Реакция #80682

Уравнение реакции

3,4-Pyridine dicarboxylic acid anhydride

AlCl3

4-(2',5'-difluorobenzoyl)nicotinic acid

1,4-difluorobenzene

→

3-(2',5'-difluorobenzoyl)isonicotinic acid

Выход 84.0%

Растворители

nitrobenzene

Условия реакции

Обработка

1. 1
   workup.ADDITIONseparately, added in five portions (one every 15')
2. 2
   workup.ADDITIONAfter about 1 hour from the last addition
3. 3
   Другоеthe majority of the 1,4-difluorobenzene was removed by distillation at normal pressure until a thick mass
4. 4
   Другоеwas obtained
5. 5
   Другоеwas lowered to 80° C.
6. 6
   workup.DISSOLUTIONto dissolve the residual mass
7. 7
   ДругоеWhile still hot, the resulting solution was cautiously quenched into ice-
8. 8
   Температураcooled
9. 9
   workup.ADDITIONThen concentrated HCl (37%, 160 mL) was added to the poured mixture at 0°-5° C.
10. 10
    workup.STIRRINGstirring
11. 11
    ФильтрацияA greasy beige precipitate (about 150 g wet) was collected by filtration while the aqueous layer
12. 12
    Другоеwas separated from nitrobenzene
13. 13
    Экстракцияextracted with AcOEt (6×500 mL)
14. 14
    workup.ADDITIONNitrobenzene layer was diluted with petroleum ether (400 mL)
15. 15
    Фильтрацияthe resulting little amount of precipitate was collected by filtration (about 2 g)
16. 16
    КонцентрированиеCombined extracts were concentrated under vacuum
17. 17
    Другоеthe residual crude solid (about 45 g), together with the previously collected
18. 18
    Другоеprecipitates
19. 19
    workup.ADDITIONwas suspended into a mixture of AcOEt/petroleum ether (1/1) (600 mL)
20. 20
    ФильтрацияAfter about 2 hours at room temperature the suspension was filtered
21. 21
    Другоеdried in vacuum
22. 22
    Другоеto give

Методика

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.

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