ethyl 2-(methylamino)-2-oxoacetate

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

Procedure: 18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester are dissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and 59 ml of a 20% solution of phosgene in toluene are added thereto. At a temperature of 5°-10°, 9.2 ml of pyridine are added dropwise. The reaction mixture is then stirred for 2 hours at 0°, nitrogen being blown through the reaction mixture during the second hour. 17.6 g (95 mmol) of 2,6-difluorophenylacetic acid hydrazide are then added. The reaction mixture is subsequently stirred for 40 minutes at room temperature, then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted three times with ether. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution and extracted by shaking three times with dichloromethane. The combined dichloromethane phases are washed twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 160 ml of xylene and stirred under reflux for 9 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and the crystalline residue is recrystallised from ethyl acetate/ether. 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 127°-128° is obtained. The reaction mixture is subsequently stirred for 40 minutes at room temperature poured onto ice-water extracted three times with ether extracted by shaking three times with dichloromethane The combined dichloromethane phases are washed twice with water dried over magnesium sulphate concentrated by evaporation stirred under reflux for 9 hours The reaction mixture is then concentrated chromatographed over silica gel The eluate is concentrated by evaporation the crystalline residue is recrystallised from ethyl acetate/ether

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

Procedure: 18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester are dissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and 59 ml of a 20% solution of phosgene in toluene are added thereto. At a temperature of 5°-10°, 9.2 ml of pyridine are added dropwise. The reaction mixture is then stirred for 2 hours at 0°, nitrogen being blown through the reaction mixture during the second hour. 17.6 g (95 mmol) of 2,6-difluorophenylacetic acid hydrazide are then added. The reaction mixture is subsequently stirred for 40 minutes at room temperature, then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted three times with ether. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution and extracted by shaking three times with dichloromethane. The combined dichloromethane phases are washed twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 160 ml of xylene and stirred under reflux for 9 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and the crystalline residue is recrystallised from ethyl acetate/ether. 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 127°-128° is obtained. The reaction mixture is subsequently stirred for 40 minutes at room temperature poured onto ice-water extracted three times with ether extracted by shaking three times with dichloromethane The combined dichloromethane phases are washed twice with water dried over magnesium sulphate concentrated by evaporation stirred under reflux for 9 hours The reaction mixture is then concentrated chromatographed over silica gel The eluate is concentrated by evaporation the crystalline residue is recrystallised from ethyl acetate/ether

Conditions: temp:175.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3-diaminotoluene (2.0 g) and ethyl N-methyloxamate (2.36 g) in N,N-dimethylformamide (10 ml) was stirred at 175° C. for 8 hours. After being cooled to ambient temperature, the mixture as poured into a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixtue of chloroform and methanol (50:1) to give 4-methyl-2-(N-methylcarbamoyl)-1H-benzimidazole (1.17 g) as a powder. After being cooled to ambient temperature the organic layer was separated The organic layer was washed with brine the solution was dried over magnesium sulfate The solvent was evaporated in vacuo the residue was chromatographed on silica gel eluting with a mixtue of chloroform and methanol (50:1)

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

Procedure: 18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester are dissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and 59 ml of a 20% solution of phosgene in toluene are added thereto. At a temperature of 5-10°, 9.2 ml of pyridine are added dropwise. The reaction mixture is then stirred for 2 hours at 0°, nitrogen being blown through the reaction mixture during the second hour. 17.6 g (95 mmol) of 2,6-difluorophenylacetic acid hydrazide are then added The reaction mixture is subsequently stirred for 40 minutes at room temperature, then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted three times with ether. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution and extracted by shaking three times with dichloromethane. The combined dichloromethane phases are washed twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 160 ml of xylene and stirred under reflux for 9 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and the crystalline residue is recrystallised from ethyl acetate/ether. 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 127-128° is obtained. is subsequently stirred for 40 minutes at room temperature poured onto ice-water extracted three times with ether extracted by shaking three times with dichloromethane The combined dichloromethane phases are washed twice with water dried over magnesium sulphate concentrated by evaporation stirred under reflux for 9 hours The reaction mixture is then concentrated chromatographed over silica gel The eluate is concentrated by evaporation the crystalline residue is recrystallised from ethyl acetate/ether

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

Procedure: 18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester are dissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and 59 ml of a 20% solution of phosgene in toluene are added thereto. At a temperature of 5-10°, 9.2 ml of pyridine are added dropwise. The reaction mixture is then stirred for 2 hours at 0°, nitrogen being blown through the reaction mixture during the second hour. 17.6 g (95 mmol) of 2,6-difluorophenylacetic acid hydrazide are then added The reaction mixture is subsequently stirred for 40 minutes at room temperature, then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted three times with ether. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution and extracted by shaking three times with dichloromethane. The combined dichloromethane phases are washed twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 160 ml of xylene and stirred under reflux for 9 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and the crystalline residue is recrystallised from ethyl acetate/ether. 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 127-128° is obtained. is subsequently stirred for 40 minutes at room temperature poured onto ice-water extracted three times with ether extracted by shaking three times with dichloromethane The combined dichloromethane phases are washed twice with water dried over magnesium sulphate concentrated by evaporation stirred under reflux for 9 hours The reaction mixture is then concentrated chromatographed over silica gel The eluate is concentrated by evaporation the crystalline residue is recrystallised from ethyl acetate/ether

Conditions: temp:175.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3-diaminotoluene (2.0 g) and ethyl N-methyloxamate (2.36 g) in N,N-dimethylformamide (10 ml) was stirred at 175° C. for 8 hours. After being cooled to ambient temperature, the mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (50:1) to give 4-methyl-2-(N-methylcarbamoyl)-1 H-benzimidazole (1.17 g) as a powder. After being cooled to ambient temperature the organic layer was separated The organic layer was washed with brine the solution was dried over magnesium sulfate The solvent was evaporated in vacuo the residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (50:1)

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

Procedure: 18.6 g (142 mmol) of oxalic acid monomethylamide monoethyl ester are dissolved under a nitrogen atmosphere in 63 ml of trichloromethane, and 59 ml of a 20% solution of phosgene in toluene are added thereto. At a temperature of 5°-10°, 9.2 ml of pyridine are added dropwise. The reaction mixture is then stirred for 2 hours at 0°, nitrogen being blown through the reaction mixture during the second hour. 17.6 g (95 mmol) of 2,6-difluorophenylacetic acid hydrazide are then added. The reaction mixture is subsequently stirred for 40 minutes at room temperature, then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted three times with ether. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution and extracted by shaking three times with dichloromethane. The combined dichloromethane phases are washed twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 160 ml of xylene and stirred under reflux for 9 hours. The reaction mixture is then concentrated and chromatographed over silica gel using ethyl acetate as eluant. The eluate is concentrated by evaporation and the crystalline residue is recrystallised from ethyl acetate/ether. 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxylic acid ethyl ester of m.p. 127°-128° is obtained. The reaction mixture is subsequently stirred for 40 minutes at room temperature poured onto ice-water extracted three times with ether extracted by shaking three times with dichloromethane The combined dichloromethane phases are washed twice with water dried over magnesium sulphate concentrated by evaporation stirred under reflux for 9 hours The reaction mixture is then concentrated chromatographed over silica gel The eluate is concentrated by evaporation the crystalline residue is recrystallised from ethyl acetate/ether

Conditions: temp:175.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,3-diaminotoluene (2.0 g) and ethyl N-methyloxamate (2.36 g) in N,N-dimethylformamide (10 ml) was stirred at 175° C. for 8 hours. After being cooled to ambient temperature, the mixture as poured into a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixtue of chloroform and methanol (50:1) to give 4-methyl-2-(N-methylcarbamoyl)-1H-benzimidazole (1.17 g) as a powder. After being cooled to ambient temperature the organic layer was separated The organic layer was washed with brine the solution was dried over magnesium sulfate The solvent was evaporated in vacuo the residue was chromatographed on silica gel eluting with a mixtue of chloroform and methanol (50:1)