2-chloro-4,5-difluorobenzoyl chloride

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Malonic acid monoethyl ester (26 g, 199 mmol) was dissolved in tetrahydrofuran (500 ml) and cooled to -70°. After the addition of n-butyllithium (112.5 ml of a 1.6M solution in hexanes, 180 mmol), the reaction mixture was allowed to warm to -10°, and additional n-butyllithium was added (112.5 ml, as above). The resulting milky-white mixture was cooled to -70°, and treated with 2-chloro-4,5-difluorobenzoyl chloride (19 g, 90 mmol) in tetrahydrofuran (200 ml). After warming to room temperature, the reaction mixture was allowed to stir for an additional 2 hours, then poured into 2N hydrochloric acid (750 ml). The aqueous mixture was extracted with ethyl ether, and the combined organic layers were dried and concentrated to provided the title product as a light amber oil (20.6 g, 78.6 mmol, 87% yield), which was used without further purification. cooled to -70° to warm to -10° The resulting milky-white mixture was cooled to -70° The aqueous mixture was extracted with ethyl ether the combined organic layers were dried concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Malonic acid monoethyl ester (26 g, 199 mmol) was dissolved in tetrahydrofuran (500 ml) and cooled to -70°. After the addition of n-butyllithium (112.5 ml of a 1.6M solution in hexanes, 180 mmol), the reaction mixture was allowed to warm to -10°, and additional n-butyllithium was added (112.5 ml, as above). The resulting milky-white mixture was cooled to -70°, and treated with 2-chloro-4,5-difluorobenzoyl chloride (19 g, 90 mmol) in tetrahydrofuran (200 ml). After warming to room temperature, the reaction mixture was allowed to stir for an additional 2 hours, then poured into 2N hydrochloric acid (750 ml). The aqueous mixture was extracted with ethyl ether, and the combined organic layers were dried and concentrated to provided the title product as a light amber oil (20.6 g, 78.6 mmol, 87% yield), which was used without further purification. cooled to -70° to warm to -10° The resulting milky-white mixture was cooled to -70° The aqueous mixture was extracted with ethyl ether the combined organic layers were dried concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Chloro-4,5-difluorobenzoic acid (19.2 g, 0.1 mol) was mixed with thionyl chloride (50 ml) and heated to reflux for 3 hours. The reaction mixture was evaporated to dryness, and the residue dissolved in methylene chloride. Solvent was removed in vacuo, and the procedure repeated once with methylene chloride and once with benzene. The material (19 g, 0.09 mol, 90% yield) was used without further purification. heated to reflux for 3 hours The reaction mixture was evaporated to dryness the residue dissolved in methylene chloride Solvent was removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Chloro-4,5-difluorobenzoic acid (19.2 g, 0.1 mol) was mixed with thionyl chloride (50 ml) and heated to reflux for 3 hours. The reaction mixture was evaporated to dryness, and the residue dissolved in methylene chloride. Solvent was removed in vacuo, and the procedure repeated once with methylene chloride and once with benzene. The material (19 g, 0.09 mol, 90% yield) was used without further purification. heated to reflux for 3 hours The reaction mixture was evaporated to dryness the residue dissolved in methylene chloride Solvent was removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 6.34 g of magnesium turnings, 13 cc of absolute ethanol and 1.2 ml of carbon tetrachloride were added, and the mixture was stirred. After the initiation of the reaction, a solution comprising 39.9 g of diethyl malonate, 22 cc of absolute ethanol and 75 cc of toluene was dropwise added thereto at a temperature of from 50° to 70° C. After the dropwise addition, the mixture was stirred for two hours. Then, the reaction solution was cooled to -10° to -5° C., and a solution comprising 50 g of 2-chloro-4,5-difluorobenzoyl chloride and 15 ml of toluene was dropwise added thereto. Then, the mixture was stirred for two hours. A dilute sulfuric acid aqueous solution cooled with ice was added thereto, and the content was dissolved, subjected to phase separation and extracted three times with 60 cc of toluene. The organic phase was washed with water, then dried over anhydrous magnesium sulfate and concentrated to obtain 79.2 g of the desired product as a slightly yellow oily substance. After the initiation of the reaction was dropwise added of from 50° to 70° C After the dropwise addition the mixture was stirred for two hours Then, the reaction solution was cooled to -10° to -5° C. was dropwise added Then, the mixture was stirred for two hours was added the content was dissolved subjected to phase separation extracted three times with 60 cc of toluene The organic phase was washed with water dried over anhydrous magnesium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 6.34 g of magnesium turnings, 13 cc of absolute ethanol and 1.2 ml of carbon tetrachloride were added, and the mixture was stirred. After the initiation of the reaction, a solution comprising 39.9 g of diethyl malonate, 22 cc of absolute ethanol and 75 cc of toluene was dropwise added thereto at a temperature of from 50° to 70° C. After the dropwise addition, the mixture was stirred for two hours. Then, the reaction solution was cooled to -10° to -5° C., and a solution comprising 50 g of 2-chloro-4,5-difluorobenzoyl chloride and 15 ml of toluene was dropwise added thereto. Then, the mixture was stirred for two hours. A dilute sulfuric acid aqueous solution cooled with ice was added thereto, and the content was dissolved, subjected to phase separation and extracted three times with 60 cc of toluene. The organic phase was washed with water, then dried over anhydrous magnesium sulfate and concentrated to obtain 79.2 g of the desired product as a slightly yellow oily substance. After the initiation of the reaction was dropwise added of from 50° to 70° C After the dropwise addition the mixture was stirred for two hours Then, the reaction solution was cooled to -10° to -5° C. was dropwise added Then, the mixture was stirred for two hours was added the content was dissolved subjected to phase separation extracted three times with 60 cc of toluene The organic phase was washed with water dried over anhydrous magnesium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 200 cc glass reactor equipped with a reflux condenser, 50 g of 2-chloro-4,5-difluorobenzoylchloride, 13.7 g of spray dried potassium fluoride and 100 g of sulforane were charged and reacted at 135° C. for 4 hours under stirring. After cooling, the inorganic salts were filtered off, and the residue was subjected to distillation under reduced pressure to obtain 42 g of 2-chloro-4,5-difluorobenzoyl fluoride. The physical properties of the obtained 2-choloro-4,5-difluorobenzoyl fluoride were as follows. Into a 200 cc glass reactor equipped with a reflux condenser reacted at 135° C. for 4 hours After cooling the inorganic salts were filtered off the residue was subjected to distillation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 300 cc glass reactor, 100 g of 2-chloro-4,5-difluorobenzoic acid and 200 g of thionyl chloride were charged and stirred at about 60° to 70° C. for 3 hours. Unreacted thionyl chloride was distilled off, and the residue was subjected to distillation under reduced pressure to obtain 101.8 g of 2-chloro-4,5-difluorobenzoyl chloride. The physical properties of the obtained 2-choloro-4,5-difluorobenzoyl chloride were as follows. was distilled off the residue was subjected to distillation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 300 cc glass reactor, 100 g of 2-chloro-4,5-difluorobenzoic acid and 200 g of thionyl chloride were charged and stirred at about 60° to 70° C. for 3 hours. Unreacted thionyl chloride was distilled off, and the residue was subjected to distillation under reduced pressure to obtain 101.8 g of 2-chloro-4,5-difluorobenzoyl chloride. The physical properties of the obtained 2-choloro-4,5-difluorobenzoyl chloride were as follows. was distilled off the residue was subjected to distillation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the chlorination of the reaction formula (a), thionyl chloride, sulfuryl chloride, phosphorus pentachloride or phosphorus oxychloride may be used as the chlorinating agents. Among them, thionyl chloride is preferred. The chlorination may be conducted by reacting 2-chloro-4,5-difluorobenzoic acid with the chlorinating agent at a reaction temperature of from 50 ° to 80° C. in an aprotic polar solvent such as DMF, DMSO or dioxane, or without a solvent, followed by isolation by a usual method such as distillation to obtain 2-chloro-4,5-difluorobenzoyl chloride. of from 50 ° to 80° C. without a solvent, followed by isolation by a usual method such as distillation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the chlorination of the reaction formula (a), thionyl chloride, sulfuryl chloride, phosphorus pentachloride or phosphorus oxychloride may be used as the chlorinating agents. Among them, thionyl chloride is preferred. The chlorination may be conducted by reacting 2-chloro-4,5-difluorobenzoic acid with the chlorinating agent at a reaction temperature of from 50 ° to 80° C. in an aprotic polar solvent such as DMF, DMSO or dioxane, or without a solvent, followed by isolation by a usual method such as distillation to obtain 2-chloro-4,5-difluorobenzoyl chloride. of from 50 ° to 80° C. without a solvent, followed by isolation by a usual method such as distillation