1-butoxy-2,3-difluorobenzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 31.0 g (0.17 mol) of 1-butoxy-2,3-difluorobenzene are initially introduced in 200 ml of THF, and 100 ml (0.16 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 2 h at this temperature, a solution of 35.6 g (0.16 mol) of 4′-propylbicyclohexyl-4-one in 200 ml of THF is metered in, and the batch is stirred for 2.5 h. The reaction mixture is hydrolysed with ice-cooling and acidified using 2 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (66.3 g of yellow solid) is used directly for the following reaction. cooling The solution is extracted with MTBE the combined organic phases are washed with sat. sodium chloride solution dried The solution is concentrated to dryness the crude product (66.3 g of yellow solid) is used directly for the following reaction

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 31.0 g (0.17 mol) of 1-butoxy-2,3-difluorobenzene are initially introduced in 200 ml of THF, and 100 ml (0.16 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 2 h at this temperature, a solution of 35.6 g (0.16 mol) of 4′-propylbicyclohexyl-4-one in 200 ml of THF is metered in, and the batch is stirred for 2.5 h. The reaction mixture is hydrolysed with ice-cooling and acidified using 2 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (66.3 g of yellow solid) is used directly for the following reaction. cooling The solution is extracted with MTBE the combined organic phases are washed with sat. sodium chloride solution dried The solution is concentrated to dryness the crude product (66.3 g of yellow solid) is used directly for the following reaction

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Butoxy-1,2-difluorobenzene (s-18) (17.7 g) and THF (500 ml) were put in a reaction vessel under an atmosphere of nitrogen and cooled to −74° C. sec-Butyllithium (a 1.00 M solution in n-hexane and cyclohexane; 114 ml) was added dropwide thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 4-(2,3-difluorophenyl)cyclohexanone (s-19) (20.0 g) dissolved in THF (100 ml) was added dropwise thereto 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 poured into a vessel containing an aqueous solution of ammonium chloride (3%; 200 ml) and ethyl acetate (200 ml), and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under the reduced pressure. p-Toluenesulfonic acid (4.1 g) and toluene (300 ml) were added to the residue 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., water (500 ml) and toluene (500 ml) were added to the mixture, and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solution was purified by column chromatography using silica gel as a stationary phase powder and a mixed solvent of toluene and heptane (1/1 by volume) as an eluent, and then by recrystallization from Solmix A-11 to give 1-butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (s-20) (7.2 g). The yield based on the compound (s-18) was 20.0%. 114 ml) was added dropwide 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 to come to 25° C The reaction mixture was poured into a vessel mixed with them had separated into organic and aqueous phases the extraction The combined organic phase was washed successively with water a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate Then, the solvent was distilled off under the reduced pressure p-Toluenesulfonic acid (4.1 g) and toluene (300 ml) were added to the residue the mixture was heated to reflux for 2 hours while distilled water was removed water (500 ml) and toluene (500 ml) were added to the mixture mixed with it had separated into two phases of organic and aqueous phases the extraction The combined organic phase was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water dried over anhydrous magnesium sulfate The solution was purified by column chromatography a mixed solvent of toluene and heptane (1/1 by volume) as an eluent, and then by recrystallization from Solmix A-11

Conditions: temp:-74.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Butoxy-1,2-difluorobenzene (s-4) (10.0 g) and THF (200 ml) were put in a reaction vessel and were cooled to −74° C. under an atmosphere of nitrogen. sec-Butyllithium (a 1.00 M solution in n-hexane and cyclohexane; 64.0 ml) was added dropwide thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 4-(1,4-dioxaspiro[4.5]decan-8-yl)-cyclohexanone (s-5) (12.8 g) in a THF (50 ml) solution was added dropwise thereto 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 mixture was poured into a vessel containing an aqueous solution of ammonium chloride (3%; 100 ml) and ethyl acetate (100 ml), and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to give 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-butoxy-2,3-difluorophenyl)-cyclohexanol. p-Toluenesulfonic acid (0.68 g) and toluene (200 ml) were mixed with this compound 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., water (200 ml) and toluene (200 ml) were added to the mixture, and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent. Pd/C (0.3 g) was added to the product and the mixture was stirred at room temperature under an atmosphere of hydrogen until hydrogen absorption had ceased. After the completion of the reaction, Pd/C was removed and the solvent was distilled off. The resulting residue was purified by recrystallization from a mixed solvent of THF/heptane (1/9 by volume) to give 8-[4-(4-butoxy-2,3-difluorophenyl)-cyclohexenyl]-1,4-dioxaspiro[4.5]decane (s-6) (7.7 g). The yield based on the compound (s-4) was 35.2%. 64.0 ml) was added dropwide in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture to come to 25° C The mixture was poured into a vessel mixed with them had separated into organic and aqueous phases the extraction The combined organic phase was washed successively with water a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate Then, the solvent was distilled off

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Butoxy-1,2-difluorobenzene (7) (10.0 g) and THF (200 ml) were added to a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M, in n-hexane and cyclohexane solution; 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. Successively, 4-(1,4-dioxaspiro[4.5]decan-8-yl)-cyclohexanone (21) (12.8 g) in THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., while the mixture was allowed to come to 25° C. The reaction mixture was poured into a 3%-aqueous solution of ammonium chloride (100 ml) and ethyl acetate (100 ml) in a vessel and mixed with them. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to leave 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-butoxy-2,3-difluorophenyl)-cyclohexanol (22) (22.7 g). The resulting compound (22) was a pale yellow oil. was added dropwise in the temperature range of −74° C. to −70° C. to come to 25° C mixed with them had separated into two phases of organic and aqueous phases the extraction into an organic phase The resulting organic phase was separated washed successively with water a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate The solvent was then distilled off under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Butoxy-1,2-difluorobenzene (7) (30.0 g) and THF (500 ml) were added to a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.66 M in n-hexane solution; 120 ml) was added dropwise in the temperature range of −74° C. to −70° C. and the stirring was continued for another 2 hours. Successively, 1,4-dioxaspiro[4.5]decan-8-one (8) (30.2 g) in THF (200 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 resulting reaction mixture was poured into a 1N—HCl aqueous solution (500 ml) and ethyl acetate (500 ml) in a vessel and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to leave 8-(4-butoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (9) (55.0 g). The resulting compound (9) was a pale yellow oil. was added dropwise in the temperature range of −74° C. to −70° C. the stirring was continued for another 8 hours while the mixture to come to 25° C The resulting reaction mixture mixed with them had separated into organic and aqueous phases the extraction into an organic phase The resulting organic phase was separated washed successively with water a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate The solvent was then distilled off under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound (22) (84.6 g) and THF (500 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. n-Butyllithium (1.65 M in a n-hexane solution; 303.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, the mixture was added dropwise to a THF (200 ml) solution of trimethyl borate (56.7 g) in the temperature range of −74° C. to −65° C., and the stirring was continued for another 8 hours while the mixture was allowed to return to 25° C. Subsequently, the reaction mixture was poured into a vessel containing 1N—HCl (100 ml) and ice-water (500 ml), and mixed. Ethyl acetate (300 ml) was added thereto and the mixture was allowed to separate into organic and aqueous phases, and the extraction was carried out. The organic phase obtained was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure, giving 4-butoxy-2,3-difluorophenylboronic acid (23) (6.4 g). The yield based on the compound (22) was 69.2%. 303.0 ml) was added dropwise in the temperature range of −74° C. to −70° C. the stirring was continued for another 8 hours while the mixture to return to 25° C Subsequently, the reaction mixture was poured into a vessel mixed to separate into organic and aqueous phases the extraction The organic phase obtained was washed sequentially with water a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate Then the solvent was distilled off under reduced pressure

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,3-Difluorophenol (21) (100.0 g) and sodium hydroxide (NaOH; 36.9 g) were added to water (300 ml) under a nitrogen atmosphere, and the stirring was continued at 70° C. 1-Bromobutane (158.0 g) was added thereto, and the stirring was continued at 70° C. for 2 hours. The reaction mixture obtained was cooled to 30° C., heptane (100 ml) and water (100 ml) were added, and mixed. The mixture was then allowed to separate into organic and aqueous phases. The extraction into an organic phase was carried out. The organic phase obtained was washed with brine and dried over anhydrous magnesium sulfate. Then, fractional distillation was carried out under reduced pressure, giving 114.4 g of 4-butoxy-2,3-difluorobenzene (22). The compound (22) obtained was a colorless oil having a boiling point of 109° C. to 110° C./20 mmHg. The yield based on the compound (21) was 80.0%. was continued at 70° C The reaction mixture obtained mixed to separate into organic and aqueous phases The extraction into an organic phase The organic phase obtained was washed with brine dried over anhydrous magnesium sulfate Then, fractional distillation