Pyridine → HCID 86722405, compound

Temperature

80 °C

Thionyl chloride (0.120 mL, 1.645 mmol) was added dropwise to a solution of (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0720 g, 0.161 mmol), pyridine (0.200 mL, 2.473 mmol), and toluene (0.300 mL) under a nitrogen atmosphere. The mixture was warmed to about 80° C. After about 4 h, the mixture was allowed to cool to rt. The volatiles were removed under reduced pressure. Saturated aq. NaHCO3 (2 mL) and EtOAc (5 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (80 g) using a gradient of 0-10% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford a 2:1 mixture of (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole (66, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) and (4 aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole (65, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0599 g, 0.140 mmol) as a light yellow film. LC/MS, method 3, Rt=3.23 min, MS m/z 429 (M+H)+. Potassium osmate dihydrate (0.0040 g, 0.011 mmol) was added in one portion to a biphasic solution of a 2:1 mixture of (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole (66, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) and (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole (65, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0560 g, 0.131 mmol), THF (1.0 mL), and water (0.50 mL). NMO (0.046 g, 0.392 mmol) was added in one portion. After about 16 h, the mixture was warmed to about 40° C. After about 33 h, the mixture was allowed to cool to rt. Water (3 mL) was added. The solution was extracted with DCM (2×5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in DCM/MeOH and 0.4 g of silica gel was added. The volatiles were removed under reduced pressure. The resulting solid was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford (2S,3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-2,3-diol (67, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0116 g, 19% yield) as an ivory solid. LC/MS, method 2, Rt=2.75 min, MS m/z 463 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 7.85 (s, 1H), 7.84-7.76 (m, 2H), 7.56 (s, 1H), 7.46-7.35 (m, 2H), 5.52 (s, 1H), 4.90 (d, J=6.7 Hz, 1H), 3.90-3.79 (m, 1H), 3.22-3.09 (m, 1H), 3.00-2.89 (m, 1H), 2.24-2.06 (m, 3H), 2.06-1.94 (m, 1H), 1.92-1.70 (m, 2H), 1.69-1.51 (m, 4H), 1.40-1.20 (m, 1H), 0.45 (t, J=7.3 Hz, 3H).

1. temperatureto cool to rt
2. customThe volatiles were removed under reduced pressure
3. additionSaturated aq. NaHCO3 (2 mL) and EtOAc (5 mL) were added
4. customThe layers were separated
5. extractionthe aqueous layer was extracted with EtOAc (5 mL)
6. dry with materialThe combined organics were dried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated
9. customThe residue was purified on silica gel (80 g)
10. additionThe fractions containing product
11. concentrationconcentrated under reduced pressure
12. customto afford
13. waitAfter about 16 h
14. temperaturethe mixture was warmed to about 40° C
15. waitAfter about 33 h
16. temperatureto cool to rt
17. extractionThe solution was extracted with DCM (2×5 mL)
18. dry with materialThe combined organics were dried over Na2SO4
19. filtrationfiltered
20. concentrationconcentrated under reduced pressure
21. dissolutionThe material was dissolved in DCM/MeOH
22. addition0.4 g of silica gel was added
23. customThe volatiles were removed under reduced pressure
24. customThe resulting solid was purified on silica gel (12 g)
25. additionThe fractions containing product
26. concentrationconcentrated under reduced pressure

ORD record

ord-b029c454f38440c9b4d5a3324ca80123

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2