反应详情

温度

62 °C

At room temperature, 2.75 N HCl (7.7 L) was added to a solution of crude ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.1 kg) in EtOH (3.85 L). The mixture was heated for 10 hrs to 60-64° C. Next, the mixture was cooled to 50-54° C. and methanol was removed by vacuum distillation. The mixture was cooled to 20-25° C. and the pH was adjusted to 8.0 to 8.5 by addition of 30% sodium carbonate solution (8.5 L). The phases were separated and the aqueous layer was washed three times with DCM (4 L). Next, charcoal (0.7 kg) was charged to the aqueous layer and the layer was filtered through a celite bed. To the filtrate was added 1.5 N HCl until the pH had reached 2.0. The resulted slurry was stirred for 20 min at room temperature. The solids were filtered off, washed with water (15 L) and dried under vacuum at 50-55° C. until the loss on drying was less than 5 wt %. The crude product was suspended in ethyl acetate (5 L) and slurried for 15 min at 40° C. After cooling to room temperature, the solids were filtered off, washed with ethyl acetate (1 L) and dried at 40-45° C. under vacuum for 10 hrs to yield 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.76 kg; 58% yield for Steps 6 and 7).

1. temperatureNext, the mixture was cooled to 50-54° C.
2. custommethanol was removed by vacuum distillation
3. temperatureThe mixture was cooled to 20-25° C.
4. additionthe pH was adjusted to 8.0 to 8.5 by addition of 30% sodium carbonate solution (8.5 L)
5. customThe phases were separated
6. washthe aqueous layer was washed three times with DCM (4 L)
7. additionNext, charcoal (0.7 kg) was charged to the aqueous layer
8. filtrationthe layer was filtered through a celite bed
9. additionTo the filtrate was added 1.5 N HCl until the pH
10. filtrationThe solids were filtered off
11. washwashed with water (15 L)
12. customdried under vacuum at 50-55° C. until the loss
13. customon drying
14. waitslurried for 15 min at 40° C
15. temperatureAfter cooling to room temperature
16. filtrationthe solids were filtered off
17. washwashed with ethyl acetate (1 L)
18. customdried at 40-45° C. under vacuum for 10 hrs