To a suspension of 8-bromo-7-chloro-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (273 mg, 0.67 mmol) and 4-chlorophenylboronic acid (210 mg, 1.34 mmol) in toluene (3.5 mL) and 2.0 M aqueous sodium carbonate (0.75 mL) was added (Ph3P)4Pd (116 mg, 0.10 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon in a 100° C. oil bath for 1.5 h. HPLC/MS analysis indicated that the majority of the product formed was a 1:1 adduct, 7-chloro-8-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. Additional 4-chlorophenylboronic acid (210 mg, 1.34 mmol), toluene (1.5 mL), 2.0 M aqueous sodium carbonate (0.75 mL) and (Ph3P)4Pd (120 mg, 0.104 mmol) were added, and the reaction mixture was stirred at 100° C. under argon for an additional 2.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc phase was washed with water twice, then saturated aqueous NaCl, dried over Na2SO4, and evaporated under reduced pressure to provide crude product as a brown oil. The crude product was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-90%) in hexanes to obtain the title compound as a light yellow foam (358 mg, about 90% pure). A fraction, 125 mg, of the title compound was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 70% to 100% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were collected, neutralized with saturated aqueous Na2CO3 and concentrated under reduced pressure to remove most of the methanol. The resulting suspension was filtered to collect a yellowish solid, which was washed with water (3×) and dried in a vacuum oven at 50° C. overnight to afford 105 mg of pure title compound, 7,8-bis(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. HPLC/MS: retention time=4.05 min, [M+H]+=516. 1H NMR (CDCl3, 400 MHz): δ 8.78 (s, 1H), 7.91 (dd, J=1.8, 7.9 Hz, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 6.64 (d, J=7.0 Hz, 1H), 5.25 (s, 2H). N-alkylation, rather than O-alkylation, in the previous step was demonstrated by the presence of a 13C NMR resonance at 47 ppm for 7,8-bis(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one.
