Ammonium Chloride → 4-(1,4-Dioxaspiro[4,5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexanol

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Reaction Steps

3-Ethoxy-1,2-difluorobenzene (s65) (10.0 g) and THF (200 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M, in n-hexane-cyclohexane; 64.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-(1,4-Dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s66) (12.8 g) in THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride (3%), and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)-cyclohexanol. The compound was mixed with p-toluenesulfonic acid (0.68 g) and toluene (200 ml), and the mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. Pd/C (0.3 g) was added to the purified product and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by recrystallization from a mixed solvent of THF and heptane (THF:heptane=1:9 by volume) to give 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohexenyl]-1,4-dioxaspiro[4.5]decane (s67) (7.7 g). The yield based on the compound (s65) was 35.2%.

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