反应详情

温度

5 °C

To a 50 liter glass reactor containing ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (2.000 kg, 1.000 equiv.) was added cesium carbonate (3.266 kg, 1.300 equiv.) and acetonitrile (15.720 kg) under nitrogen. To the resulting mixture was added 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (2.228 kg, 1.100 equiv.) over approximately one hour while maintaining the stirred reactor contents at 40° C.±5° C. After the addition of 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene the reactor contents were heated to 65° C.±5° C. with stirring until the concentration of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate in the reaction mixture was less than 2.0% area by HPLC. The reaction mixture was cooled to 50° C.±5° C. and filtered under nitrogen through a fine filter cloth with suction to remove cesium salts (Note: ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate may precipitate below 30° C.). The filter cake was washed with fresh hot (50° C.±5° C.) acetonitrile (5.658 kg divided in approximately three equal portions). The filtrates were returned to the reactor. The combined filtrates were concentrated by vacuum distillation with a jacket temperature of 60° C.±10° C. To the reactor was added ethyl alcohol (3.156 kg) and once again concentrated with stirring by vacuum distillation with a jacket temperature of 60° C.±10° C. Once again, ethyl alcohol (3.156 kg) was added to the reactor and the contents were concentrated by vacuum distillation with a jacket temperature of 60° C.±10° C. to a reactor volume of approximately 14 L. The stirred reactor contents were cooled to 0° C. f 5° C. and the temperature maintained for 4 hours to facilitate the crystallization of the product. The resulting slurry was filtered. The filter cake was washed with cold 0° C.±5° C. ethyl alcohol (2×3.156 kg). The filter cake was dried under vacuum at 35° C.±5° C. until the weight loss over hour was to provide 3.0943 kg (81.0% yield) of the title compound as a solid.

1. temperaturewhile maintaining the stirred reactor contents at 40° C.±5° C
2. temperaturewere heated to 65° C.±5° C.
3. temperatureThe reaction mixture was cooled to 50° C.±5° C.
4. filtrationfiltered under nitrogen through a fine filter cloth with suction
5. customto remove cesium salts (Note: ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate may precipitate below 30° C.)
6. washThe filter cake was washed with fresh hot (50° C.±5° C.) acetonitrile (5.658 kg
7. concentrationThe combined filtrates were concentrated by vacuum distillation with a jacket temperature of 60° C.±10° C
8. additionTo the reactor was added ethyl alcohol (3.156 kg)
9. concentrationonce again concentrated
10. additionOnce again, ethyl alcohol (3.156 kg) was added to the reactor
11. concentrationthe contents were concentrated by vacuum distillation with a jacket temperature of 60° C.±10° C. to a reactor volume of approximately 14 L
12. temperaturethe temperature maintained for 4 hours
13. customthe crystallization of the product
14. filtrationThe resulting slurry was filtered
15. washThe filter cake was washed with cold 0° C.±5° C. ethyl alcohol (2×3.156 kg)
16. customThe filter cake was dried under vacuum at 35° C.±5° C. until the weight loss over hour