(3-chloro-4-ethoxy-2-fluorophenyl)boronic acid

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6.0 g of the compound (16), 5.5 g of the compound (12), 5.9 g of potassium carbonate and 0.13 g of Pd(PPh3)2Cl2 were added to a reactor having 60 mL of IPA placed therein under nitrogen atmosphere. The mixture was stirred under refluxing and heating for 3 hours. After cooling the reaction mixture to 25° C., 200 mL of toluene and 200 mL of water were added thereto, and the resulting toluene solution was washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water. Thereafter, the solvent was removed by distillation to obtain a residue. The resulting residue was purified by recrystallization from a mixed solvent of toluene and ethyl acetate (toluene/ethyl acetate=1/1 by volume). The resulting crystals were purified by silica gel column chromatography using toluene as eluent, and then further purified by recrystallization from a mixed solvent of heptane and ethanol (heptane/ethanol=5/1 by volume) to obtain 5.9 g of 3-chloro-4-ethoxy-2-fluoro-4′-(4-propylcyclohexa-1-enyl)biphenyl (No. 130). The resulting compound (No. 130) was colorless crystals. The yield based on the compound (13) was 45.0%. under refluxing heating for 3 hours the resulting toluene solution was washed with a 2N sodium hydroxide aqueous solution Thereafter, the solvent was removed by distillation to obtain a residue The resulting residue was purified by recrystallization from a mixed solvent of toluene and ethyl acetate (toluene/ethyl acetate=1/1 by volume) The resulting crystals were purified by silica gel column chromatography further purified by recrystallization from a mixed solvent of heptane and ethanol (heptane/ethanol=5/1 by volume)

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: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

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:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6.0 g of the compound (16), 5.5 g of the compound (12), 5.9 g of potassium carbonate and 0.13 g of Pd(PPh3)2Cl2 were added to a reactor having 60 mL of IPA placed therein under nitrogen atmosphere. The mixture was stirred under refluxing and heating for 3 hours. After cooling the reaction mixture to 25° C., 200 mL of toluene and 200 mL of water were added thereto, and the resulting toluene solution was washed with a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution and water. Thereafter, the solvent was removed by distillation to obtain a residue. The resulting residue was purified by recrystallization from a mixed solvent of toluene and ethyl acetate (toluene/ethyl acetate=1/1 by volume). The resulting crystals were purified by silica gel column chromatography using toluene as eluent, and then further purified by recrystallization from a mixed solvent of heptane and ethanol (heptane/ethanol=5/1 by volume) to obtain 5.9 g of 3-chloro-4-ethoxy-2-fluoro-4′-(4-propylcyclohexa-1-enyl)biphenyl (No. 130). The resulting compound (No. 130) was colorless crystals. The yield based on the compound (13) was 45.0%. under refluxing heating for 3 hours the resulting toluene solution was washed with a 2N sodium hydroxide aqueous solution Thereafter, the solvent was removed by distillation to obtain a residue The resulting residue was purified by recrystallization from a mixed solvent of toluene and ethyl acetate (toluene/ethyl acetate=1/1 by volume) The resulting crystals were purified by silica gel column chromatography further purified by recrystallization from a mixed solvent of heptane and ethanol (heptane/ethanol=5/1 by volume)

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