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

온도

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. Acetonitrlle (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. IPC 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. additionAcetonitrlle (250 mL) was charged into the flask
2. temperaturewhile heating the reaction mixture
3. customwas about 21° C.
4. customwas about 82° C
5. customReaction temperature
6. waitAfter 2.5 hours the reaction temperature was reduced from about 78° C. to about 54° C. over 33 minutes
7. filtrationsintered filter funnel
8. washto wash
9. washThe acetonitrile wash
10. temperatureThe reaction mixture was cooled to about 54° C.
11. filtrationfiltered through the Celite®
12. filtrationfilter aid in the glass
13. filtrationsintered filter funnel
14. washwashed with the 125 mL acetonitrile
15. temperatureheated to about 50° C
16. stirringThe acetonitrile filtrate was stirred under nitrogen at ambient temperature for 1.0 hour
17. concentrationThe filtrate was concentrated under reduced pressure at about 24° C.
18. customforming a thick slurry
19. distillation260 mL of distillate was collected
20. stirringThe slurry was stirred under nitrogen at ambient temperature for 15.0 hours
21. customThe slurry was placed in an ice/salt bath
22. stirringstirred under nitrogen for 1.2 hours
23. custom150 mL of methanol was placed in an ice/salt bath
24. filtrationThe solids were filtered in a Whatman disposable filter cup at about −11° C.
25. washwashed with chilled methanol (125 mL)
26. waitset at about 29° C. for 22.5 hours

ORD 기록

ord-80a5187ecc7d41489cbab93bd83828d9

출처 데이터셋

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09447041B2