Cesium carbonate → Ethyl 2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate

Temperature

78 °C

Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (24.0 g, 1.0 eq) was charged into a 1 L, 3-neck round bottom flask set in a heating mantel with a J-KEM controller. Cesium carbonate (39.2 g, 1.3 eq) was charged into the flask. Acetonitrile (250 mL) was charged into the flask and the reaction mixture was stirred with a magnetic stir bar. 4-(Chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (26.7 g, 1.1 eq) was charged slowly over 20 minutes while heating the reaction mixture. The internal temperature at the beginning of the charge was about 21° C. and the internal temperature at the end of the charge was about 82° C. Reaction temperature was maintained at 78° C. 1PC taken after 2.0 hours indicated 95% conversion to product by HPLC. After 2.5 hours the reaction temperature was reduced from about 78° C. to about 54° C. over 33 minutes. 125 mL of acetonitrile (5 vol) was heated to 50° C. in a 250 mL Ehrlenmeyer flask. Celite® was placed in a glass sintered filter funnel and acetonitrile used to wash and pack the filter aid. The acetonitrile wash was discarded to waste. The packed Celite® was approximately 0.5 inches. The reaction mixture was cooled to about 54° C. and filtered through the Celite® filter aid in the glass sintered filter funnel and washed with the 125 mL acetonitrile heated to about 50° C. The acetonitrile filtrate was stirred under nitrogen at ambient temperature for 1.0 hour. The filtrate was concentrated under reduced pressure at about 24° C. forming a thick slurry; 260 mL of distillate was collected. 375 mL of methanol was used to transfer the slurry into a 1 L round bottom flask. The slurry was stirred under nitrogen at ambient temperature for 15.0 hours. The slurry was placed in an ice/salt bath and stirred under nitrogen for 1.2 hours. 150 mL of methanol was placed in an ice/salt bath. The solids were filtered in a Whatman disposable filter cup at about −11° C. and washed with chilled methanol (125 mL). The off-white solids were placed in a vacuum oven set at about 29° C. for 22.5 hours to afford 35.7 g of ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (Compound of Formula (IIk), wherein R3 is ethyl), 79% yield with 99.57 Area % by HPLC.

1. temperaturewhile heating the reaction mixture
2. customwas about 21° C.
3. customwas about 82° C
4. customReaction temperature
5. waitAfter 2.5 hours the reaction temperature was reduced from about 78° C. to about 54° C. over 33 minutes
6. filtrationsintered filter funnel
7. washto wash
8. washThe acetonitrile wash
9. temperatureThe reaction mixture was cooled to about 54° C.
10. filtrationfiltered through the Celite®
11. filtrationfilter aid in the glass
12. filtrationsintered filter funnel
13. washwashed with the 125 mL acetonitrile
14. temperatureheated to about 50° C
15. stirringThe acetonitrile filtrate was stirred under nitrogen at ambient temperature for 1.0 hour
16. concentrationThe filtrate was concentrated under reduced pressure at about 24° C.
17. customforming a thick slurry
18. distillation260 mL of distillate was collected
19. stirringThe slurry was stirred under nitrogen at ambient temperature for 15.0 hours
20. customThe slurry was placed in an ice/salt bath
21. stirringstirred under nitrogen for 1.2 hours
22. custom150 mL of methanol was placed in an ice/salt bath
23. filtrationThe solids were filtered in a Whatman disposable filter cup at about −11° C.
24. washwashed with chilled methanol (125 mL)
25. waitset at about 29° C. for 22.5 hours

ORD record

ord-ceeb0e03302d450d98646422107cd0af

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08853419B2