Reaction Steps
4-[3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindol-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (750 mg, 1.52 mmol) was dissolved in TFA (10 ml) and stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated K2CO3 (aq). The organic layer was dried (MgSO4), filtered, concentrated in vacuo. The residue was purified by alumina chromatography, using dichloromethane→5% methanol/dichloromethane (in 1% methanol gradient) as the eluant, to yield the title compound (460 mg, 77%). 1H NMR (360 MHz, CDCl3) δ 8.02 (1H, d, J=1.04 Hz), 7.54–7.52 (2H, m), 7.47–7.38 (4H, m), 7.21 (1H, d, J=8.1 Hz), 6.23 (1H, t), 4.00 (2H, s), 3.59–3.58 (2H, m), 3.16 (2H, m), 2.71 (3H, s), 2.52–2.50 (2H, m). m/z (ES) 396 (M+H)+. d) 3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindole Under nitrogen atmosphere, 3-(5-Methyl-3-phenylisoxazol-4-yl)-8-(1,2,3,6-tetrahydropyridin-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindole (50 mg, 0.13 mmol) was dissolved in methanol (2 ml) and formalin solution (65 μl, 0.8 mmol) and sodium cyanoborohydride (32 mg, 0.52 mmol) were added. The reaction was stirred at room temperature for 3 hours. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaCl (aq), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by alumina chromatography eluting with dichloromethane→2% methanol/dichloromethane (in 0.5% methanol gradient) to yield the title compound (21 mg, 41%). 1H NMR (400 MHz, d4 McOH) δ 8.01 (1H, d, J=1.3 Hz), 7.59 (1H, dd, J=1.6, 8.2 Hz), 7.52–7.42 (5H, m), 7.40 (1H, d, J=8.2 Hz), 6.28–6.27 (1H m), 4.31 (2H, s), 3.21–3.20 (2H, m), 2.78 (2H, m), 2.69–2.66 (2H, m), 2.64 (3H, s), 2.43 (3H, s).
