4-[2-(Dimethylamino)ethoxy]benzylamine

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

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

Procedure: FR 2549828 discloses a multistage process for preparing 4-[2-(dimethylamino)ethoxy]benzylamine starting from phenol. Reaction of phenol with ethylenechlorohydrin initially delivers 2-phenoxyethanol which is reacted with thionyl chloride to give 2-phenoxyethyl chloride. After distilling this intermediate, it is reacted with acetamide and paraformaldehyde and then treated with mineral acid to give N-(2-chloroethoxybenzyl)acetamide. Reaction with dimethylamine then leads to N-[2-(dimethylamino)-ethoxy]acetamide, from which the desired product is released by acid hydrolysis. The process disclosed which has 6 separate process steps and an overall yield of 50% based on the phenol used is uneconomic.

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

Procedure: To a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 20 ml of ethyl acetate was added 1.04 g of isatoic anhydride. The mixture was stirred at room temperature for 15 minutes. Hydrochloric acid (10%) was added to the mixture. The aqueous layer was separated, made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. Recrystallization of the residue from ethyl acetate gave 1.85 g of colorless pillars, m.p. 104°-105° C. The aqueous layer was separated extracted with ethyl acetate The extract was washed with water dried evaporated Recrystallization of the residue from ethyl acetate gave 1.85 g of colorless pillars, m.p. 104°-105° C.

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

Procedure: To a cooled solution of 1.50 g of 4-[2-(dimethylamino)ethoxy]benzylamine and 0.87 g of triethylamine in 10 ml of chloroform was added 1.87 g of 4-sulfamoylbenzyl chloride, which was prepared from 1.71 g of 4-sulfamoylbenzoic acid with 16.3 g of thionyl chloride in the usual way, with stirring. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was washed with ethyl acetate to give 1.19 g of pale yellow crystals, which were recrystallized from ethanol to give colorless crystals, m.p. 173.5°-174.5° C. The mixture was stirred at room temperature for 30 minutes the solvent was evaporated Hydrochloric acid (10%) was added to the residue the aqueous solution was washed with ethyl acetate was extracted with ethyl acetate The extract was washed with water dried evaporated The residue was washed with ethyl acetate

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

Procedure: To a cooled suspension of 3.20 g of 5-dimethylaminosulfonyl-2-methoxybenzoic acid in 10 ml of tetrahydrofuran were successively added dropwise 1.25 g of triethylamine and 1.34 g of ethyl chloroformate with stirring. The mixture was stirred at the same temperature for 30 minutes and then a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 10 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was dried and evaporated. The residue was washed with isopropyl ether to give 4.10 g of colorless crystals, which were recrystallized from a mixture of ethyl acetate and ether to give colorless needles, m.p. 99.5°-100.5° C. The mixture was stirred at the same temperature for 30 minutes with stirring The mixture was stirred at room temperature for 2 hours the solvent was evaporated Hydrochloric acid (10%) was added to the residue the aqueous solution was washed with ethyl acetate was extracted with ethyl acetate The extract was dried evaporated The residue was washed with isopropyl ether

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

Procedure: To a cooled suspension of 3.20 g of 5-dimethylaminosulfonyl-2-methoxybenzoic acid in 10 ml of tetrahydrofuran were successively added dropwise 1.25 g of triethylamine and 1.34 g of ethyl chloroformate with stirring. The mixture was stirred at the same temperature for 30 minutes and then a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 10 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was dried and evaporated. The residue was washed with isopropyl ether to give 4.10 g of colorless crystals, which were recrystallized from a mixture of ethyl acetate and ether to give colorless needles, m.p. 99.5°-100.5° C. The mixture was stirred at the same temperature for 30 minutes with stirring The mixture was stirred at room temperature for 2 hours the solvent was evaporated Hydrochloric acid (10%) was added to the residue the aqueous solution was washed with ethyl acetate was extracted with ethyl acetate The extract was dried evaporated The residue was washed with isopropyl ether

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

Procedure: To a cooled suspension of 14.3 g of 2-methoxy-5-sulfamoylbenzoic acid in 60 ml of tetrahydrofuran were successively added dropwise 6.25 g of triethylamine and 7.45 g of pivaloyl chloride with stirring. The mixture was stirred at the same temperature for 1 hour and then a solution of 10.0 g of 4-[2-(dimethylamino)ethoxy]-benzylamine in 40 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 14 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate to give a precipitate, which was washed with water and ethyl acetate, of 16.6 g of colorless crystals. Recrystallization of the crystals from ethanol gave the title compound as colorless needles, m.p. 154°-155° C. The mixture was stirred at the same temperature for 1 hour with stirring The mixture was stirred at room temperature for 14 hours the solvent was evaporated Hydrochloric acid (10%) was added to the residue the aqueous solution was washed with ethyl acetate to give a precipitate, which was washed with water and ethyl acetate, of 16.6 g of colorless crystals Recrystallization of the crystals from ethanol

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

Procedure: To a cooled solution of 20.0 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 60 ml of toluene was added a solution of 21.7 g of 3,4-dimethoxybenzoyl chloride (which was prepared with 19.7 g of 3,4-dimethoxybenzoic acid and 38.5 g of thionyl chloride in the usual manner) in 60 ml of toluene with stirring. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 120 ml of water and 1 ml of concentrated hydrochloric acid. The aqueous layer was separated, washed with 20 ml of toluene and made alkaline with 20% sodium hydroxide solution to give a precipitate, which was washed with isopropyl ether, of 37.0 g of pale brownish crystals. Recrystallization of the crystals from ethanol and isopropyl ether gave the title compound as colorless needles, m.p. 111°-112° C. The mixture was stirred at room temperature for 30 minutes The aqueous layer was separated washed with 20 ml of toluene to give a precipitate, which was washed with isopropyl ether, of 37.0 g of pale brownish crystals Recrystallization of the crystals from ethanol and isopropyl ether

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

Procedure: To a cooled solution of 20.0 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 60 ml of toluene was added a solution of 21.7 g of 3,4-dimethoxybenzoyl chloride (which was prepared with 19.7 g of 3,4-dimethoxybenzoic acid and 38.5 g of thionyl chloride in the usual manner) in 60 ml of toluene with stirring. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 120 ml of water and 1 ml of concentrated hydrochloric acid. The aqueous layer was separated, washed with 20 ml of toluene and made alkaline with 20% sodium hydroxide solution to give a precipitate, which was washed with isopropyl ether, of 37.0 g of pale brownish crystals. Recrystallization of the crystals from ethanol and isopropyl ether gave the title compound as colorless needles, m.p. 111°-112° C. The mixture was stirred at room temperature for 30 minutes The aqueous layer was separated washed with 20 ml of toluene to give a precipitate, which was washed with isopropyl ether, of 37.0 g of pale brownish crystals Recrystallization of the crystals from ethanol and isopropyl ether

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

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

Procedure: FR 2549828 discloses a multistage process for preparing 4-[2-(dimethylamino)ethoxy]benzylamine starting from phenol. Reaction of phenol with ethylenechlorohydrin initially delivers 2-phenoxyethanol which is reacted with thionyl chloride to give 2-phenoxyethyl chloride. After distilling this intermediate, it is reacted with acetamide and paraformaldehyde and then treated with mineral acid to give N-(2-chloroethoxybenzyl)acetamide. Reaction with dimethylamine then leads to N-[2-(dimethylamino)-ethoxy]acetamide, from which the desired product is released by acid hydrolysis. The process disclosed which has 6 separate process steps and an overall yield of 50% based on the phenol used is uneconomic.

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

Procedure: To a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 20 ml of ethyl acetate was added 1.04 g of isatoic anhydride. The mixture was stirred at room temperature for 15 minutes. Hydrochloric acid (10%) was added to the mixture. The aqueous layer was separated, made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. Recrystallization of the residue from ethyl acetate gave 1.85 g of colorless pillars, m.p. 104°-105° C. The aqueous layer was separated extracted with ethyl acetate The extract was washed with water dried evaporated Recrystallization of the residue from ethyl acetate gave 1.85 g of colorless pillars, m.p. 104°-105° C.