Reaction Steps
(3R,4aR,12bS)-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) (0.030 g, 0.067 mmol), NBS (0.013 g, 0.074 mmol), and AIBN (0.0011 g, 0.0067 mmol) were dissolved in CCl4 (1 mL) and then mixed at reflux for about 2 h. The reaction was diluted with DCM (10 mL) and then washed with water (2×3 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-30% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to dryness. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to dryness. The residue was further purified by reverse phase HPLC (Atlantis Prep T3 OBD (Waters), 5 μm particle size 19×100 mm) using a gradient of 10-95% MeCN in aq. NH4OAc (50 mM). The fractions containing product were combined and concentrated under reduced pressure to remove the organic volatiles. The resulting mixture was frozen then lyophilized to give (3R,4aR,12bS)-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 (47, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.0050 g, 16% yield); LC/MS, method 2, Rt=3.00 min.; MS m/z: 445 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.85-7.79 (m, 2H), 7.72 (s, 1H), 7.44-7.37 (m, 2H), 6.58 (dd, J=12.4, 2.5 Hz, 1H), 5.84-5.76 (m, 1H), 5.59 (s, 1H), 2.84-2.73 (m, 1H), 2.64-2.56 (m, 1H), 2.23-2.08 (m, 2H), 2.06-1.96 (m, 1H), 1.78-1.38 (m, 6H), 0.65 (t, J=7.3 Hz, 3H).
