反应详情

温度

82.5 °C

Under a N2 atmosphere add phosphoryl chloride (124 g, 819 mmol) to a mixture of 7-chloro-2-methyl-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (100 g, 405 mmol), N,N-dimethylaniline (138 g, 1.14 mol) and anisole (550 mL). Heat to 80-85° C. and stir for 4 hr. to 6 hr. Concentrate to a total of 1.5 volumes to 2.5 volumes while maintaining the temperature below 75° C. Cool to 15-25° C. Add dichloromethane (600 mL) dropwise and stir for 1 hr. Add the resulting mixture to water (600 mL) while maintaining the temperature between 10° C. and 35° C. Stir for 1 hr. and then separate the layers. Extract the aqueous layer with dichloromethane (600 mL). Wash the combined organic layers with 1.0 N HCl (600 g) followed by 7% NaHCO3 (600 g). Filter the organic layer through diatomite (20 g to 30 g) and silica gel (60 g to 100 g). Concentrate the resulting filtrate to a total of 1.5 volumes to 2.5 volumes while maintaining the temperature below 45° C. Add heptane (270 g to 410 g) and concentrate the resulting filtrate to a total of 1.5 volumes to 2.5 volumes while maintaining the temperature below 45° C. Add heptane (150 g to 210 g), cool to 5° C. to 10° C., and stir for 2 hr. to 3 hr. Filter, rinse the filter the cake with heptane, and dry under vacuum, at below 45° C., to obtain the title compound as a pale yellow solid (90% to 95% yield)

1. waitto 6 hr
2. concentrationConcentrate to a total of 1.5 volumes to 2.5 volumes
3. temperaturewhile maintaining the temperature below 75° C
4. temperatureCool to 15-25° C
5. stirringAdd dichloromethane (600 mL) dropwise and stir for 1 hr
6. additionAdd the resulting mixture to water (600 mL)
7. temperaturewhile maintaining the temperature between 10° C. and 35° C
8. stirringStir for 1 hr
9. customand then separate the layers
10. extractionExtract the aqueous layer with dichloromethane (600 mL)
11. washWash the combined organic layers with 1.0 N HCl (600 g)
12. filtrationFilter the organic layer through diatomite (20 g to 30 g) and silica gel (60 g to 100 g)
13. concentrationConcentrate the resulting filtrate to a total of 1.5 volumes to 2.5 volumes
14. temperaturewhile maintaining the temperature below 45° C
15. concentrationAdd heptane (270 g to 410 g) and concentrate the resulting filtrate to a total of 1.5 volumes to 2.5 volumes
16. temperaturewhile maintaining the temperature below 45° C
17. temperatureAdd heptane (150 g to 210 g), cool to 5° C. to 10° C.
18. stirringstir for 2 hr
19. waitto 3 hr
20. filtrationFilter
21. washrinse the
22. filtrationfilter the cake with heptane
23. customdry under vacuum, at below 45° C.