反应详情

温度

22.5 °C

Add 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[(piperidin-4-yloxy)methyl] isoxazole hydrochloride (15.609 Kg, 38.66 mol) to toluene (229.5 Kg) under a nitrogen atmosphere. Add tert-butyl 6-iodo-1-methylindole-3-carboxylate (18.0 Kg, 50.39 mol) and sodium tert-butoxide (9.3 Kg, 96.76 mol) and heat to 55-60° C. for at least 1 hour. Add 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (304 g, 0.77 mol) and tris(dibenzylidene acetone)dipalladium, Pd2 dba3, (354 g, 0.39 mol) and heat the mixture to 55-60° C. Do not allow temperature to go above 65° C. Follow by TLC until no starting material (5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[(piperidin-4-yloxy)methyl] isoxazole hydrochloride is observed). Discontinue heating, add water (31.2 Kg) and cool mixture to 15-30° C. Separate the layers and filter the aqueous layer and emulsion through diatomaceous earth. Wash the filter cake with toluene (2×5.4 Kg) and combine the washes with the aqueous filtrate. Stir for 10 minutes and separate the layers. Combine the organic layer with the original organic layer. Re-extract the aqueous layer with toluene (13.5 Kg). Combine organics and wash with brine (2×30.3 Kg) and separate the layers. Add magnesium sulfate (5.0 Kg) and charcoal (800 g) to the organic layer and stir for 20 minutes. Filter the mixture. Rinse filter cake with toluene (5.4 Kg) and combine the organics. Add silica gel (7.0 Kg), and stir for 20-30 minutes. Add thiol derivatized silica gel (6.2 Kg) and stir for at least 15 hours. Filter solids. Wash the filter cake with toluene (2×10.8 Kg) and combine washes with filtrate. Concentrate washes at 50-55° C. to lowest stirrable volume. Cool to 15-30° C. and add heptane (22.3 Kg) in a thin stream. Stir for 30-60 minutes. Add heptane (21.3 Kg) in a thin stream and stir for at least 1 hour. Cool to 0-5° C. and stir for 1-2 hours. Collect solids by filtration. Wash the filter cake with heptane (2×4.2 kg) cooled to 0-5° C. Dry the solids at 50-55° C. for 12-72 hours under vacuum. Add the dry solids to toluene (45.7 Kg) and heat until a clear solution is obtained. Cool to 15-30° C. and add heptane (36.2 Kg). Stir for 30-90 minutes at room temperature. Add heptane (18.1 Kg) and stir 30-90 minutes. Repeat the addition of heptane (18.1 Kg) and stir for 1-2 hours. Cool the suspension to 0-5° C. and stir for 30-90 minutes. Collect the solids by filtration. Wash the filter cake with heptane (2×9.0 kg) cooled to 0-5° C. Dry the solids at 50-55° C. for 12-72 hours under vacuum. Add the dry solids to methanol (118.6 Kg) and heat the suspension to reflux for 30-60 minutes. Cool the suspension to 0-5° C. and stir for 30-60 minutes. Collect the solids by filtration. Wash the filter cake with methanol (16.9 kg) cooled to 0-5° C. Dry the solids at 45-50° C. for 12-72 hours under vacuum to give 19.102 Kg (89%) of the title compound.

1. customto go above 65° C
2. temperatureDiscontinue heating
3. customSeparate the layers
4. filtrationfilter the aqueous layer and emulsion through diatomaceous earth
5. washWash the filter cake with toluene (2×5.4 Kg)
6. customseparate the layers
7. washCombine organics and wash with brine (2×30.3 Kg)
8. customseparate the layers
9. stirringAdd magnesium sulfate (5.0 Kg) and charcoal (800 g) to the organic layer and stir for 20 minutes
10. filtrationFilter the mixture
11. washRinse
12. filtrationfilter cake with toluene (5.4 Kg)
13. stirringAdd silica gel (7.0 Kg), and stir for 20-30 minutes
14. stirringstir for at least 15 hours
15. filtrationFilter solids
16. washWash the filter cake with toluene (2×10.8 Kg)
17. concentrationConcentrate
18. customat 50-55° C.
19. temperatureCool to 15-30° C.
20. additionadd heptane (22.3 Kg) in a thin stream
21. stirringStir for 30-60 minutes
22. stirringAdd heptane (21.3 Kg) in a thin stream and stir for at least 1 hour
23. temperatureCool to 0-5° C.
24. stirringstir for 1-2 hours
25. customCollect solids
26. filtrationby filtration
27. washWash the filter cake with heptane (2×4.2 kg)
28. temperaturecooled to 0-5° C
29. customDry the solids at 50-55° C. for 12-72 hours under vacuum
30. additionAdd the dry solids to toluene (45.7 Kg)
31. temperatureheat until a clear solution
32. customis obtained
33. temperatureCool to 15-30° C.
34. stirringStir for 30-90 minutes at room temperature
35. stirringstir for 1-2 hours
36. temperatureCool the suspension to 0-5° C.
37. stirringstir for 30-90 minutes
38. customCollect the solids
39. filtrationby filtration
40. washWash the filter cake with heptane (2×9.0 kg)
41. temperaturecooled to 0-5° C
42. customDry the solids at 50-55° C. for 12-72 hours under vacuum
43. additionAdd the dry solids to methanol (118.6 Kg)
44. temperatureheat the suspension
45. temperatureto reflux for 30-60 minutes
46. temperatureCool the suspension to 0-5° C.
47. stirringstir for 30-60 minutes
48. customCollect the solids
49. filtrationby filtration
50. washWash the filter cake with methanol (16.9 kg)
51. temperaturecooled to 0-5° C
52. customDry the solids at 45-50° C. for 12-72 hours under vacuum