2-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 ml of dimethylformamide was added to a mixture of 25.8 g of 2-chloro-N-(3,4-dimetoxyphenethyl)acetamide, 13.6 g of m-aminobenzamide, 15.0 g of sodium iodide and 20.0 g of calcium carbonate, and the mixture was stirred at 60° C. for 4 hours. The same procedure as described in Example 1 was followed to obtain 2-(3-carbamoylphenylamino)-N-(3,4-dimethoxyphenethyl)acetamide. The product was converted to the corresponding hydrochloride salt as described in Example 5. The salt was recrystallized from a mixture of methanol and diethyl ether to obtain 21.7 g of 2-(3-carbamoylphenylamino)-N-(3,4-dimethoxyphenethyl)acetamide hydrochloride having a melting point of 142°-155° C. (dec.).

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

Procedure: To a mixture of 7.73 g of 2-chloro-N-(3,4-dimetoxyphenethyl)acetamide, 5.12 g of 2-amino-4-chlorobenzamide, 13.5 g of sodium iodide and 3.63 g of magnesium oxide was added 30 ml of dimethylformamide and the resulting mixture was stirred at 90° to 100° C. for 4.5 hours. The reaction solution was concentrated under reduced pressure and the residue was extracted with 500 ml of chloroform. The chloroform extract was washed successively with 10% hydrochloric acid, water, a 5% aqueous sodium carbonate solution, a 5% aqueous sodium sulfite solution and water, dried and then concentrated to dryness under reduced pressure. The residue was recrystallized from methanol to obtain 8.01 g of 2-(2-carbamoyl-5-chlorophenylamino)-N-(3,4-dimethoxyphenethyl)acetamide having a melting point of 167.5°-168.5° C. The reaction solution was concentrated under reduced pressure the residue was extracted with 500 ml of chloroform The chloroform extract was washed successively with 10% hydrochloric acid, water a 5% aqueous sodium carbonate solution, a 5% aqueous sodium sulfite solution and water, dried concentrated to dryness under reduced pressure The residue was recrystallized from methanol

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

Procedure: To a mixture of 7.73 g of 2-chloro-N-(3,4-dimetoxyphenethyl)acetamide, 5.12 g of 2-amino-4-chlorobenzamide, 13.5 g of sodium iodide and 3.63 g of magnesium oxide was added 30 ml of dimethylformamide and the resulting mixture was stirred at 90° to 100° C. for 4.5 hours. The reaction solution was concentrated under reduced pressure and the residue was extracted with 500 ml of chloroform. The chloroform extract was washed successively with 10% hydrochloric acid, water, a 5% aqueous sodium carbonate solution, a 5% aqueous sodium sulfite solution and water, dried and then concentrated to dryness under reduced pressure. The residue was recrystallized from methanol to obtain 8.01 g of 2-(2-carbamoyl-5-chlorophenylamino)-N-(3,4-dimethoxyphenethyl)acetamide having a melting point of 167.5°-168.5° C. The reaction solution was concentrated under reduced pressure the residue was extracted with 500 ml of chloroform The chloroform extract was washed successively with 10% hydrochloric acid, water a 5% aqueous sodium carbonate solution, a 5% aqueous sodium sulfite solution and water, dried concentrated to dryness under reduced pressure The residue was recrystallized from methanol

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

Procedure: 75 ml of dimethylformamide was added to a mixture of 15.0 g of 2-chloro-N-(2-(3,4-dimethoxyphenyl)ethyl)acetamide, 9.5 g of 3-amino-N-ethylbenzamide, 8.7 g of sodium iodide and 11.6 g of calcium carbonate, and the mixture was stirred for 4.5 hours at 55° to 60° C. After cooling, an insoluble material was removed by filtration and, the filtrate was concentrated in vacuo. The residue was extracted with 500 ml of chloroform, and the extract was washed successively with a 10% sodium sulfite aqueous solution and a saturated aqueous solution of sodium chloride. The washings were extracted with 500 ml of chloroform, and the extract was added to the chloroform solution. The combined chloroform solution was dried over sodium sulfate, and the solvent was distilled off. 120 ml of 10% hydrochloric acid was added to the residue, and the mixture was washed 6 times with 30 ml of dichloroethane. The aqueous solution was made alkaline by adding sodium carbonate to form an aggluten-like material. The material was extracted with 300 ml of dichloroethane, and the extract was washed with a saturated aqueous solution of sodium chloride. The washings were extracted with 200 ml of dichloroethane. The extract was added to the above dichloroethane solution, and the mixture was dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on 390 g of silica gel using a mixture of ethyl acetate and ethanol (10:1 by volume) for elution to obtain a fraction containing a product. The solvent of the fraction was distilled off and the residue was recrystallized from a mixture of methanol and diethyl ether to give 10.0 g of 3-((2-((2-(3,4-dimethoxyphenyl)ethyl)amino)-2-oxoethyl)amino)-N-ethylbenzamide as colorless needles with m.p. 99° to 101° C. After cooling an insoluble material was removed by filtration the filtrate was concentrated in vacuo The residue was extracted with 500 ml of chloroform the extract was washed successively with a 10% sodium sulfite aqueous solution The washings were extracted with 500 ml of chloroform the extract was added to the chloroform solution The combined chloroform solution was dried over sodium sulfate the solvent was distilled off 120 ml of 10% hydrochloric acid was added to the residue the mixture was washed 6 times with 30 ml of dichloroethane by adding sodium carbonate to form an aggluten-like material The material was extracted with 300 ml of dichloroethane the extract was washed with a saturated aqueous solution of sodium chloride The washings were extracted with 200 ml of dichloroethane The extract was added to the above dichloroethane solution the mixture was dried over sodium sulfate The solvent was distilled off the residue was purified by column chromatography on 390 g of silica gel using a mixture of ethyl acetate and ethanol (10:1 by volume) for elution to obtain a fraction containing a product The solvent of the fraction was distilled off the residue was recrystallized from a mixture of methanol and diethyl ether

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

Procedure: 75 ml of dimethylformamide was added to a mixture of 15.0 g of 2-chloro-N-(2-(3,4-dimethoxyphenyl)ethyl)acetamide, 9.5 g of 3-amino-N-ethylbenzamide, 8.7 g of sodium iodide and 11.6 g of calcium carbonate, and the mixture was stirred for 4.5 hours at 55° to 60° C. After cooling, an insoluble material was removed by filtration and, the filtrate was concentrated in vacuo. The residue was extracted with 500 ml of chloroform, and the extract was washed successively with a 10% sodium sulfite aqueous solution and a saturated aqueous solution of sodium chloride. The washings were extracted with 500 ml of chloroform, and the extract was added to the chloroform solution. The combined chloroform solution was dried over sodium sulfate, and the solvent was distilled off. 120 ml of 10% hydrochloric acid was added to the residue, and the mixture was washed 6 times with 30 ml of dichloroethane. The aqueous solution was made alkaline by adding sodium carbonate to form an aggluten-like material. The material was extracted with 300 ml of dichloroethane, and the extract was washed with a saturated aqueous solution of sodium chloride. The washings were extracted with 200 ml of dichloroethane. The extract was added to the above dichloroethane solution, and the mixture was dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on 390 g of silica gel using a mixture of ethyl acetate and ethanol (10:1 by volume) for elution to obtain a fraction containing a product. The solvent of the fraction was distilled off and the residue was recrystallized from a mixture of methanol and diethyl ether to give 10.0 g of 3-((2-((2-(3,4-dimethoxyphenyl)ethyl)amino)-2-oxoethyl)amino)-N-ethylbenzamide as colorless needles with m.p. 99° to 101° C. After cooling an insoluble material was removed by filtration the filtrate was concentrated in vacuo The residue was extracted with 500 ml of chloroform the extract was washed successively with a 10% sodium sulfite aqueous solution The washings were extracted with 500 ml of chloroform the extract was added to the chloroform solution The combined chloroform solution was dried over sodium sulfate the solvent was distilled off 120 ml of 10% hydrochloric acid was added to the residue the mixture was washed 6 times with 30 ml of dichloroethane by adding sodium carbonate to form an aggluten-like material The material was extracted with 300 ml of dichloroethane the extract was washed with a saturated aqueous solution of sodium chloride The washings were extracted with 200 ml of dichloroethane The extract was added to the above dichloroethane solution the mixture was dried over sodium sulfate The solvent was distilled off the residue was purified by column chromatography on 390 g of silica gel using a mixture of ethyl acetate and ethanol (10:1 by volume) for elution to obtain a fraction containing a product The solvent of the fraction was distilled off the residue was recrystallized from a mixture of methanol and diethyl ether

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

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

Procedure: 4.5 ml of triethylamine were added to a solution of 5.11 g of 2-(3,4-dimethoxyphenyl)ethylamine dissolved in 35 ml of methylene chloride, and the mixture was stirred, whilst ice-cooling. 2.4 ml of chloroacetyl chloride were then added dropwise to the mixture over a period of 5 minutes, after which the mixture was stirred for 15 minutes, whilst ice-cooling. The reaction mixture was then concentrated by evaporation under reduced pressure, and ethyl acetate was added to the resulting residue. The ethyl acetate solution was washed, in turn, with water, with a 5% w/v aqueous solution of sodium bicarbonate, with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride. It was then dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and hexane, to give 5.77 g of the title compound as pale yellow-brown, feather-like crystals melting at 92-94° C. cooling after which the mixture was stirred for 15 minutes, whilst ice- cooling The reaction mixture was then concentrated by evaporation under reduced pressure, and ethyl acetate was added to the resulting residue The ethyl acetate solution was washed, in turn, with water, with a 5% w/v aqueous solution of sodium bicarbonate, with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride It was then dried the solvent was distilled off under reduced pressure The residue was recrystallized from a mixture of ethyl acetate and hexane

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

Procedure: 442 mg of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-5-methyl-1,2,4-triazin-3(2H)-one [prepared as described in step (a) above] were added to a stirred suspension of 85 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 7 ml of anhydrous dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the ice-cooled suspension were then added 472 mg of α-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (prepared as described in Preparation 1), and the reaction mixture was stirred at room temperature for 1 hour and then at 100° C. (bath temperature) for a further 1 hour. The dimethylformamide used as the solvent was removed by evaporation under reduced pressure, and then the mixture was diluted with ethyl acetate. It was then washed with water and with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The residue was collected by filtration and then recrystallized from a mixture of chloroform and ethyl acetate, to give 326 mg of the title compound as a white powder melting at 167°-169° C. (with decomposition). whilst ice-cooling the reaction mixture was stirred at room temperature for 1 hour at 100° C. (bath temperature) for a further 1 hour was removed by evaporation under reduced pressure the mixture was diluted with ethyl acetate It was then washed with water and with a saturated aqueous solution of sodium chloride dried concentrated by evaporation under reduced pressure The residue was collected by filtration recrystallized from a mixture of chloroform and ethyl acetate

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

Procedure: 505 mg of ethyl N-[2-(3-chloro-4-hydroxyphenyl)-1-methyl-2-oxoethyl]carbamate [prepared as described in step (b) above] were added to a suspension of 81 mg of sodium hydride (as a 55% w/w suspension in mineral oil) in 6 ml of anhydrous dimethylformamide, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour. The suspension was then cooled, and 476 mg of α-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (prepared as described in Preparation 1) were added thereto. The mixture was stirred at room temperature for 2 hours and then at 100° C. (bath temperature) for 3 hours. At the end of this time, the dimethylformamide used as the solvent was removed by evaporation under reduced pressure, and water was added to the residue. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel. After elution of impurities with a 2:1 by volume mixture of ethyl acetate and hexane, 556 mg of the title compound were obtained from the fractions eluted with ethyl acetate as a pale yellow powder melting at 113°-114° C. whilst ice-cooling The suspension was then cooled The mixture was stirred at room temperature for 2 hours at 100° C. (bath temperature) for 3 hours was removed by evaporation under reduced pressure, and water was added to the residue The aqueous mixture was extracted with ethyl acetate the extract was washed with a saturated aqueous solution of sodium chloride dried concentrated by evaporation under reduced pressure The residue was purified by column chromatography through silica gel After elution of impurities with a 2:1 by volume mixture of ethyl acetate and hexane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 ml of dimethylformamide was added to a mixture of 25.8 g of 2-chloro-N-(3,4-dimetoxyphenethyl)acetamide, 13.6 g of m-aminobenzamide, 15.0 g of sodium iodide and 20.0 g of calcium carbonate, and the mixture was stirred at 60° C. for 4 hours. The same procedure as described in Example 1 was followed to obtain 2-(3-carbamoylphenylamino)-N-(3,4-dimethoxyphenethyl)acetamide. The product was converted to the corresponding hydrochloride salt as described in Example 5. The salt was recrystallized from a mixture of methanol and diethyl ether to obtain 21.7 g of 2-(3-carbamoylphenylamino)-N-(3,4-dimethoxyphenethyl)acetamide hydrochloride having a melting point of 142°-155° C. (dec.).

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

Procedure: To a mixture of 7.73 g of 2-chloro-N-(3,4-dimetoxyphenethyl)acetamide, 5.12 g of 2-amino-4-chlorobenzamide, 13.5 g of sodium iodide and 3.63 g of magnesium oxide was added 30 ml of dimethylformamide and the resulting mixture was stirred at 90° to 100° C. for 4.5 hours. The reaction solution was concentrated under reduced pressure and the residue was extracted with 500 ml of chloroform. The chloroform extract was washed successively with 10% hydrochloric acid, water, a 5% aqueous sodium carbonate solution, a 5% aqueous sodium sulfite solution and water, dried and then concentrated to dryness under reduced pressure. The residue was recrystallized from methanol to obtain 8.01 g of 2-(2-carbamoyl-5-chlorophenylamino)-N-(3,4-dimethoxyphenethyl)acetamide having a melting point of 167.5°-168.5° C. The reaction solution was concentrated under reduced pressure the residue was extracted with 500 ml of chloroform The chloroform extract was washed successively with 10% hydrochloric acid, water a 5% aqueous sodium carbonate solution, a 5% aqueous sodium sulfite solution and water, dried concentrated to dryness under reduced pressure The residue was recrystallized from methanol