Reaction Steps
The sodium salt (15.7 mg) obtained in Example 18 was dissolved in 0.3 mL of DMF, 0.009 mL of methyl iodide was added to it, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and saturated brine in order, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel chromatography (chloroform/methanol=10/1) to obtain 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 1-isomer) and 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(2-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 2-isomer) both as colorless powders. 1-Isomer: 1H-NMR (CDCl3) δ: 8.20 (1H, d, J=2.3 Hz), 8.05 (1H, dd, J=8.5, 2.3 Hz), 7.78 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=8.4, 7.9 Hz), 7.25 (1H, d, J=8.5 Hz), 7.20 (1H, s), 7.09 (1H, d, J=7.9 Hz), 4.67-4.57 (1H, m), 4.29-4.18 (1H, m), 4.22 (3H, s), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.58 (1H, m), 3.46-3.33 (1H, m), 2.91 (1H, d, J=16.8 Hz), 2.84 (1H, d, J=16.8 Hz), 2.30-2.20 (1H, m), 2.16-1.88 (3H, m). MS [M+H]+=515. 2-Isomer: 1H-NMR (CDCl3) δ: 8.65 (1H, d, J=2.3 Hz), 8.29 (1H, dd, J=8.7, 2.3 Hz), 7.77 (1H, d, J=8.5 Hz), 7.47 (1H, dd, J=8.5, 7.6 Hz), 7.19 (1H, s), 7.15 (1H, d, J=8.7 Hz), 7.08 (1H, d, J=7.6 Hz), 4.65-4.54 (1H, m), 4.39 (3H, s), 4.23-4.13 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.69-3.57 (1H, m), 3.46-3.33 (1H, m), 2.88 (1H, d, J=16.7 Hz), 2.80 (1H, d, J=16.7 Hz), 2.28-2.19 (1H, m), 2.15-2.05 (1H, m), 2.01-1.85 (2H, m). MS [M+H]+=515.
