2-(3-methoxy-4-phenylmethoxyphenyl)ethanamine

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

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

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

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

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

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

Procedure: 32.9 g of BOC-L-valine and 16.7 ml of N-methylmorpholine are dissolved in 350 ml of tetrahydrofuran and cooled to −20° C. 19.8 ml of isobutyl chloroformate are added dropwise to that solution over a period of 15 minutes. The mixture is stirred for 30 minutes, during which time the temperature rises to −7° C. The mixture is then cooled to −20° C., and 35.4 g of 2-(4-benzyloxy-3-methoxy-phenyl)-ethylamine in 50 ml of tetrahydrofuran are added dropwise over a period of 10 minutes. The reaction mixture is stirred for 30 minutes at −20° C. and then for 4 hours at room temperature. It is introduced into 300 ml of 1N hydrochloric acid. Extraction is carried out twice using 400 ml of ethyl acetate each time. The organic phases are washed once with 300 ml of 1N hydrochloric acid and once with 300 ml of saturated sodium chloride solution, dried over magnesium chloride and concentrated, yielding (S)-2-(tert-butoxycarbonyl-amino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-amide, which is recrystallised from ethyl acetate/n-hexane, m.p. 115-118° C. rises to −7° C The mixture is then cooled to −20° C. The reaction mixture is stirred for 30 minutes at −20° C. for 4 hours at room temperature Extraction The organic phases are washed once with 300 ml of 1N hydrochloric acid and once with 300 ml of saturated sodium chloride solution dried over magnesium chloride concentrated

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

Procedure: 21.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 12 ml of N-methylmorpholine in 450 ml of tetrahydrofuran are cooled, with stirring, to −20° C. 13.2 ml of isobutyl chloroformate are added dropwise thereto over a period of 10 minutes. The reaction mixture is then stirred at −10° C. for 1 hour. The mixture is again cooled to −20° C., and a solution of 26.1 g of 2-(4-benzyloxy-3-methoxyphenyl)-ethylamine in 100 ml of tetrahydrofuran is added dropwise thereto over a period of 20 minutes. The reaction mixture is then stirred, without cooling, for 4 hours, the internal temperature gradually rising to room temperature. The reaction mixture is then introduced into 400 ml of 2N hydrochloric acid. Extraction is carried out twice using 500 ml of ethyl acetate each time. The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution, twice using 250 ml of 2N potassium hydrogen carbonate solution each time and once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)-3methyl-butyric acid N-[2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-amide, m.p. 140-142° C., which can be purified further by digestion in 200 ml of tert-butyl methyl ether. The reaction mixture is then stirred at −10° C. for 1 hour The mixture is again cooled to −20° C. over a period of 20 minutes The reaction mixture is then stirred without cooling, for 4 hours gradually rising to room temperature Extraction The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate concentrated

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

Procedure: 21.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 12 ml of N-methylmorpholine are cooled in 450 ml of tetrahydrofuran, with stirring, to −20° C. 13.2 ml of chloroformic acid isobutyl ester are added dropwise thereto over 10 min and the reaction mixture is subsequently stirred for 1 hour at −10° C. It is then cooled to −20° C. and a solution of 26.1 g of 2-(4-benzyloxy-3-methoxyphenyl)-ethylamine in 100 ml of tetrahydrofuran is added dropwise over 20 min. The reaction mixture is then stirred for 4 hours without cooling, the internal temperature gradually rising to room temperature. The reaction mixture is introduced into 400 ml of 2N hydrochloric acid and extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution, twice with 250 ml of 2N potassium hydrogen carbonate solution each time and once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-amide, which can be purified by recrystallisation from tert-butyl methyl ether, m.p. 140-142° C. the reaction mixture is subsequently stirred for 1 hour at −10° C It is then cooled to −20° C. The reaction mixture is then stirred for 4 hours without cooling gradually rising to room temperature extracted twice with 500 ml of ethyl acetate each time The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution, twice with 250 ml of 2N potassium hydrogen carbonate solution each time once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate concentrated

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

Procedure: 21.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 12 ml of N-methylmorpholine are cooled in 450 ml of tetrahydrofuran, with stirring, to −20° C. 13.2 ml of chloroformic acid isobutyl ester are added dropwise thereto over 10 min and the reaction mixture is subsequently stirred for 1 hour at −10° C. It is then cooled to −20° C. and a solution of 26.1 g of 2-(4-benzyloxy-3-methoxyphenyl)-ethylamine in 100 ml of tetrahydrofuran is added dropwise over 20 min. The reaction mixture is then stirred for 4 hours without cooling, the internal temperature gradually rising to room temperature. The reaction mixture is introduced into 400 ml of 2N hydrochloric acid and extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution, twice with 250 ml of 2N potassium hydrogen carbonate solution each time and once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-amide, which can be purified by recrystallisation from tert-butyl methyl ether, m.p. 140-142° C. the reaction mixture is subsequently stirred for 1 hour at −10° C It is then cooled to −20° C. The reaction mixture is then stirred for 4 hours without cooling gradually rising to room temperature extracted twice with 500 ml of ethyl acetate each time The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution, twice with 250 ml of 2N potassium hydrogen carbonate solution each time once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate concentrated

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

Procedure: 1-(2-Bromophenyl)cyclobutanecarbonyl chloride (9.4 g) was added to a solution of 4-benzyloxy-3-methoxy phenethylamine (8 g) and triethylamine (3.15 g) in ethyl acetate (50 ml) and tetrahydrofuran (50 ml). The mixture was stirred for two days, 2M aqueous potassium hydroxide solution (50 ml) added and the mixture stirred for 20 minutes. The aqueous layer was separated and extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid and brine and yielded an oil which was dissolved in acetonitrile (180 ml). Phosphorus oxychloride (12 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was cooled and added to a mixture of concentrated aqueous ammonia solution (100 ml) and water (100 ml) and the mixture stirred for 10 minutes and extracted with ethyl acetate. The extract yielded an oil which was triturated with ether and the resulting solid recrystallised from cyclohexane to give 7-benzyloxy-1-[1-(2-bromophenyl)cyclobutyl]-6-methoxy-3,4,-dihydroisoquinoline (m.p. 115°-116° C.). A sample (3.1 g) of this material in methanol (16 ml) and acetic acid (35 ml) was treated with sodium cyanoborohydride (1 g). The mixture was stirred for 16 hours, diluted with water, basified with 50% aqueous sodium hydroxide solution and extracted with ether. The extract gave a residue which was dissolved in acetonitrile (115 ml) and then 37-40% aqueous formaldehyde solution (3.2 ml) and sodium cyanoborohydride (0.83 g) were added. The mixture was stirred for 15 minutes and then neutralised with acetic acid and stirred for 45 minutes. After concentration, 2M aqueous sodium hydroxide solution was added and the mixture extracted with ethyl acetate. The extract gave 7-benzyloxy-1-[1-(2-bromophenyl)cyclobutyl]-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, a sample of which (3 g) was mixed with ethanol (70 ml) and concentrated hydrochloric acid (70 ml) and the mixture heated under reflux for 45 minutes. The solvent was removed by evaporation and the residue dried by azeotropic distillation with propan-2-ol. The dried residue was suspended in propan-2-ol (20 ml) and the mixture filtered. The filtrate was decolourised with charcoal in methanol. The free base was liberated by basification and dissolved in ether. Removal of the ether gave 1-[1-(2-bromophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (m.p. 48°-51° C.) which was dried in vacuo (ca 0.1 mmHg) for four hours. the mixture stirred for 20 minutes The aqueous layer was separated extracted with ethyl acetate The extract was washed with 1M hydrochloric acid and brine yielded an oil which the mixture heated under reflux for 2.5 hours The mixture was cooled the mixture stirred for 10 minutes extracted with ethyl acetate The extract yielded an oil which was triturated with ether the resulting solid recrystallised from cyclohexane

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

Procedure: 1-(2-Bromophenyl)cyclobutanecarbonyl chloride (9.4 g) was added to a solution of 4-benzyloxy-3-methoxy phenethylamine (8 g) and triethylamine (3.15 g) in ethyl acetate (50 ml) and tetrahydrofuran (50 ml). The mixture was stirred for two days, 2M aqueous potassium hydroxide solution (50 ml) added and the mixture stirred for 20 minutes. The aqueous layer was separated and extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid and brine and yielded an oil which was dissolved in acetonitrile (180 ml). Phosphorus oxychloride (12 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was cooled and added to a mixture of concentrated aqueous ammonia solution (100 ml) and water (100 ml) and the mixture stirred for 10 minutes and extracted with ethyl acetate. The extract yielded an oil which was triturated with ether and the resulting solid recrystallised from cyclohexane to give 7-benzyloxy-1-[1-(2-bromophenyl)cyclobutyl]-6-methoxy-3,4,-dihydroisoquinoline (m.p. 115°-116° C.). A sample (3.1 g) of this material in methanol (16 ml) and acetic acid (35 ml) was treated with sodium cyanoborohydride (1 g). The mixture was stirred for 16 hours, diluted with water, basified with 50% aqueous sodium hydroxide solution and extracted with ether. The extract gave a residue which was dissolved in acetonitrile (115 ml) and then 37-40% aqueous formaldehyde solution (3.2 ml) and sodium cyanoborohydride (0.83 g) were added. The mixture was stirred for 15 minutes and then neutralised with acetic acid and stirred for 45 minutes. After concentration, 2M aqueous sodium hydroxide solution was added and the mixture extracted with ethyl acetate. The extract gave 7-benzyloxy-1-[1-(2-bromophenyl)cyclobutyl]-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, a sample of which (3 g) was mixed with ethanol (70 ml) and concentrated hydrochloric acid (70 ml) and the mixture heated under reflux for 45 minutes. The solvent was removed by evaporation and the residue dried by azeotropic distillation with propan-2-ol. The dried residue was suspended in propan-2-ol (20 ml) and the mixture filtered. The filtrate was decolourised with charcoal in methanol. The free base was liberated by basification and dissolved in ether. Removal of the ether gave 1-[1-(2-bromophenyl)cyclobutyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (m.p. 48°-51° C.) which was dried in vacuo (ca 0.1 mmHg) for four hours. the mixture stirred for 20 minutes The aqueous layer was separated extracted with ethyl acetate The extract was washed with 1M hydrochloric acid and brine yielded an oil which the mixture heated under reflux for 2.5 hours The mixture was cooled the mixture stirred for 10 minutes extracted with ethyl acetate The extract yielded an oil which was triturated with ether the resulting solid recrystallised from cyclohexane

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