2,4-difluoro-3-formylbenzonitrile

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

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

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

Procedure: A total of 8.55 g of 2,4-difluoro-3-formyl-benzonitrile obtained in Production Example II-13-a was dissolved in 40 ml of tetrahydrofuran and 40 ml of methanol, and 5.1 ml of hydrazine monohydrate was added, followed by stirring at room temperature for three days and was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours. The reaction mixture was added with 150 ml of ice-water, 300 ml of ethyl acetate and 100 ml of tetrahydrofuran were added, and unnecessary matters were filtered off. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4), to give 509 mg of the title compound as bright yellow crystals. In addition, a portion with impurities was purified again by silica gel column chromatography (ethyl acetate:n-hexane=1:4 to 1:0), to give 1.80 g of the title compound as bright yellow crystals. was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours were added unnecessary matters were filtered off The organic layer was sequentially washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an atmosphere of nitrogen gas, 66 ml of a 1.6 M solution of n-butyllithium in hexane was added to an ice-cold solution of 11.1 g of N,N-diisopropylamine in 100 ml tetrahydrofuran, and the mixture was stirred at the same temperature for 20 minutes. After cooling to −78° C., a solution of 13.9 g of 2,4-difluorobenzonitrile in 15 ml tetrahydrofuran was added dropwise. After stirring at the same temperature for 10 minutes, 8.6 ml of dimethylformamide was added dropwise and the mixture was stirred at the same temperature for 15 minutes. After adding 20 ml of glacial acetic acid to the reaction mixture, 200 ml of water was added and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with 0.2 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were triturated with diethyl ether-n-hexane, to give 8.61 g of the title compound as bright yellow crystals. After stirring at the same temperature for 10 minutes the mixture was stirred at the same temperature for 15 minutes was added the mixture was extracted with diethyl ether for two times The organic layer was sequentially washed with 0.2 N hydrochloric acid and brine dried over anhydrous magnesium sulfate the solvent was evaporated The resulting crude crystals were triturated with diethyl ether-n-hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under nitrogen atmosphere and ice cooling, to a solution of 11.1 g of N,N-diisopropylamine in 100 mL of tetrahydrofuran was added 66 mL of 1.6 M n-butyllithium in n-hexane and stirred at this temperature for 20 minutes. After cooling to −78° C., 15 mL of a solution containing 13.9 g of 2,4-difluorobenzonitrile in tetrahydrofuran was added dropwise. After stirring at this temperature for 10 minutes, 8.6 mL of N,N-dimethylformamide was added dropwise and stirred at this temperature for 15 minutes. The reaction solution was added with 20 mL of glacial acetic acid, followed by 200 mL water, and extracted twice with diethyl ether. The organic layer was washed successively with 0.2N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant crude crystals were triturated with diethyl ether n-hexane, to afford 8.61 g of the title compound as bright yellow crystals. was added dropwise After stirring at this temperature for 10 minutes stirred at this temperature for 15 minutes extracted twice with diethyl ether The organic layer was washed successively with 0.2N hydrochloric acid and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated the resultant crude crystals were triturated with diethyl ether n-hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under nitrogen atmosphere and ice cooling, to a solution of 11.1 g of N,N-diisopropylamine in 100 mL of tetrahydrofuran was added 66 mL of 1.6 M n-butyllithium in n-hexane and stirred at this temperature for 20 minutes. After cooling to −78° C., 15 mL of a solution containing 13.9 g of 2,4-difluorobenzonitrile in tetrahydrofuran was added dropwise. After stirring at this temperature for 10 minutes, 8.6 mL of N,N-dimethylformamide was added dropwise and stirred at this temperature for 15 minutes. The reaction solution was added with 20 mL of glacial acetic acid, followed by 200 mL water, and extracted twice with diethyl ether. The organic layer was washed successively with 0.2N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant crude crystals were triturated with diethyl ether n-hexane, to afford 8.61 g of the title compound as bright yellow crystals. was added dropwise After stirring at this temperature for 10 minutes stirred at this temperature for 15 minutes extracted twice with diethyl ether The organic layer was washed successively with 0.2N hydrochloric acid and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated the resultant crude crystals were triturated with diethyl ether n-hexane

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

Procedure: A total of 8.55 g of 2,4-difluoro-3-formyl-benzonitrile obtained in Production Example II-13-a was dissolved in 40 ml of tetrahydrofuran and 40 ml of methanol, and 5.1 ml of hydrazine monohydrate was added, followed by stirring at room temperature for three days and was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours. The reaction mixture was added with 150 ml of ice-water, 300 ml of ethyl acetate and 100 ml of tetrahydrofuran were added, and unnecessary matters were filtered off. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4), to give 509 mg of the title compound as bright yellow crystals. In addition, a portion with impurities was purified again by silica gel column chromatography (ethyl acetate:n-hexane=1:4 to 1:0), to give 1.80 g of the title compound as bright yellow crystals. was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours were added unnecessary matters were filtered off The organic layer was sequentially washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an atmosphere of nitrogen gas, 66 ml of a 1.6 M solution of n-butyllithium in hexane was added to an ice-cold solution of 11.1 g of N,N-diisopropylamine in 100 ml tetrahydrofuran, and the mixture was stirred at the same temperature for 20 minutes. After cooling to −78° C., a solution of 13.9 g of 2,4-difluorobenzonitrile in 15 ml tetrahydrofuran was added dropwise. After stirring at the same temperature for 10 minutes, 8.6 ml of dimethylformamide was added dropwise and the mixture was stirred at the same temperature for 15 minutes. After adding 20 ml of glacial acetic acid to the reaction mixture, 200 ml of water was added and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with 0.2 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were triturated with diethyl ether-n-hexane, to give 8.61 g of the title compound as bright yellow crystals. After stirring at the same temperature for 10 minutes the mixture was stirred at the same temperature for 15 minutes was added the mixture was extracted with diethyl ether for two times The organic layer was sequentially washed with 0.2 N hydrochloric acid and brine dried over anhydrous magnesium sulfate the solvent was evaporated The resulting crude crystals were triturated with diethyl ether-n-hexane

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

Procedure: A total of 8.55 9 of 2,4-difluoro-3-formyl-benzonitrile obtained in Production Example II-13-a was dissolved in 40 ml of tetrahydrofuran and 40 ml of methanol, and 5.1 ml of hydrazine monohydrate was added, followed by stirring at room temperature for three days and was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours. The reaction mixture was added with 150 ml of ice-water, 300 ml of ethyl acetate and 100 ml of tetrahydrofuran were added, and unnecessary matters were filtered off. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4), to give 509 mg of the title compound as bright yellow crystals. In addition, a portion with impurities was purified again by silica gel column chromatography (ethyl acetate:n-hexane=1:4 to 1:0), to give 1.80 g of the title compound as bright yellow crystals. was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours were added unnecessary matters were filtered off The organic layer was sequentially washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an atmosphere of nitrogen gas, 66 ml of a 1.6 M solution of n-butyllithium in hexane was added to an ice-cold solution of 11.1 g of N,N-diisopropylamine in 100 ml tetrahydrofuran, and the mixture was stirred at the same temperature for 20 minutes. After cooling to −78° C., a solution of 13.9 g of 2,4-difluorobenzonitrile in 15 ml tetrahydrofuran was added dropwise. After stirring at the same temperature for 10 minutes, 8.6 ml of dimethylformamide was added dropwise and the mixture was stirred at the same temperature for 15 minutes. After adding 20 ml of glacial acetic acid to the reaction mixture, 200 ml of water was added and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with 0.2 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were triturated with diethyl ether-n-hexane, to give 8.61 g of the title compound as bright yellow crystals. After stirring at the same temperature for 10 minutes the mixture was stirred at the same temperature for 15 minutes was added the mixture was extracted with diethyl ether for two times The organic layer was sequentially washed with 0.2 N hydrochloric acid and brine dried over anhydrous magnesium sulfate the solvent was evaporated The resulting crude crystals were triturated with diethyl ether-n-hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 300 mg (3.48 mmol) of 2,4-difluoro-3-formylbenzonitrile (CAS 149489-14-5) in 10 ml of ethanol at 0° C. was admixed with 34 mg (0.89 mmol) of sodium borohydride in portions. After stirring at 0° C. for 1 h, the reaction mixture was mixed with water and extracted three times with methyl tert-butyl ether. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, and dried with a phase separation cartridge. The solvent was drawn off to dryness under reduced pressure, which gave 280 mg (82% of theory) of the target compound. at 0° C. extracted three times with methyl tert-butyl ether The combined organic extracts were washed with water and saturated aqueous sodium chloride solution dried with a phase separation cartridge gave 280 mg (82% of theory) of the target compound

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

Procedure: A total of 8.55 g of 2,4-difluoro-3-formyl-benzonitrile obtained in Production Example II-13-a was dissolved in 40 ml of tetrahydrofuran and 40 ml of methanol, and 5.1 ml of hydrazine monohydrate was added, followed by stirring at room temperature for three days and was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours. The reaction mixture was added with 150 ml of ice-water, 300 ml of ethyl acetate and 100 ml of tetrahydrofuran were added, and unnecessary matters were filtered off. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4), to give 509 mg of the title compound as bright yellow crystals. In addition, a portion with impurities was purified again by silica gel column chromatography (ethyl acetate:n-hexane=1:4 to 1:0), to give 1.80 g of the title compound as bright yellow crystals. was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours were added unnecessary matters were filtered off The organic layer was sequentially washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated The crude product was purified separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4)