Cesium carbonate → (5S)-4-(4,4-Difluorocyclohexyl)-2-(1-{5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidin-2-yl}piperidin-4-yl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

Participants

Reaction Conditions

Reaction Steps

To 6.02 g (8.92 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 2.16 g (8.35 mmol) of 2-chloro-5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine, which was prepared by a method similar to that of Reference Example 20, and 6.06 g (18.6 mmol) of cesium carbonate, 30 ml of 4-heptanol was added, and the reaction mixture was stirred at 150° C. for 8 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate three times. The obtained organic phases were combined, washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Reaction and aftertreatment similar to those described above were further performed using 2.00 g (2.96 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, 0.72 g (2.78 mmol) of 2-chloro-5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine and 2.02 g (5.73 mmol) of cesium carbonate. The obtained residues were combined and subjected to silica gel column chromatography [n-hexane/ethyl acetate=85/15-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, then n-heptane was added thereto, and the precipitate was obtained by filtration to provide 7.35 g of the title compound as a white solid (yield: 74%).

Provenance & Evidence