ethyl 2-(cyclopentylamino)acetate;hydrochloride

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Carbobenzoxy-L-alanine (11.4 g) and triethylamine (6.7 ml) are dissolved in 100 ml of tetrahydrofuran and under stirring at -10° C., 6.5 ml of isobutyl chlorocarbonate is added in small portions. Then, at -10° C. to -5° C., a solution of N-cyclopentylglycine ethyl ester hydrochloride (10 g) and triethylamine (6.7 ml) in chloroform (100 ml) is added and the mixture is allowed to stand at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated. To the residue is added 300 ml of water, followed by extraction with 200 ml of ethyl acetate. The ethyl acetate layer is washed with 5% hydrochloric acid, aqueous sodium hydrogen carbonate and water in that order and dried over sodium sulfate. Removal of the solvent by distillation gives an oil, which is separated and purified by column chromatography using 150 g of silica gel. The fractions eluted with toluene-ethyl acetate (5:1) are collected to give 11 g of N-carbobenzoxy-L-alanyl-N-cyclopentylglycine ethyl ester as an oil. This product (10 g) is dissolved in 100 ml of ethanol, then 16 ml of 2N sodium hydroxide is added, and the mixture is stirred at room temperature for 5 hours. The reaction mixture is concentrated and the concentrate is diluted with 100 ml of water and acidified with 10% hydrochloric acid, whereupon an oil separates out. This oil is extracted with 300 ml of ethyl acetate and the extract is washed with water, dried and concentrated to give 8 g of N-carbobenzoxy-L-alanyl-N-cyclopentylglycine as colorless oil. The reaction mixture is filtered the filtrate is concentrated To the residue is added 300 ml of water followed by extraction with 200 ml of ethyl acetate The ethyl acetate layer is washed with 5% hydrochloric acid, aqueous sodium hydrogen carbonate and water in that order dried over sodium sulfate Removal of the solvent by distillation gives an oil, which is separated purified by column chromatography The fractions eluted with toluene-ethyl acetate (5:1) are collected

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

Procedure: Cyclopentanone (10 g) and glycine ethyl ester hydrochloride (21.6 g) are dissolved in 200 ml of methanol, and 7.48 g of sodium cyanoborohydride is added in small portions with stirring at room temperature. The mixture is further stirred at room temperature for 3 hours and the reaction mixture is concentrated under reduced pressure. To the residue is added 500 ml of water and the mixture is adjusted to pH 10 with diluted sodium hydroxide solution and extracted with 300 ml of ethyl acetate. The extract is washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is then distilled off under reduced pressure and the resulting oily product is dissolved in 200 ml of ether, followed by addition of 10 ml of 10% alcoholic hydrochloride, whereupon crystals immediately separates out. The crystals are collected by filtration to give 12.7 g of N-cyclopentylglycine ethyl ester hydrochloride as colorless needles melting at 174°-175° C. The mixture is further stirred at room temperature for 3 hours the reaction mixture is concentrated under reduced pressure To the residue is added 500 ml of water extracted with 300 ml of ethyl acetate The extract is washed with saturated aqueous sodium chloride dried over sodium sulfate The solvent is then distilled off under reduced pressure the resulting oily product is dissolved in 200 ml of ether followed by addition of 10 ml of 10% alcoholic hydrochloride, whereupon crystals The crystals are collected by filtration

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

Procedure: Cyclopentanone (10 g) and glycine ethyl ester hydrochloride (21.6 g) are dissolved in 200 ml of methanol, and 7.48 g of sodium cyanoborohydride is added in small portions with stirring at room temperature. The mixture is further stirred at room temperature for 3 hours and the reaction mixture is concentrated under reduced pressure. To the residue is added 500 ml of water and the mixture is adjusted to pH 10 with diluted sodium hydroxide solution and extracted with 300 ml of ethyl acetate. The extract is washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is then distilled off under reduced pressure and the resulting oily product is dissolved in 200 ml of ether, followed by addition of 10 ml of 10% alcoholic hydrochloride, whereupon crystals immediately separates out. The crystals are collected by filtration to give 12.7 g of N-cyclopentylglycine ethyl ester hydrochloride as colorless needles melting at 174°-175° C. The mixture is further stirred at room temperature for 3 hours the reaction mixture is concentrated under reduced pressure To the residue is added 500 ml of water extracted with 300 ml of ethyl acetate The extract is washed with saturated aqueous sodium chloride dried over sodium sulfate The solvent is then distilled off under reduced pressure the resulting oily product is dissolved in 200 ml of ether followed by addition of 10 ml of 10% alcoholic hydrochloride, whereupon crystals The crystals are collected by filtration

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

Procedure: Cyclopentylglycine ethyl ester hydrochloride salt was prepared by the procedure in Example 1(B) utilizing cyclopentylglycine (5.0 g, 38.7 mmol), thionyl chloride (6.0 mL, 77.4 mmol) and EtOH (34.10 mL, 58.1 mmol). The ethyl ester 14aj was obtained as a white solid (2.25 g, 10.86 mmol, 56%).