1-Bromo-3-chloro-4-ethoxy-2-fluorobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.5 g of well dried magnesium and 30 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 40° C. 15.3 g of the compound (1) dissolved in 30 mL of THF was slowly added dropwise thereto at a temperature range of from 35 to 49° C., followed by stirring for 30 minutes. Thereafter, 5.0 g of the compound (23) dissolved in 5 mL of THF was slowly added dropwise thereto at a temperature range of from 30 to 40° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was poured into and mixed with a mixture of 100 mL of 1N hydrochloric acid and 100 mL of toluene. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 16.0 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-vinylcyclohexanol (24) as a yellow liquid. was slowly added dropwise of from 35 to 49° C. was slowly added dropwise of from 30 to 40° C. by stirring for 30 minutes After cooling the resulting reaction mixture to 25° C. the reaction mixture was poured into and The mixture was separated into an organic layer extraction to the organic layer washed with water by drying over anhydrous magnesium sulfate Thereafter, the solvent was removed by distillation under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.5 g of well dried magnesium and 30 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 40° C. 15.3 g of the compound (1) dissolved in 30 mL of THF was slowly added dropwise thereto at a temperature range of from 35 to 49° C., followed by stirring for 30 minutes. Thereafter, 5.0 g of the compound (23) dissolved in 5 mL of THF was slowly added dropwise thereto at a temperature range of from 30 to 40° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was poured into and mixed with a mixture of 100 mL of 1N hydrochloric acid and 100 mL of toluene. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 16.0 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-vinylcyclohexanol (24) as a yellow liquid. was slowly added dropwise of from 35 to 49° C. was slowly added dropwise of from 30 to 40° C. by stirring for 30 minutes After cooling the resulting reaction mixture to 25° C. the reaction mixture was poured into and The mixture was separated into an organic layer extraction to the organic layer washed with water by drying over anhydrous magnesium sulfate Thereafter, the solvent was removed by distillation under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.79 g of well dried magnesium and 50 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 50° C. 50.0 g of the compound (1) dissolved in 200 mL of THF was added dropwise thereto at a temperature range of from 43 to 48° C. over 60 minutes, followed by stirring for 60 minutes. The reaction mixture was cooled to 25° C. Thereafter, the resulting reaction mixture was added dropwise to a solution of 24.6 g of trimethyl borate and 100 mL of THF having been cooled to −50° C. in a nitrogen atmosphere at a temperature range of from −60 to −40° C. over 60 minutes. The reaction mixture was warmed to 0° C. and then put in 400 mL of 3N hydrochloric acid at 0° C. 700 mL of ethyl acetate was added to and mixed with the resulting solution, and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue. The residue was recrystallized from heptane. The recrystallization operation was again repeated to obtain 35.9 g of 3-chloro-4-ethoxy-2-fluorophenylboronic acid (12). The resulting compound (12) was a pale yellow solid matter. was added dropwise The reaction mixture was cooled to 25° C Thereafter, the resulting reaction mixture been cooled to −50° C. in a nitrogen atmosphere at a temperature range of from −60 to −40° C. over 60 minutes The reaction mixture was warmed to 0° C. mixed with the resulting solution separated into an organic layer extraction to the organic layer washed with a saturated sodium bicarbonate aqueous solution and water by drying over anhydrous magnesium sulfate Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue The residue was recrystallized from heptane

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.79 g of well dried magnesium and 50 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 50° C. 50.0 g of the compound (1) dissolved in 200 mL of THF was added dropwise thereto at a temperature range of from 43 to 48° C. over 60 minutes, followed by stirring for 60 minutes. The reaction mixture was cooled to 25° C. Thereafter, the resulting reaction mixture was added dropwise to a solution of 24.6 g of trimethyl borate and 100 mL of THF having been cooled to −50° C. in a nitrogen atmosphere at a temperature range of from −60 to −40° C. over 60 minutes. The reaction mixture was warmed to 0° C. and then put in 400 mL of 3N hydrochloric acid at 0° C. 700 mL of ethyl acetate was added to and mixed with the resulting solution, and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue. The residue was recrystallized from heptane. The recrystallization operation was again repeated to obtain 35.9 g of 3-chloro-4-ethoxy-2-fluorophenylboronic acid (12). The resulting compound (12) was a pale yellow solid matter. was added dropwise The reaction mixture was cooled to 25° C Thereafter, the resulting reaction mixture been cooled to −50° C. in a nitrogen atmosphere at a temperature range of from −60 to −40° C. over 60 minutes The reaction mixture was warmed to 0° C. mixed with the resulting solution separated into an organic layer extraction to the organic layer washed with a saturated sodium bicarbonate aqueous solution and water by drying over anhydrous magnesium sulfate Thereafter, the solvent was removed by distillation under reduced pressure to obtain a residue The residue was recrystallized from heptane

Conditions: temp:43.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.9 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 43° C. 30.0 g of 1-bromo-3-chloro-4-ethoxy-2-fluoro benzene (1) dissolved in 80 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 46° C., followed by stirring for 90 minutes. Thereafter, 19.0 g of 4-pentylcyclo hexanone dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 44° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 100 mL of 3N hydrochloric acid and 100 mL of toluene in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 39.5 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-pentylcyclohexanol (3). The resulting compound (3) was a yellow oily matter. was slowly added dropwise of from 38 to 46° C. was slowly added dropwise of from 38 to 44° C. by stirring for 60 minutes After cooling the resulting reaction mixture to 30° C. separated into an organic layer extraction washed with water by drying over anhydrous magnesium sulfate Thereafter, the solvent was removed by distillation under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:43.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.9 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 43° C. 30.0 g of 1-bromo-3-chloro-4-ethoxy-2-fluoro benzene (1) dissolved in 80 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 46° C., followed by stirring for 90 minutes. Thereafter, 19.0 g of 4-pentylcyclo hexanone dissolved in 20 mL of THF was slowly added dropwise thereto at a temperature range of from 38 to 44° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 100 mL of 3N hydrochloric acid and 100 mL of toluene in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 39.5 g of 1-(3-chloro-4-ethoxy-2-fluorophenyl)-4-pentylcyclohexanol (3). The resulting compound (3) was a yellow oily matter. was slowly added dropwise of from 38 to 46° C. was slowly added dropwise of from 38 to 44° C. by stirring for 60 minutes After cooling the resulting reaction mixture to 30° C. separated into an organic layer extraction washed with water by drying over anhydrous magnesium sulfate Thereafter, the solvent was removed by distillation under reduced pressure

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

Procedure: 30.02 g of the compound (C2) was dissolved in 300 mL of THF. sec-BuLi (1.01 M solution, 124 mL) was added dropwise to the resulting solution in a temperature range of −70 to −75° C., and after completing the dropwise addition, the mixture was stirred for 1 hour in that temperature range. 40 mL of a THF solution having 18.71 g triisopropyl borate dissolved therein was added dropwise to the resulting solution in a temperature range of −70 to −75° C., and after completing the dropwise addition, the mixture was stirred for 1 hour in that temperature range. Thereafter, the temperature of the solution was gradually increased to room temperature, followed by stirring over night. After adding 11.92 g of acetic acid to the reaction mixture, followed by stirring for 30 minutes, 29.95 g of hydrogen peroxide was added dropwise thereto slowly at room temperature, and after completing the dropwise addition, the mixture was stirred for 4.5 hours at room temperature. A sodium nitrite aqueous solution and ethyl acetate were added to the reaction mixture, followed by mixing, and the mixture was left at rest to separate into an organic layer and an aqueous layer, followed by extracting to the organic layer. The resulting organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was a yellowish solid. 30.97 g of the residue was purified by a preparative column chromatography using a mixed solvent of heptane and ethyl acetate (heptane/ethyl acetate=5/1 by volume) as a developing solvent and silica gel as a mediator to obtain 13.29 g of 3-chloro-4-ethoxy-2-fluorophenol (b64). The resulting compound (b64) was a yellowish solid. the dropwise addition dissolved therein was added dropwise to the resulting solution in a temperature range of −70 to −75° C. the dropwise addition the mixture was stirred for 1 hour in that temperature range by stirring over night by stirring for 30 minutes slowly at room temperature the dropwise addition the mixture was stirred for 4.5 hours at room temperature by mixing the mixture was left at rest to separate into an organic layer by extracting to the organic layer The resulting organic layer was washed sequentially with water a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate concentrated under reduced pressure to obtain a residue 30.97 g of the residue was purified by a preparative column chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.79 g of well dried magnesium and 50 mL of THF were added to a reactor in a nitrogen atmosphere and heated to 50° C. 50.0 g of the compound (C2) dissolved in 200 mL of THF was added dropwise thereto over 60 minutes in a temperature range of 43 to 48° C., followed by stirring for 60 minutes. The resulting reaction mixture was cooled to 25° C. Thereafter, the reaction mixture was added dropwise to a solution of 24.6 g of trimethyl borate and 100 mL of THF cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C. The reaction mixture was warmed to 0° C. and then poured into 400 mL of 3N hydrochloric acid at 0° C. 700 mL of acetic acid was added to the solution, followed by mixing, and the mixture was then left to rest to separate into an organic layer and an aqueous layer, followed by extracting. The resulting organic layer was collected and washed with a saturated sodium hydrogen carbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue. The residue was recrystallized from heptane. The recrystallization operation was repeated to obtain 35.9 g of 3-chloro-4-ethoxy-2-fluorophenylboronic acid (b58). The resulting compound (b58) was a yellowish solid. was added dropwise The resulting reaction mixture was cooled to 25° C cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C The reaction mixture was warmed to 0° C. by mixing the mixture was then left to separate into an organic layer by extracting The resulting organic layer was collected washed with a saturated sodium hydrogen carbonate aqueous solution and water by drying over anhydrous magnesium sulfate Thereafter, the solvent was distilled off under reduced pressure to obtain a residue The residue was recrystallized from heptane

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.79 g of well dried magnesium and 50 mL of THF were added to a reactor in a nitrogen atmosphere and heated to 50° C. 50.0 g of the compound (C2) dissolved in 200 mL of THF was added dropwise thereto over 60 minutes in a temperature range of 43 to 48° C., followed by stirring for 60 minutes. The resulting reaction mixture was cooled to 25° C. Thereafter, the reaction mixture was added dropwise to a solution of 24.6 g of trimethyl borate and 100 mL of THF cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C. The reaction mixture was warmed to 0° C. and then poured into 400 mL of 3N hydrochloric acid at 0° C. 700 mL of acetic acid was added to the solution, followed by mixing, and the mixture was then left to rest to separate into an organic layer and an aqueous layer, followed by extracting. The resulting organic layer was collected and washed with a saturated sodium hydrogen carbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue. The residue was recrystallized from heptane. The recrystallization operation was repeated to obtain 35.9 g of 3-chloro-4-ethoxy-2-fluorophenylboronic acid (b58). The resulting compound (b58) was a yellowish solid. was added dropwise The resulting reaction mixture was cooled to 25° C cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C The reaction mixture was warmed to 0° C. by mixing the mixture was then left to separate into an organic layer by extracting The resulting organic layer was collected washed with a saturated sodium hydrogen carbonate aqueous solution and water by drying over anhydrous magnesium sulfate Thereafter, the solvent was distilled off under reduced pressure to obtain a residue The residue was recrystallized from heptane

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.79 g of well dried magnesium and 50 mL of THF were added to a reactor in a nitrogen atmosphere and heated to 50° C. 50.0 g of the compound (C2) dissolved in 200 mL of THF was added dropwise thereto over 60 minutes in a temperature range of 43 to 48° C., followed by stirring for 60 minutes. The resulting reaction mixture was cooled to 25° C. Thereafter, the reaction mixture was added dropwise to a solution of 24.6 g of trimethyl borate and 100 mL of THF cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C. The reaction mixture was warmed to 0° C. and then poured into 400 mL of 3N hydrochloric acid at 0° C. 700 mL of acetic acid was added to the solution, followed by mixing, and the mixture was then left to rest to separate into an organic layer and an aqueous layer, followed by extracting. The resulting organic layer was collected and washed with a saturated sodium hydrogen carbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue. The residue was recrystallized from heptane. The recrystallization operation was repeated to obtain 35.9 g of 3-chloro-4-ethoxy-2-fluorophenylboronic acid (b58). The resulting compound (b58) was a yellowish solid. was added dropwise The resulting reaction mixture was cooled to 25° C cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C The reaction mixture was warmed to 0° C. by mixing the mixture was then left to separate into an organic layer by extracting The resulting organic layer was collected washed with a saturated sodium hydrogen carbonate aqueous solution and water by drying over anhydrous magnesium sulfate Thereafter, the solvent was distilled off under reduced pressure to obtain a residue The residue was recrystallized from heptane