ethyl 3-amino-2,2-dimethylbutanoate

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

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

Procedure: 229.3 g (3.5 mol) of zinc in 3.0 liters of dichloromethane are mixed with 230 ml of trimethylchlorosilane under nitrogen and stirred for 20 minutes at ambient temperature. Then 1.1 liters of absolute tetrahydrofuran are added and the mixture is heated to reflux temperature. To this mixture is added dropwise a mixture of 500 g (2.6 mol) of ethyl bromoisobutyrate (1) and 226.4 g (1.5 mol) of m-methoxybenzylcyanide (2) and the resulting mixture is then refluxed for 1.5 hours. It is allowed to cool, decanted off from the excess zinc and after cooling to about 10° C. mixed with 96.7 g (1.5 mol) of sodium cyanoborohydride. Then 300 ml of ethanol are slowly added dropwise (gas evolved). The reaction is allowed to continue for 20 minutes, 1.0 liters of conc. ammonia solution are added, the phases are separated and the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The residue is taken up in 2.3 liters of toluene and extracted twice with 1.8 liters of 2N hydrochloric acid. Then the aqueous phase is made alkaline with 700 ml of conc. ammonia solution and extracted twice with 2.2 liters of dichloromethane. After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo. The ethyl 3-amino-4-(3-methoxyphenyl)-2-dimethylbutanoate (4) is isolated in a yield of 322.5 g (81% of theory) as a yellow oil. the mixture is heated to reflux temperature To this mixture is added dropwise the resulting mixture is then refluxed for 1.5 hours to cool decanted off from the excess zinc after cooling to about 10° C. to continue for 20 minutes the phases are separated the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water The organic phase is dried over sodium sulphate evaporated down in vacuo extracted twice with 1.8 liters of 2N hydrochloric acid extracted twice with 2.2 liters of dichloromethane After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo

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

Procedure: In order to carry out this Michael addition, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is dissolved with ethyl acrylate in a reaction medium which is inert under the reaction conditions chosen, preferably in a straight-chained or branched C1-4 -alkanol, most preferably ethanol, and heated, preferably to reflux temperature. After the reaction has taken place the solvent is eliminated in vacuo and the resulting ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate 5 is isolated. this Michael addition is inert under the reaction conditions preferably to reflux temperature

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

Procedure: In the second stage of the reaction, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is reacted with ethyl acrylate to obtain the corresponding ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative 5--which in the case of the preparation of BIII 277 might be, for example: ethyl 3-(2-ethoxycarbonylethyl)amino-4-(3-methoxyphenyl)-2,2-dimethylbutanoate (R2 =CH3O): ##STR4## In the second stage of the reaction

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

Procedure: 229.3 g (3.5 mol) of zinc in 3.0 liters of dichloromethane are mixed with 230 ml of trimethylchlorosilane under nitrogen and stirred for 20 minutes at ambient temperature. Then 1.1 liters of absolute tetrahydrofuran are added and the mixture is heated to reflux temperature. To this mixture is added dropwise a mixture of 500 g (2.6 mol) of ethyl bromoisobutyrate (1) and 226.4 g (1.5 mol) of m-methoxybenzylcyanide (2) and the resulting mixture is then refluxed for 1.5 hours. It is allowed to cool, decanted off from the excess zinc and after cooling to about 10° C. mixed with 96.7 g (1.5 mol) of sodium cyanoborohydride. Then 300 ml of ethanol are slowly added dropwise (gas evolved). The reaction is allowed to continue for 20 minutes, 1.0 liters of conc. ammonia solution are added, the phases are separated and the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water. The organic phase is dried over sodium sulphate and evaporated down in vacue. The residue is taken up in 2.3 liters of toluene and extracted twice with 1.8 liters of 2N hydrochloric acid. Then the aqueous phase is made alkaline with 700 ml of conc. ammonia solution and extracted twice with 2.2 liters of dichloromethane. After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo. The ethyl 3-amino-4-(3-methoxyphenyl)-2-dimethylbutanoate (4) is isolated in a yield of 322.5 g (81% of theory) as a yellow oil. the mixture is heated to reflux temperature To this mixture is added dropwise the resulting mixture is then refluxed for 1.5 hours to cool decanted off from the excess zinc after cooling to about 10° C. to continue for 20 minutes the phases are separated the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water The organic phase is dried over sodium sulphate evaporated down in vacue extracted twice with 1.8 liters of 2N hydrochloric acid extracted twice with 2.2 liters of dichloromethane After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo

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

Procedure: In order to carry out this Michael addition, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is dissolved with ethyl acrylate in a reaction medium which is inert under the reaction conditions chosen, preferably in a straight-chained or branched C1-4 -alkanol, most preferably ethanol, and heated, preferably to reflux temperature. After the reaction has taken place the solvent is eliminated in vacuo and the resulting ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate 5 is isolated. this Michael addition is inert under the reaction conditions preferably to reflux temperature

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

Procedure: In the second stage of the reaction, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is reacted with ethyl acrylate to obtain the corresponding ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative 5--which in the case of the preparation of BIII 277 might be, for example: ethyl 3-(2-ethoxycarbonylethyl)amino-4-(3-methoxyphenyl)-2,2-dimethylbutanoate (R2 =CH3O): ##STR4## In the second stage of the reaction

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

Procedure: 229.3 g (3.5 mol) of zinc in 3.0 liters of dichloromethane are mixed with 230 ml of trimethylchlorosilane under nitrogen and stirred for 20 minutes at ambient temperature. Then 1.1 liters of absolute tetrahydrofuran are added and the mixture is heated to reflux temperature. To this mixture is added dropwise a mixture of 500 g (2.6 mol) of ethyl bromoisobutyrate (1) and 226.4 g (1.5 mol) of m-methoxybenzylcyanide (2) and the resulting mixture is then refluxed for 1.5 hours. It is allowed to cool, decanted off from the excess zinc and after cooling to about 10° C. mixed with 96.7 g (1.5 mol) of sodium cyanoborohydride. Then 300 ml of ethanol are slowly added dropwise (gas evolved). The reaction is allowed to continue for 20 minutes, 1.0 liters of conc. ammonia solution are added, the phases are separated and the organic phase is washed once more with a mixture of 500 ml of conc. amnonia solution and 500 ml of water. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The residue is taken up in 2.3 liters of toluene and extracted twice with 1.8 liters of 2N hydrochloric acid. Then the aqueous phase is made alkaline with 700 ml of conc. ammonia solution and extracted twice with 2.2 liters of dichloromethane. After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo. The ethyl 3-amino-4-(3-methoxyphenyl)-2-dimethylbutanoate (4) is isolated in a yield of 322.5 g (81% of theory) as a yellow oil. the mixture is heated to reflux temperature To this mixture is added dropwise the resulting mixture is then refluxed for 1.5 hours to cool decanted off from the excess zinc after cooling to about 10° C. to continue for 20 minutes the phases are separated the organic phase is washed once more with a mixture of 500 ml of conc. amnonia solution and 500 ml of water The organic phase is dried over sodium sulphate evaporated down in vacuo extracted twice with 1.8 liters of 2N hydrochloric acid extracted twice with 2.2 liters of dichloromethane After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo

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

Procedure: In the second stage of the reaction, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is reacted with ethyl acrylate to obtain the corresponding ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative 5--which in the case of the preparation of BIII 277 might be, for example: ethyl 3-(2-ethoxycarbonylethyl)amino-4-(3-methoxyphenyl)-2,2-dimethylbutanoate (R2 =CH3O): ##STR4## In the second stage of the reaction

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

Procedure: In the second stage of the reaction, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is reacted with ethyl acrylate to obtain the corresponding ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative 5--which in the case of the preparation of BIII 277 might be, for example: ethyl 3-(2-ethoxycarbonylethyl)amino-4-(3-methoxyphenyl)-2,2-dimethylbutanoate (R2 =CH3O): ##STR4## In the second stage of the reaction

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

Procedure: 229.3 g (3.5 mol) of zinc in 3.0 liters of dichloromethane are mixed with 230 ml of trimethylchlorosilane under nitrogen and stirred for 20 minutes at ambient temperature. Then 1.1 liters of absolute tetrahydrofuran are added and the mixture is heated to reflux temperature. To this mixture is added dropwise a mixture of 500 g (2.6 mol) of ethyl bromoisobutyrate (1) and 226.4 g (1.5 mol) of m-methoxybenzylcyanide (2) and the resulting mixture is then refluxed for 1.5 hours. It is allowed to cool, decanted off from the excess zinc and after cooling to about 10° C. mixed with 96.7 g (1.5 mol) of sodium cyanoborohydride. Then 300 ml of ethanol are slowly added dropwise (gas evolved). The reaction is allowed to continue for 20 minutes, 1.0 liters of conc. ammonia solution are added, the phases are separated and the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The residue is taken up in 2.3 liters of toluene and extracted twice with 1.8 liters of 2N hydrochloric acid. Then the aqueous phase is made alkaline with 700 ml of conc. ammonia solution and extracted twice with 2.2 liters of dichloromethane. After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo. The ethyl 3-amino-4-(3-methoxyphenyl)-2-dimethylbutanoate (4) is isolated in a yield of 322.5 g (81% of theory) as a yellow oil. the mixture is heated to reflux temperature To this mixture is added dropwise the resulting mixture is then refluxed for 1.5 hours to cool decanted off from the excess zinc after cooling to about 10° C. to continue for 20 minutes the phases are separated the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water The organic phase is dried over sodium sulphate evaporated down in vacuo extracted twice with 1.8 liters of 2N hydrochloric acid extracted twice with 2.2 liters of dichloromethane After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo

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

Procedure: 229.3 g (3.5 mol) of zinc in 3.0 liters of dichloromethane are mixed with 230 ml of trimethylchlorosilane under nitrogen and stirred for 20 minutes at ambient temperature. Then 1.1 liters of absolute tetrahydrofuran are added and the mixture is heated to reflux temperature. To this mixture is added dropwise a mixture of 500 g (2.6 mol) of ethyl bromoisobutyrate (1) and 226.4 g (1.5 mol) of m-methoxybenzylcyanide (2) and the resulting mixture is then refluxed for 1.5 hours. It is allowed to cool, decanted off from the excess zinc and after cooling to about 10° C. mixed with 96.7 g (1.5 mol) of sodium cyanoborohydride. Then 300 ml of ethanol are slowly added dropwise (gas evolved). The reaction is allowed to continue for 20 minutes, 1.0 liters of conc. ammonia solution are added, the phases are separated and the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The residue is taken up in 2.3 liters of toluene and extracted twice with 1.8 liters of 2N hydrochloric acid. Then the aqueous phase is made alkaline with 700 ml of conc. ammonia solution and extracted twice with 2.2 liters of dichloromethane. After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo. The ethyl 3-amino-4-(3-methoxyphenyl)-2-dimethylbutanoate (4) is isolated in a yield of 322.5 g (81% of theory) as a yellow oil. the mixture is heated to reflux temperature To this mixture is added dropwise the resulting mixture is then refluxed for 1.5 hours to cool decanted off from the excess zinc after cooling to about 10° C. to continue for 20 minutes the phases are separated the organic phase is washed once more with a mixture of 500 ml of conc. ammonia solution and 500 ml of water The organic phase is dried over sodium sulphate evaporated down in vacuo extracted twice with 1.8 liters of 2N hydrochloric acid extracted twice with 2.2 liters of dichloromethane After the organic phase has been dried over sodium sulphate it is evaporated down in vacuo