反应详情

温度

85 °C

Bromine (154 g; 0.964 mole; 0.10 eq.) was added to a slurry of zinc (particle size <10 microns; 192 g; 2.940 moles; 0.30 eq.) in DMF (10 L) at room temperature. The resulting mixture was then stirred fast for 30 minutes while 4-(3-bromo-5-chlorophenoxy)-5-chloro-1H-indazole (3.508 kg; 9.798 moles; 1.00 eq., zinc cyanide (690 g; 5.879 moles; 0.60 eq.), triphenylphosphine (308 g; 1.176 moles; 0.12 eq.), palladium acetate (66 g; 0.294 mole; 0.03 eq.) and DMF (11 L) were added at room temperature. The reaction mixture was then degassed for 15 minutes using a subsurface stream of nitrogen, heated to 85° C., and then aged for 4.5 hours. The reaction mixture was then cooled to room temperature and stirred overnight. The reaction mixture was then diluted with THF (18 L) and heated to 50° C., after which aqueous EDTA.3Na (0.5M, 20 L) was added and the mixture aged at 50° C.-60° C. for 1 hour. The mixture was then filtered through solka floc and washed with THF (20 L), and the filtrate transferred to an extractor (100 L) filled with brine (15 L) and separated. The aqueous layer was extracted with EtOAc (15 L), and the combined organic layers were washed with a second portion of EDTA.3Na (0.5M, 20 L), then water (20 L), and then brine (15 L). The solution was treated with activated carbon (Darko KB), filtered through solka floc, concentrated to a slurry of less than 10 L, switched to toluene (6 L), concentrated to half volume, heated to 40° C., added heptane (6 L), and cooled below 25° C. The resulting slurry was filtered, washed with extra toleuene:heptane (1:3; 4 L), heptane (4 L), and dried to provide the title product as a solid.

1. customThe reaction mixture was then degassed for 15 minutes
2. temperatureThe reaction mixture was then cooled to room temperature
3. additionThe reaction mixture was then diluted with THF (18 L)
4. temperatureheated to 50° C.
5. addition3Na (0.5M, 20 L) was added
6. waitthe mixture aged at 50° C.-60° C. for 1 hour
7. filtrationThe mixture was then filtered through solka floc
8. washwashed with THF (20 L)
9. additionfilled with brine (15 L)
10. customseparated
11. extractionThe aqueous layer was extracted with EtOAc (15 L)
12. washthe combined organic layers were washed with a second portion of EDTA
13. additionThe solution was treated with activated carbon (Darko KB)
14. filtrationfiltered through solka floc
15. concentrationconcentrated to a slurry of less than 10 L
16. concentrationconcentrated to half volume
17. temperatureheated to 40° C.
18. additionadded heptane (6 L)
19. temperaturecooled below 25° C
20. filtrationThe resulting slurry was filtered
21. washwashed with extra toleuene
22. dry with materialheptane (1:3; 4 L), heptane (4 L), and dried