反应详情

Heat a mixture of 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (10.0 g, 37.7 mmol), methyl 2,2-dimethyl-3-(piperazin-1-yl)-propionate dihydrochloride (19.4 g, 71.0 mmol), diisopropylamine (22.9 g, 226 mmol), and acetonitrile (80 g) at 80° C. to 85° C. for 22 hr. to 26 hr. Cool to 30° C. to 40° C. and add ethyl acetate (80 g). Add water (80 g) dropwise. Stir 40 min. to 60 min. and separate the layers. Extract the aqueous layer with ethyl acetate (60 g to 80 g). Wash the combined organic layers with 25% aqueous sodium chloride (2×40 g). Concentrate the organic layer to a total of 1.5 volumes and 3.5 volumes while maintaining the temperature below 50° C. Add heptane (41 g to 55 g) at 40° C. to 50° C.)\ and stir for 2 hr. to 3 hr. Concentrate to a total of 1.5 volumes to 3.0 volumes while maintaining the temperature below 50° C. Cool to 0° C. to 10° C. and stir for 2 hr. to 3 hr. Filter, wash the filtercake with heptane (3.0 g to 10.0 g), and dry under vacuum, at below 60° C., to afford the title compound (16.0 g, 94.7% w/w % assay, 94% yield) as a light, yellow solid.

1. temperatureHeat
2. temperatureCool to 30° C. to 40° C.
3. customseparate the layers
4. extractionExtract the aqueous layer with ethyl acetate (60 g to 80 g)
5. washWash the combined organic layers with 25% aqueous sodium chloride (2×40 g)
6. concentrationConcentrate the organic layer to a total of 1.5 volumes and 3.5 volumes
7. temperaturewhile maintaining the temperature below 50° C
8. stirringAdd heptane (41 g to 55 g) at 40° C. to 50° C.)\ and stir for 2 hr
9. waitto 3 hr
10. concentrationConcentrate to a total of 1.5 volumes to 3.0 volumes
11. temperaturewhile maintaining the temperature below 50° C
12. temperatureCool to 0° C. to 10° C.
13. stirringstir for 2 hr
14. waitto 3 hr
15. filtrationFilter
16. washwash the filtercake with heptane (3.0 g to 10.0 g)
17. customdry under vacuum, at below 60° C.