反应详情

温度

2.5 °C

Charge (R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile (30 g, 1 eq.) and imidazole-4-carboxaldehyde (7.8 g, 1.1 eq.) into 300 mL of CH2Cl2. Cool the mixture to 0-5° C., add trifluoroacetic acid (30 mL, 5 eq.), and follow with trifluoroacetic acid anhydride (15 mL, 1.5 eq.). Stir the solution at 0-5° C. for 15 min, then add a slurry of Na(OAc)3BH (21 g, 1.3 eq.) in 50 mL of CH2Cl2 while keeping the temperature below 20° C. Remove the ice-bath and stir the mixture at room temperature for 18 h. Cool the mixture to 0-5° C., adjust pH with 10% NaOH to 12.5 (ca. 250 mL used). Stir at room temperature for 30 min. Split the phases, and extract the aqueous phase with 50 mL of CH2Cl2. Wash the combined organic layer with 100 mL of water. Swap the CH2Cl2 to 300 mL of EtOH by distillation at normal pressure. Cool the solution to 20-25° C. over 1 h and stir for 30 min. Filter the slurry and wash the wet cake with 50 mL of EtOH. Transfer the wet cake to a 500-mL 3-neck flask, and add 300 mL of EtOH. Heat to reflux for 10 minutes. Slowly add methanesulfonic acid (4.8 mL). Keep stirring the clear solution at reflux for 30 min. Cool the mixture to room temperature over 1 h and stir at room temperature for 1 h. A slurry forms at 65° C. Filter the slurry and wash the cake with 50 mL of EtOH. Dry the cake at 40° C. in a vacuum oven overnight. The product is obtained as white solid (36.5 g, 84% yield).

1. customthe temperature below 20° C
2. customRemove the ice-bath
3. stirringstir the mixture at room temperature for 18 h
4. temperatureCool the mixture to 0-5° C.
5. stirringStir at room temperature for 30 min
6. customSplit the phases
7. extractionextract the aqueous phase with 50 mL of CH2Cl2
8. washWash the combined organic layer with 100 mL of water
9. distillationby distillation at normal pressure
10. temperatureCool the solution to 20-25° C. over 1 h
11. stirringstir for 30 min
12. filtrationFilter the slurry
13. washwash the wet cake with 50 mL of EtOH
14. additionadd 300 mL of EtOH
15. temperatureHeat
16. temperatureto reflux for 10 minutes
17. stirringKeep stirring the clear solution
18. temperatureat reflux for 30 min
19. temperatureCool the mixture to room temperature over 1 h
20. stirringstir at room temperature for 1 h
21. customat 65° C
22. filtrationFilter the slurry
23. washwash the cake with 50 mL of EtOH
24. customDry the cake at 40° C. in a vacuum oven overnight