反应详情

To a flask containing 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (2.6 kg, 6.6 mol) and N,N′-carbonyldiimidazole (1.1 kg, 6.8 mol) under nitrogen atmosphere, was added 12 L of dry acetonitrile. After stirring at 22°±5° C. for about 90 minutes, a solution of (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in toluene was added (8.5 L total volume, about 8 moles of amine). The solution was stirred for at least 6 hours at 22°±5 C. Aqueous hydrochloric acid (9 L, 1.5 molar) was added, and after stirring for about 5 minutes, the layers were separated. Aqueous hydrochloric acid (9 L, 1.5 molar) was added to the remaining top layer, and after stirring for about 20 hours, the layers were separated. The remaining top layer was concentrated by vacuum distillation, and then diluted with 15 L toluene and 2 L ethanol. The mixture was warmed to 35–45° C. and diluted with 20 L warm water, then cooled to 0–5° C. The product was collected by filtration and washed with 2 L toluene. The product was recrystallized by dissolving in 12 L toluene and 2 L ethanol (50°±5 C), adding 10 L water and cooling to 0–5° C. After collecting the product by filtration and washing with toluene, the product was dried in a vacuum oven resulting in 2.6 kg of N-[(R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

1. stirringThe solution was stirred for at least 6 hours at 22°±5 C
2. stirringafter stirring for about 5 minutes
3. customthe layers were separated
4. additionAqueous hydrochloric acid (9 L, 1.5 molar) was added to the remaining top layer
5. stirringafter stirring for about 20 hours
6. customthe layers were separated
7. concentrationThe remaining top layer was concentrated by vacuum distillation
8. additiondiluted with 15 L toluene and 2 L ethanol
9. temperatureThe mixture was warmed to 35–45° C.
10. additiondiluted with 20 L
11. temperaturewarm water
12. temperaturecooled to 0–5° C
13. filtrationThe product was collected by filtration
14. washwashed with 2 L toluene
15. customThe product was recrystallized
16. dissolutionby dissolving in 12 L toluene
17. addition2 L ethanol (50°±5 C), adding 10 L water
18. temperaturecooling to 0–5° C
19. customAfter collecting the product
20. filtrationby filtration
21. washwashing with toluene
22. customthe product was dried in a vacuum oven
23. customresulting in 2.6 kg of N-[(R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide