) was added to the poured mixture at 0°-5° C.
10. stirringstirring
11. filtrationA greasy beige precipitate (about 150 g wet) was collected by filtration while the aqueous layer
12. customwas separated from nitrobenzene
13. extractionextracted with AcOEt (6×500 mL)
14. additionNitrobenzene layer was diluted with petroleum ether (400 mL)
15. filtrationthe resulting little amount of precipitate was collected by filtration (about 2 g)
16. concentrationCombined extracts were concentrated under vacuum
17. customthe residual crude solid (about 45 g), together with the previously collected
18. customprecipitates
19. additionwas suspended into a mixture of AcOEt/petroleum ether (1/1) (600 mL)
20. filtrationAfter about 2 hours at room temperature the suspension was filtered
21. customdried in vacuum
22. customto give