反应详情

温度

60 °C

To a 200 liter Hastelloy reactor was added ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate (E/Z mixture, 12 kg), 10% Pd/C (50% wet with H2O; 1.80 kg) and ethyl acetate (108 kg). The suspension was degassed 3× with N2 and triethylamine (1.76 kg) was added. To the resulting mixture was added formic acid (3.34 kg) while maintaining the internal temperature at below 35° C. The reaction progression was followed by HPLC to monitor the complete consumption of starting material (i.e., E/Z mixture of ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate) and the debenzylated intermediate. After approximately 30 minutes an additional amount of formic acid (0.50 kg) was added and the combined peak area of ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate and the related debenzylated intermediate was determined to be <1% area by HPLC. The reactor contents were filtered through a 1.2 μm cartridge filter followed by an in-line 0.2 μm inline polishing filter. To the filtrate was added water (60 kg) and the biphasic mixture was partitioned. The organics were separated and concentrated under vacuum at approximately 60° C.±5° C. to a minimum stir volume, ethyl acetate (21.6 kg) was added and the mixture was further concentrated under vacuum to a minimum stir volume. Once again ethyl acetate (16.8 kg) was charged to the crude mixture and the resulting solution was heated to approximately 60° C. Heptanes (37.2 kg) were charged maintaining the internal temperature at 60° C. The solution was slowly cooled to approximately 0 to 5° C. and approximately 2-3 hr to facilitate crystallization. The slurry was filtered, the filter cake was reslurried in heptanes (27.12 kg) and ethyl acetate (7.08 kg). The resulting suspension was filtered and the solids dried under vacuum at approximately 40±5° C. (until the loss on drying (LOD) is <1%) to afford the title compound (6.23 kg, 70.3% yield) as a solid.

1. customThe suspension was degassed 3× with N2 and triethylamine (1.76 kg)
2. additionwas added
3. additionTo the resulting mixture was added formic acid (3.34 kg)
4. temperaturewhile maintaining the internal temperature at below 35° C
5. customthe complete consumption of starting material (i.e., E/Z mixture of ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate)
6. additionAfter approximately 30 minutes an additional amount of formic acid (0.50 kg) was added
7. filtrationThe reactor contents were filtered through a 1.2 μm cartridge
8. filtrationfilter
9. filtrationfilter
10. additionTo the filtrate was added water (60 kg)
11. customthe biphasic mixture was partitioned
12. customThe organics were separated
13. concentrationconcentrated under vacuum at approximately 60° C.±5° C. to a minimum stir volume, ethyl acetate (21.6 kg)
14. additionwas added
15. concentrationthe mixture was further concentrated under vacuum to a minimum stir volume
16. additionOnce again ethyl acetate (16.8 kg) was charged to the crude mixture
17. additionHeptanes (37.2 kg) were charged
18. temperaturemaintaining the internal temperature at 60° C
19. temperatureThe solution was slowly cooled to approximately 0 to 5° C. and approximately 2-3 hr
20. customcrystallization
21. filtrationThe slurry was filtered
22. filtrationThe resulting suspension was filtered
23. customthe solids dried under vacuum at approximately 40±5° C. (until the loss
24. customon drying (LOD)