2-chloro-3,4-difluorobenzamide

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzamide (11.85 g, 62 mmol) was dissolved in tetrahydrofuran (200 ml) and treated with 1M borane tetrahydrofuran (247 ml, 247 mmol). The mixture was heated to 70° C. and stirred for 18 hrs. The mixture was then cooled in an ice-water bath and concentrated aqueous hydrogen chloride (150 ml) was added dropwise. Heating, with stirring, at 70° C. was then resumed for a further 2 hrs. The mixture was then allowed to cool and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml). The aqueous layer was separated and the pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide. The resulting cloudy suspension was extracted with ethyl acetate (4×200 ml) and the combined organic extracts were then passed through a hydrophobic frit and reduced in volume to ˜200 ml. The mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml) resulting in formation of a precipitate. The solvent was evaporated in vacuo to give a white solid. The solid was recrystallised from methylated spirit (60 ml) to give three crops of pure [(2-chloro-3,4-difluorophenyl)methyl]amine hydrochloride (combined mass=4.46 g) as a white solid. The mixture was then cooled in an ice-water bath Heating with stirring, at 70° C. was then resumed for a further 2 hrs to cool the solvent was evaporated in vacuo The residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml) The aqueous layer was separated the pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide The resulting cloudy suspension was extracted with ethyl acetate (4×200 ml) The mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml) resulting in formation of a precipitate The solvent was evaporated in vacuo to give a white solid The solid was recrystallised from methylated spirit (60 ml)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzoic acid (2 g, 10.4 mmol) was treated with thionyl chloride (3.04 ml) and the mixture was heated to 80° C. for 90 minutes. The mixture was then cooled and reduced in vacuo. The residue was dissolved in anhydrous 1,4-dioxane (10 ml) and the mixture was then cooled in an ice-water bath. 0.88 Ammonia (aqueous, 25 ml) was added dropwise to the mixture which was subsequently allowed to warm to 22° C. over a period of 2 hrs. This process was repeated using 10.8 g of 2-chloro-3,4-difluorobenzoic acid, 8.2 ml of thionyl chloride, and 45 ml of 0.88 ammonia and then both mixtures were combined and partitioned between ethyl acetate (150 ml) and water (100 ml). The aqueous layer was separated and extracted with 2×150 ml aliquots of ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml), dried using a hydrophobic frit, and reduced in vacuo to give 2-chloro-3,4-difluorobenzamide (11.86 g) as a white solid. The mixture was then cooled the mixture was then cooled in an ice-water bath to warm to 22° C. over a period of 2 hrs partitioned between ethyl acetate (150 ml) and water (100 ml) The aqueous layer was separated extracted with 2×150 ml aliquots of ethyl acetate The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml) dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzoic acid (2 g, 10.4 mmol) was treated with thionyl chloride (3.04 ml) and the mixture was heated to 80° C. for 90 minutes. The mixture was then cooled and reduced in vacuo. The residue was dissolved in anhydrous 1,4-dioxane (10 ml) and the mixture was then cooled in an ice-water bath. 0.88 Ammonia (aqueous, 25 ml) was added dropwise to the mixture which was subsequently allowed to warm to 22° C. over a period of 2 hrs. This process was repeated using 10.8 g of 2-chloro-3,4-difluorobenzoic acid, 8.2 ml of thionyl chloride, and 45 ml of 0.88 ammonia and then both mixtures were combined and partitioned between ethyl acetate (150 ml) and water (100 ml). The aqueous layer was separated and extracted with 2×150 ml aliquots of ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml), dried using a hydrophobic frit, and reduced in vacuo to give 2-chloro-3,4-difluorobenzamide (11.86 g) as a white solid. The mixture was then cooled the mixture was then cooled in an ice-water bath to warm to 22° C. over a period of 2 hrs partitioned between ethyl acetate (150 ml) and water (100 ml) The aqueous layer was separated extracted with 2×150 ml aliquots of ethyl acetate The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml) dried

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzamide (11.85 g, 62 mmol) was dissolved in tetrahydrofuran (200 ml) and treated with 1M borane tetrahydrofuran (247 ml, 247 mmol). The mixture was heated to 70° C. and stirred for 18 hrs. The mixture was then cooled in an ice-water bath and concentrated aqueous hydrogen chloride (150 ml) was added dropwise. Heating, with stirring, at 70° C. was then resumed for a further 2 hrs. The mixture was then allowed to cool and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml). The aqueous layer was separated and the pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide. The resulting cloudy suspension was extracted with ethyl acetate (4×200 ml) and the combined organic extracts were then passed through a hydrophobic frit and reduced in volume to ˜200 ml. The mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml) resulting in formation of a precipitate. The solvent was evaporated in vacuo to give a white solid. The solid was recrystallised from methylated spirit (60 ml) to give three crops of pure [(2-chloro-3,4-difluorophenyl)methyl]amine hydrochloride (combined mass=4.46 g) as a white solid. The mixture was then cooled in an ice-water bath Heating with stirring, at 70° C. was then resumed for a further 2 hrs to cool the solvent was evaporated in vacuo The residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml) The aqueous layer was separated the pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide The resulting cloudy suspension was extracted with ethyl acetate (4×200 ml) The mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml) resulting in formation of a precipitate The solvent was evaporated in vacuo to give a white solid The solid was recrystallised from methylated spirit (60 ml)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzoic acid (2 g, 10.4 mmol) was treated with thionyl chloride (3.04 ml) and the mixture was heated to 80° C. for 90 minutes. The mixture was then cooled and reduced in vacuo. The residue was dissolved in anhydrous 1,4-dioxane (10 ml) and the mixture was then cooled in an ice-water bath. 0.88 Ammonia (aqueous, 25 ml) was added dropwise to the mixture which was subsequently allowed to warm to 22° C. over a period of 2 hrs. This process was repeated using 10.8 g of 2-chloro-3,4-difluorobenzoic acid, 8.2 ml of thionyl chloride, and 45 ml of 0.88 ammonia and then both mixtures were combined and partitioned between ethyl acetate (150 ml) and water (100 ml). The aqueous layer was separated and extracted with 2×150 ml aliquots of ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml), dried using a hydrophobic frit, and reduced in vacuo to give 2-chloro-3,4-difluorobenzamide (11.86 g) as a white solid. The mixture was then cooled the mixture was then cooled in an ice-water bath to warm to 22° C. over a period of 2 hrs partitioned between ethyl acetate (150 ml) and water (100 ml) The aqueous layer was separated extracted with 2×150 ml aliquots of ethyl acetate The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml) dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzoic acid (2 g, 10.4 mmol) was treated with thionyl chloride (3.04 ml) and the mixture was heated to 80° C. for 90 minutes. The mixture was then cooled and reduced in vacuo. The residue was dissolved in anhydrous 1,4-dioxane (10 ml) and the mixture was then cooled in an ice-water bath. 0.88 Ammonia (aqueous, 25 ml) was added dropwise to the mixture which was subsequently allowed to warm to 22° C. over a period of 2 hrs. This process was repeated using 10.8 g of 2-chloro-3,4-difluorobenzoic acid, 8.2 ml of thionyl chloride, and 45 ml of 0.88 ammonia and then both mixtures were combined and partitioned between ethyl acetate (150 ml) and water (100 ml). The aqueous layer was separated and extracted with 2×150 ml aliquots of ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml), dried using a hydrophobic frit, and reduced in vacuo to give 2-chloro-3,4-difluorobenzamide (11.86 g) as a white solid. The mixture was then cooled the mixture was then cooled in an ice-water bath to warm to 22° C. over a period of 2 hrs partitioned between ethyl acetate (150 ml) and water (100 ml) The aqueous layer was separated extracted with 2×150 ml aliquots of ethyl acetate The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml) dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzoic acid (2 g, 10.4 mmol) was treated with thionyl chloride (3.04 ml) and the mixture was heated to 80° C. for 90 minutes. The mixture was then cooled and reduced in vacuo. The residue was dissolved in anhydrous 1,4-dioxane (10 ml) and the mixture was then cooled in an ice-water bath. 0.88 Ammonia (aqueous, 25 ml) was added dropwise to the mixture which was subsequently allowed to warm to 22° C. over a period of 2 hrs. This process was repeated using 10.8 g of 2-chloro-3,4-difluorobenzoic acid, 8.2 ml of thionyl chloride, and 45 ml of 0.88 ammonia and then both mixtures were combined and partitioned between ethyl acetate (150 ml) and water (100 ml). The aqueous layer was separated and extracted with 2×150 ml aliquots of ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml), dried using a hydrophobic frit, and reduced in vacuo to give 2-chloro-3,4-difluorobenzamide (11.86 g) as a white solid. The mixture was then cooled the mixture was then cooled in an ice-water bath to warm to 22° C. over a period of 2 hrs partitioned between ethyl acetate (150 ml) and water (100 ml) The aqueous layer was separated extracted with 2×150 ml aliquots of ethyl acetate The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml) dried

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

Procedure: To a mixture of 2-chloro-3,4-difluorobenzamide (1.20 g), pyridine (1.01 mL) and N,N-dimethylformamide (18 mL) was added oxalyl chloride (0.82 mL) at 0° C. over 10 min. The mixture was stirred for 1 hr while raising the temperature to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane) to give the title compound as a solid (yield: 983 mg). extracted with ethyl acetate The organic layer was washed with water dried over anhydrous sodium sulfate concentrated The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane)

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

Procedure: To a mixture of 2-chloro-3,4-difluorobenzoic acid (2.50 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.99 g), 1-hydroxybenztriazole (2.39 g) and N,N-dimethylformamide (72 mL) was added 28% aqueous ammonia (1.6 mL) at room temperature, and the mixture was stirred for 40 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane). The obtained solid was washed with dichloromethane to give the title compound as a solid (yield: 1.30 g). extracted with ethyl acetate The organic layer was washed with water dried over anhydrous sodium sulfate concentrated The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane) The obtained solid was washed with dichloromethane

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzamide (11.85 g, 62 mmol) was dissolved in tetrahydrofuran (200 ml) and treated with 1M borane tetrahydrofuran (247 ml, 247 mmol). The mixture was heated to 70° C. and stirred for 18 hrs. The mixture was then cooled in an ice-water bath and concentrated aqueous hydrogen chloride (150 ml) was added dropwise. Heating, with stirring, at 70° C. was then resumed for a further 2 hrs. The mixture was then allowed to cool and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml). The aqueous layer was separated and the pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide. The resulting cloudy suspension was extracted with ethyl acetate (4×200 ml) and the combined organic extracts were then passed through a hydrophobic frit and reduced in volume to ˜200 ml. The mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml) resulting in formation of a precipitate. The solvent was evaporated in vacuo to give a white solid. The solid was recrystallised from methylated spirit (60 ml) to give three crops of pure [(2-chloro-3,4-difluorophenyl)methyl]amine hydrochloride (combined mass=4.46 g) as a white solid. The mixture was then cooled in an ice-water bath Heating with stirring, at 70° C. was then resumed for a further 2 hrs to cool the solvent was evaporated in vacuo The residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml) The aqueous layer was separated the pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide The resulting cloudy suspension was extracted with ethyl acetate (4×200 ml) The mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml) resulting in formation of a precipitate The solvent was evaporated in vacuo to give a white solid The solid was recrystallised from methylated spirit (60 ml)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-3,4-difluorobenzoic acid (2 g, 10.4 mmol) was treated with thionyl chloride (3.04 ml) and the mixture was heated to 80° C. for 90 minutes. The mixture was then cooled and reduced in vacuo. The residue was dissolved in anhydrous 1,4-dioxane (10 ml) and the mixture was then cooled in an ice-water bath. 0.88 Ammonia (aqueous, 25 ml) was added dropwise to the mixture which was subsequently allowed to warm to 22° C. over a period of 2 hrs. This process was repeated using 10.8 g of 2-chloro-3,4-difluorobenzoic acid, 8.2 ml of thionyl chloride, and 45 ml of 0.88 ammonia and then both mixtures were combined and partitioned between ethyl acetate (150 ml) and water (100 ml). The aqueous layer was separated and extracted with 2×150 ml aliquots of ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml), dried using a hydrophobic frit, and reduced in vacuo to give 2-chloro-3,4-difluorobenzamide (11.86 g) as a white solid. The mixture was then cooled the mixture was then cooled in an ice-water bath to warm to 22° C. over a period of 2 hrs partitioned between ethyl acetate (150 ml) and water (100 ml) The aqueous layer was separated extracted with 2×150 ml aliquots of ethyl acetate The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml) dried