反应详情

温度

-20 °C

Concentrate the ethanolic solution of (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine to dryness prior to use in the coupling reaction. Dissolve 15.0 g (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine and 18.03 g 1-[(4-Chlorobenzoyl)amino]cyclopropanecarboxylic acid in 120 ml of dichloromethane and 32 ml triethylamine. After cooling to −20° C., add 53.0 ml (1.2 eq.) of T3P within 40 minutes maintaining a temperature of −19° C. Allow the reaction to warm to room temperature over night. Test by HPLC for complete consumption of starting materials. After aqueous quench (75 ml of water) at 0 to 6° C. and further dilution with dichloromethane (precipitating solids dissolved after adding additional 180 ml of dichloromethane), separate the phases. Wash the organic layer two times with 75 ml of water and then back-extract the combined aqueous layers once with 75 ml of dichloromethane. Concentrate the organic extract phases (420 ml) removing 290 ml of solvents (beginning precipitation of solids). Add 240 ml of isopropyl acetate and then remove a further 250 ml of solvents. Warm the resulting thick suspension to 70° C., add 30 ml of n-heptane and slowly cool the suspension to room temperature over night. Filter the suspension via glass filter nutsch and wash the filter cake with n-heptane. After drying with a rotavap, results in a pale brown solid, 29.65 g (93.58% yield, HPLC (achiral). LC-MS (mass spectrometry) (m/z): 421.

1. concentrationConcentrate the ethanolic solution of (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine to dryness
2. customto use in the coupling reaction
3. temperaturemaintaining a temperature of −19° C
4. customthe reaction
5. temperatureto warm to room temperature over night
6. customTest by HPLC for complete consumption of starting materials
7. customAfter aqueous quench (75 ml of water) at 0 to 6° C.
8. customfurther dilution with dichloromethane (precipitating solids dissolved after adding additional 180 ml of dichloromethane), separate the phases
9. washWash the organic layer two times with 75 ml of water
10. extractionback-extract the combined aqueous layers once with 75 ml of dichloromethane
11. concentrationConcentrate the organic extract phases (420 ml)
12. customremoving 290 ml of solvents (beginning precipitation of solids)
13. additionAdd 240 ml of isopropyl acetate
14. customremove a further 250 ml of solvents
15. temperatureWarm the resulting thick suspension to 70° C.
16. additionadd 30 ml of n-heptane
17. temperatureslowly cool the suspension to room temperature over night
18. filtrationFilter the suspension via glass
19. filtrationfilter nutsch
20. washwash the filter cake with n-heptane
21. customAfter drying with a rotavap
22. customresults in a pale brown solid, 29.65 g (93.58% yield, HPLC (achiral)