反应详情

温度

25 °C

To formic acid (116.5 Kg), add tert-butyl 6-(4-{[3-(2,6-dichlorophenyl)-5-cyclopropylisoxazol-4-yl]methoxy}piperidyl)-1-methylindole-3-carboxylate (19.102 Kg, 34.45 mol) under a nitrogen atmosphere. Stir the mixture at 20-30° C. for 24-72 hours. Follow by HPLC until no starting material is observed. Add water (286.5 Kg) and stir for at least 1 hour. Add water (133.7 Kg) and stir for at least 30 minutes, repeat with a further addition of water (133.7 Kg) with stirring for at least 30 minutes. Collect the solids by filtration and rinse the filter cake with water (3×30 Kg). Add the wet solids to methanol (75.5 Kg) and stir the suspension for at least 12 hours. Cool the suspension to 0-5° C. and stir for at least 1 hour. Collect the solids by filtration. Wash the solids with a solution of methanol (9.1 Kg) and water (1.1 Kg) cooled to 0-5° C. and repeat. Dry solids at 50-55° C. for 12-72 hours under vacuum. Add the solids to formic acid (28.5 Kg) and water (2.3 Kg) and stir for 10-20 minutes. Filter the mixture. Add water (49.7 Kg) and stir for 30-60 minutes. Add water (2×36.6 Kg) and stir for at least 30 minutes. Collect solids by filtration and rinse with water (3×15.9 Kg). Add collected solids to methanol (58.2 Kg). Stir for at least 12 hours, cool to 0-5° C. and stir for at least 1 hour. Collect solids by filtration. Wash solids with a solution of methanol (8.1 Kg) and water (1.1 Kg) cooled to 0-5° C., repeat once. Add the collected solids to a solution of methanol (115.6 Kg) and water (14.6 Kg). Heat the suspension to reflux for 2-3 hours, cool to 0-5° C. and stir 1 hour. Collect the solids by filtration. Wash the solids with a solution of methanol (17.3 Kg) and water (2.2 Kg) cooled to 0-5° C., repeat once. Dry collected solids at 60-65° C. for 12-72 hours under vacuum to give 13.584 Kg (73%) of the title compound.

1. stirringwith stirring for at least 30 minutes
2. customCollect the solids
3. filtrationby filtration
4. washrinse the filter cake with water (3×30 Kg)
5. additionAdd the wet solids to methanol (75.5 Kg)
6. stirringstir the suspension for at least 12 hours
7. temperatureCool the suspension to 0-5° C.
8. stirringstir for at least 1 hour
9. customCollect the solids
10. filtrationby filtration
11. washWash the solids with a solution of methanol (9.1 Kg) and water (1.1 Kg)
12. temperaturecooled to 0-5° C.
13. customDry solids at 50-55° C. for 12-72 hours under vacuum
14. additionAdd the solids to formic acid (28.5 Kg) and water (2.3 Kg)
15. stirringstir for 10-20 minutes
16. filtrationFilter the mixture
17. stirringAdd water (49.7 Kg) and stir for 30-60 minutes
18. stirringAdd water (2×36.6 Kg) and stir for at least 30 minutes
19. customCollect solids
20. filtrationby filtration
21. washrinse with water (3×15.9 Kg)
22. additionAdd
23. customcollected solids to methanol (58.2 Kg)
24. stirringStir for at least 12 hours
25. temperaturecool to 0-5° C.
26. stirringstir for at least 1 hour
27. customCollect solids
28. filtrationby filtration
29. washWash solids with a solution of methanol (8.1 Kg) and water (1.1 Kg)
30. temperaturecooled to 0-5° C.
31. additionAdd the collected solids to a solution of methanol (115.6 Kg) and water (14.6 Kg)
32. temperatureHeat the suspension
33. temperatureto reflux for 2-3 hours
34. temperaturecool to 0-5° C.
35. stirringstir 1 hour
36. customCollect the solids
37. filtrationby filtration
38. washWash the solids with a solution of methanol (17.3 Kg) and water (2.2 Kg)
39. temperaturecooled to 0-5° C.
40. customDry
41. customcollected solids at 60-65° C. for 12-72 hours under vacuum