N'-benzyl-N'-methylethane-1,2-diamine

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 solution of 17.90 g (0.045 mole) of N-methyl-N-(phenylmethyl)-1,2-ethanediamine and 1,1'-carbonyldiimidazole (0.05 mole) in 100 ml of tetrahydrofuran was stirred at room temperature for 1 hour. To the mixture was added 10.52 g, (0.04 mole) of 1-methyl-N-[2-(phenylsulfonyl)ethyl]ethanamine and the resulting solution heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform and water; removal of chloroform gave a dark brown oil. The oil was dissolved in chloroform and extracted with 1N sulfuric acid (saturated with sodium chloride). The acidic layer was made alkaline, extracted with chloroform, and the solvent removed to give a light brown oil. The oil was subjected to chromatography on a Florisil column and eluted with methanol-methylene chloride. After combining appropriate fractions from the column and removing solvent, an oil was obtained. The oil was triturated with diethyl ether and dried at 80° C. in vacuo overnight. This furnished 6.75 g (40.4%) of clear oil. the resulting solution heated overnight at gentle reflux partitioned between chloroform and water removal of chloroform gave a dark brown oil extracted with 1N sulfuric acid (saturated with sodium chloride) extracted with chloroform the solvent removed to give a light brown oil eluted with methanol-methylene chloride removing solvent an oil was obtained The oil was triturated with diethyl ether dried at 80° C. in vacuo overnight

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

Procedure: A solution of 17.90 g (0.045 mole) of N-methyl-N-(phenylmethyl)-1,2-ethanediamine and 1,1'-carbonyldiimidazole (0.05 mole) in 100 ml of tetrahydrofuran was stirred at room temperature for 1 hour. To the mixture was added 10.52 g, (0.04 mole) of 1-methyl-N-[2-(phenylsulfonyl)ethyl]ethanamine and the resulting solution heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform and water; removal of chloroform gave a dark brown oil. The oil was dissolved in chloroform and extracted with 1N sulfuric acid (saturated with sodium chloride). The acidic layer was made alkaline, extracted with chloroform, and the solvent removed to give a light brown oil. The oil was subjected to chromatography on a Florisil column and eluted with methanol-methylene chloride. After combining appropriate fractions from the column and removing solvent, an oil was obtained. The oil was triturated with diethyl ether and dried at 80° C. in vacuo overnight. This furnished 6.75 g (40.4%) of clear oil. the resulting solution heated overnight at gentle reflux partitioned between chloroform and water removal of chloroform gave a dark brown oil extracted with 1N sulfuric acid (saturated with sodium chloride) extracted with chloroform the solvent removed to give a light brown oil eluted with methanol-methylene chloride removing solvent an oil was obtained The oil was triturated with diethyl ether dried at 80° C. in vacuo overnight

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

Procedure: In 70 ml of methylene chloride were dissolved 3.24 g of 2-(N-methyl-N-benzylamino)ethylamine and 2.0 g of triethylamine, and to the solution was added dropwise 50 ml of a methylene chloride solution containing 3.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for one hour, and then the reaction solution was washed with water and extracted with a 10% aqueous hydrochloric acid solution. The aqueous layer was washed with chloroform, rendered alkaline with a 1N aqueous sodium hydroxide solution, extracted with chloroform, and then the chloroform layer was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel:100 g; solvent:chloroform) to give 3.84 g of N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (65) in a yield of 84%. under cooling with ice the reaction solution was washed with water extracted with a 10% aqueous hydrochloric acid solution The aqueous layer was washed with chloroform extracted with chloroform the chloroform layer was washed with water dried with anhydrous magnesium sulfate the chloroform was distilled The residue thus obtained

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

Procedure: In 70 ml of methylene chloride were dissolved 3.24 g of 2-(N-methyl-N-benzylamino)ethylamine and 2.0 g of triethylamine, and to the solution was added dropwise 50 ml of a methylene chloride solution containing 3.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for one hour, and then the reaction solution was washed with water and extracted with a 10% aqueous hydrochloric acid solution. The aqueous layer was washed with chloroform, rendered alkaline with a 1N aqueous sodium hydroxide solution, extracted with chloroform, and then the chloroform layer was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel:100 g; solvent:chloroform) to give 3.84 g of N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (65) in a yield of 84%. under cooling with ice the reaction solution was washed with water extracted with a 10% aqueous hydrochloric acid solution The aqueous layer was washed with chloroform extracted with chloroform the chloroform layer was washed with water dried with anhydrous magnesium sulfate the chloroform was distilled The residue thus obtained

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

Procedure: Reaction of 2-(2-aminoethyl)-5-chloro-7,10-bis-(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one with N-methyl-N-(phenylmethyl)-1,2-ethanediamine as described in Example 78 gives the product; mp 169°-172° C. gives the product

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 17 ml dry dimethylformamide in 40 ml dry dioxan are cooled to 0° C. and 1.0 g (7.9 mMole) oxalyl chloride added dropwise thereto under an atmosphere of nitrogen. After 20 minutes, 2.7 g (6.9 mMole) (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid (European Patent Application 173 933) are added portionwise thereto at 0° C. and the reaction mixture is warmed to 20° C. After 30 minutes at 20° C., this solution is added dropwise to a solution, cooled to 0° C., of 2.6 g (15.8 mMole) N-benzyl-N-methylethylene-diamine in 20 ml n-hexane. After warming to 20° C., the reaction mixture is stirred for 30 minutes then, with renewed ice cooling, 2 N aqueous sodium carbonate solution is added dropwise thereto and the reaction mixture is extracted twice with dichloromethane. The dichloromethane solutions are washed with water and dried over anhydrous sodium sulphate. The solvent is removed in a vacuum and the residue is chromatographed on silica gel with dichloromethane/methanol (9:1 v/v). The fraction with the Rf of 0.5 is isolated, dissolved in diethyl ether and the dihydrochloride precipitated out with hydrogen chloride in diethyl ether. This is recrystallized twice from acetonitrile. There is obtained (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid 2-(N-benzyl-N-methylamino)-ethylamide dihydrochloride in the form of colorless crystals; mp 178°-180° C. After 30 minutes at 20° C. this solution is added dropwise to a solution After warming to 20° C. the reaction mixture is extracted twice with dichloromethane The dichloromethane solutions are washed with water dried over anhydrous sodium sulphate The solvent is removed in a vacuum the residue is chromatographed on silica gel with dichloromethane/methanol (9:1 v/v) The fraction with the Rf of 0.5 is isolated the dihydrochloride precipitated out with hydrogen chloride in diethyl ether This is recrystallized twice from acetonitrile

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 17 ml dry dimethylformamide in 40 ml dry dioxan are cooled to 0° C. and 1.0 g (7.9 mMole) oxalyl chloride added dropwise thereto under an atmosphere of nitrogen. After 20 minutes, 2.7 g (6.9 mMole) (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid (European Patent Application 173 933) are added portionwise thereto at 0° C. and the reaction mixture is warmed to 20° C. After 30 minutes at 20° C., this solution is added dropwise to a solution, cooled to 0° C., of 2.6 g (15.8 mMole) N-benzyl-N-methylethylene-diamine in 20 ml n-hexane. After warming to 20° C., the reaction mixture is stirred for 30 minutes then, with renewed ice cooling, 2 N aqueous sodium carbonate solution is added dropwise thereto and the reaction mixture is extracted twice with dichloromethane. The dichloromethane solutions are washed with water and dried over anhydrous sodium sulphate. The solvent is removed in a vacuum and the residue is chromatographed on silica gel with dichloromethane/methanol (9:1 v/v). The fraction with the Rf of 0.5 is isolated, dissolved in diethyl ether and the dihydrochloride precipitated out with hydrogen chloride in diethyl ether. This is recrystallized twice from acetonitrile. There is obtained (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid 2-(N-benzyl-N-methylamino)-ethylamide dihydrochloride in the form of colorless crystals; mp 178°-180° C. After 30 minutes at 20° C. this solution is added dropwise to a solution After warming to 20° C. the reaction mixture is extracted twice with dichloromethane The dichloromethane solutions are washed with water dried over anhydrous sodium sulphate The solvent is removed in a vacuum the residue is chromatographed on silica gel with dichloromethane/methanol (9:1 v/v) The fraction with the Rf of 0.5 is isolated the dihydrochloride precipitated out with hydrogen chloride in diethyl ether This is recrystallized twice from acetonitrile

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

Procedure: A solution of 17.90 g (0.045 mole) of N-methyl-N-(phenylmethyl)-1,2-ethanediamine and 1,1'-carbonyldiimidazole (0.05 mole) in 100 ml of tetrahydrofuran was stirred at room temperature for 1 hour. To the mixture was added 10.52 g, (0.04 mole) of 1-methyl-N-[2-(phenysulfonyl)ethyl]ethanamine and the resulting solution heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform and water; removal of chloroform gave a dark brown oil. The oil was dissolved in chloroform and extracted with 1N sulfuric acid (saturated with sodium chloride). The acidic layer was made alkaline, extracted with chloroform, and the solvent removed to give a light brown oil. The oil was subjected to chromatography on a Florisil column and eluted with methanol-methylene chloride. After combining appropriate fractions from the column and removing solvent, an oil was obtained. The oil was triturated with diethyl ether and dried at 80° C. in vacuo overnight. This furnished 6.75 g (40.4%) of clear oil. the resulting solution heated overnight at gentle reflux partitioned between chloroform and water removal of chloroform gave a dark brown oil extracted with 1N sulfuric acid (saturated with sodium chloride) extracted with chloroform the solvent removed to give a light brown oil eluted with methanol-methylene chloride removing solvent an oil was obtained The oil was triturated with diethyl ether dried at 80° C. in vacuo overnight

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

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

Procedure: A solution of 17.90 g (0.045 mole) of N-methyl-N-(phenylmethyl)-1,2-ethanediamine and 1,1'-carbonyldiimidazole (0.05 mole) in 100 ml of tetrahydrofuran was stirred at room temperature for 1 hour. To the mixture was added 10.52 g, (0.04 mole) of 1-methyl-N-[2-(phenysulfonyl)ethyl]ethanamine and the resulting solution heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform and water; removal of chloroform gave a dark brown oil. The oil was dissolved in chloroform and extracted with 1N sulfuric acid (saturated with sodium chloride). The acidic layer was made alkaline, extracted with chloroform, and the solvent removed to give a light brown oil. The oil was subjected to chromatography on a Florisil column and eluted with methanol-methylene chloride. After combining appropriate fractions from the column and removing solvent, an oil was obtained. The oil was triturated with diethyl ether and dried at 80° C. in vacuo overnight. This furnished 6.75 g (40.4%) of clear oil. the resulting solution heated overnight at gentle reflux partitioned between chloroform and water removal of chloroform gave a dark brown oil extracted with 1N sulfuric acid (saturated with sodium chloride) extracted with chloroform the solvent removed to give a light brown oil eluted with methanol-methylene chloride removing solvent an oil was obtained The oil was triturated with diethyl ether dried at 80° C. in vacuo overnight