Reaction Steps
A flask with stir bar and nitrogen line was charged with (3S,4aS,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 (11, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.15 g, 0.336 mmol), THF (3 mL) and sodium hydride (60 wt % in oil, 0.027 g, 0.672 mmol) then warmed to about 65° C. for about 15 min. The mixture was cooled to rt then benzyl 2-bromoacetate (0.096 g, 0.420 mmol) was added and the mixture was stirred for about 20 min. Benzyl 2-bromoacetate (0.096 g, 0.420 mmol) was added to the mixture then after about 20 min sodium hydride (60 wt % in oil, 0.027 g, 0.672 mmol) and another portion of benzyl 2-bromoacetate (385 mg, 1.68 mmol). The mixture was transferred to a microwave vial then it was heated in a microwave at about 130° C. for about 20 min. Water (1 mL) and lithium hydroxide (200 mg, 8.33 mmol) were added then the mixture was heated in microwave at about 130° C. for about 20 min. Acetic acid (1.5 mL) was added then the reaction mixture was purified without further manipulation in one portion by preparative reverse phase HPLC using a Hypersil HS C18 column (250 mm×21.2 mm, 8 μm particle size) with a gradient of 15-100% MeCN in 0.05 N aq. ammonium acetate pH 4.5 buffer. Product fractions were concentrated under reduced pressure then the material was suspended in water (˜3 mL), collected by filtration then dried to yield 2-(((3S,4aS,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-yl)oxy)acetic acid (18.3 mg, 10.80%); LC/MS, method 2, Rt=2.60 min, MS m/z 505 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.82-7.78 (m, 2H), 7.57 (s, 1H), 7.43-7.37 (m, 2H), 4.21 (s, 2H), 3.27-3.20 (m, 1H), 2.96-2.91 (m, 1H), 2.31-2.09 (m, 3H), 2.08-1.98 (m, 2H), 1.89-1.76 (m, 4H), 1.70-1.61 (m, 3H), 1.40-1.29 (m, 1H), 0.44 (t, J=7.2 Hz, 3H).
