Azobisisobutyronitrile → HCID 86722397, compound

NBS (0.110 g, 0.618 mmol) was added in one portion 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) (0.248 g, 0.555 mmol) and CCl4 (9.5 mL) under a nitrogen atmosphere. AIBN (0.009 g, 0.055 mmol) was added in one portion. The reaction vessel was evacuated and back-filled with nitrogen three times then the solution was warmed to reflux. After 2 h, the solution was cooled to rt. NBS (0.020 g, 0.11 mmol) and AIBN (0.001 g, 0.006 mmol) were added sequentially. The reaction vessel was evacuated and back-filled with nitrogen three times then the solution was warmed to reflux. After 45 min, the mixture was allowed to cool to rt. 75% Sat. aq. NaHCO3 (20 mL), water (5 mL), and DCM (25 mL) were added. The layers were separated and the aqueous layer was extracted with DCM (25 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (40 g) using a gradient of 0-20% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (60, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0671 g, 27% yield). LC/MS, method 3, Rt=2.83 min, MS m/z 445 (M+H)+. Borane tetrahydrofuran complex (1 M solution in THF, 0.750 mL, 0.750 mmol) was added dropwise to a solution of (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (60, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0671 g, 0.151 mmol) and THF (1.5 mL) under a nitrogen atmosphere at about 0° C. After about 15 min, the ice bath was removed and the solution was left to stir at rt for about 18 h. The reaction was cooled to about 0° C. NaOH (3.8 M aq. solution, 0.800 mL, 3.04 mmol) was added dropwise over about 5 min). H2O2 (30% aq. solution, 0.770 mL, 7.54 mmol) was added dropwise over about 5 min. After about 15 min, the ice bath was removed and the mixture was stirred at rt for about 2 h. The mixture was warmed to about 40° C. After about 1 h, the mixture was allowed to cool to rt. Water (10 mL), EtOAc (10 mL) and MeOH (1 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organics were washed with sat. aq. NaCl (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel (40 g) using a gradient of 0-30% EtOAc in heptane. The fractions containing each product were combined and concentrated under reduced pressure. The first eluting band afforded (3R,4aR,7R,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-3,7-diol (62, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0061 g, 9% yield). LC/MS, method 2, Rt=2.44 min, MS m/z 463 (M+H)+. The second eluting band afforded (3R,4aR,7 S,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-3,7-diol (61, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.024 g, 35% yield) of an ivory solid. LC/MS, method 3, Rt=2.36 min, MS m/z 463 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27-8.25 (m, 1H), 8.20 (s, 1H), 7.84 (s, 1H), 7.81-7.72 (m, 2H), 7.50-7.41 (m, 2H), 5.87 (s, 1H), 5.47 (d, J=6.28 Hz, 1H), 5.12-5.03 (m, 1H), 2.19-1.37 (m, 13H), 0.42 (t, J=7.2 Hz, 3H).

1. customThe reaction vessel was evacuated
2. additionback-filled with nitrogen three times
3. temperaturethe solution was warmed to reflux
4. customThe reaction vessel was evacuated
5. additionback-filled with nitrogen three times
6. temperaturethe solution was warmed to reflux
7. waitAfter 45 min
8. temperatureto cool to rt
9. addition75% Sat. aq. NaHCO3 (20 mL), water (5 mL), and DCM (25 mL) were added
10. customThe layers were separated
11. extractionthe aqueous layer was extracted with DCM (25 mL)
12. dry with materialThe combined organics were dried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated
15. customThe residue was purified on silica gel (40 g)
16. additionThe fractions containing product
17. concentrationconcentrated under reduced pressure

ORD record

ord-b255fc52c18d43fb96f28f7506d7e01d

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2