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 (6x500 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 (6x500 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