Tetrahydrofuran → HCID 86722392, compound

Temperature

40 °C

To a vessel containing pyridine (0.886 g, 11.2 mmol) was added rac-(3S,4aS,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 (15, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.100 g, 0.224 mmol), and thionyl chloride (0.480 g, 4.03 mmol). The reaction was warmed to about 80° C. for about 3 h. The reaction was cooled to rt, slowly quenched with sat. aq. NaHCO3 (10 mL) and then extracted with EtOAc (3×10 mL). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-30% EtOAc in heptane. The product fractions were concentrated to give about a 2.5:1 mixture of rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole and rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole as a colorless oil (0.048 g, 50% yield). LC/MS, method 3, Rt=3.21 min.; MS m/z: 429 (M+H)+. Potassium osmate dihydrate (0.081 g, 0.22 mmol) and 4-methylmorpholine N-oxide (0.771 g, 6.58 mmol) were added sequentially, each in one portion, to a biphasic solution of a mixture of rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole and rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole (0.940 g, 2.194 mmol), THF (15 mL), and water (7.5 mL). After about 20 h, potassium osmate dihydrate (0.081 g, 0.22 mmol) and 4-methylmorpholine N-oxide (0.771 g, 6.58 mmol) were added sequentially, each in one portion. The reaction was warmed to about 40° C. for about 30 h. The reaction was allowed to cool to rt and after about 3 days at rt, water (300 mL) was added. The solution was extracted with DCM (2×200 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (120 g) using a gradient of 0-15% EtOAc in DCM. The product fractions were concentrated under reduced pressure to afford rac-(3R,4S,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-3,4-diol (52, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.520 g, 51% yield) LC/MS, method 3, Rt=2.71 min.; MS m/z: 463 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.85-7.78 (m, 2H), 7.71 (s, 1H), 7.60 (s, 1H), 7.44-7.37 (m, 2H), 5.48 (s, 1H), 4.68 (d, J=9.0 Hz, 1H), 3.30-3.27 (m, 1H), 3.12-2.98 (m, 2H), 2.46-2.36 (m, 1H), 2.28-2.16 (m, 2H), 2.15-2.04 (m, 1H), 1.96-1.77 (m, 3H), 1.77-1.42 (m, 4H), 0.59 (t, J=7.3 Hz, 3H) and rac-(2R,3S,4aS,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 (51, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.280 g, 27%, yield) LC/MS, method 3, Rt=2.74 min.; MS m/z: 463 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.87-7.75 (m, 3H), 7.59 (s, 1H), 7.45-7.36 (m, 2H), 5.52 (s, 1H), 4.96 (d, J=6.6 Hz, 1H), 4.11-3.99 (m, 1H), 3.09-2.93 (m, 2H), 2.56-2.51 (m, 1H), 2.35-2.17 (m, 2H), 2.16-2.03 (m, 1H), 1.83-1.71 (m, 1H), 1.71-1.58 (m, 2H), 1.54-1.20 (m, 4H), 0.61 (t, J=7.3 Hz, 3H).

1. temperatureto cool to rt and after about 3 days at rt
2. extractionThe solution was extracted with DCM (2×200 mL)
3. dry with materialThe combined organics were dried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. customThe residue was purified on silica gel (120 g)
7. concentrationThe product fractions were concentrated under reduced pressure

ORD record

ord-5a3598acfdea410d80958d10cde15f55

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2