(2S)-N-ethylpyrrolidine-2-carboxamide

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

Procedure: Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (S)-proline ethyl amide (0.108 g, 0.76 mmol) gives the title compound.

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

Procedure: 7.33 g (29.7 mmoles) of Z-Arg(NO2)-OH and 1.034 g of N-hydroxy-benzotriazole are added to a solution containing 3.24 g (22.8 mmoles) of proline ethylamide in 70 ml of THF. The reaction mixture is cooled in an iced water bath and 5.34 g (25.8 mmoles) of DCC dissolved in 50 ml of THF are portionwise added under stirring. The mixture is stirred under cooling with ice for 5 hours, at room temperature for additional 20 hours, then filtered and washed with THF. The filtrate is evaporated under reduced pressure, the residue is dissolved in chloroform and successively washed 3 times with 35 ml of an 1:5 mixture of ammonium hydroxide with water each, twice with 20 ml of water each, 3 times with 35 ml of 1N hydrochloric acid each and finally twice with 20 ml of water each. The chloroformic solution is dried over anhydrous sodium sulfate, filtered, washed with chloroform, then the filtrate is evaporated. The residue is dissolved in a mixture of 35 ml of THF and 50 ml of ethyl acetate, filtered and washed with 30 ml of an 1:2 mixture of THF with ethyl acetate. After evaporating the solution, 100 ml of ethyl ether are added to the solid foamy residue. The thus-obtained product is filtered, washed with ether and dried under reduced pressure to afford 9.69 g (98% yield) of the aimed compound, m.p.: 125° C. The reaction mixture is cooled in an iced water bath are portionwise added The mixture is stirred filtered washed with THF The filtrate is evaporated under reduced pressure the residue is dissolved in chloroform successively washed 3 times with 35 ml of an 1:5 mixture of ammonium hydroxide with water each, twice with 20 ml of water each, 3 times with 35 ml of 1N hydrochloric acid each and finally twice with 20 ml of water each The chloroformic solution is dried over anhydrous sodium sulfate filtered washed with chloroform the filtrate is evaporated The residue is dissolved in a mixture of 35 ml of THF and 50 ml of ethyl acetate filtered washed with 30 ml of an 1:2 mixture of THF with ethyl acetate After evaporating the solution, 100 ml of ethyl ether are added to the solid foamy residue The thus-obtained product is filtered washed with ether dried under reduced pressure

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

Procedure: Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (S)-proline ethyl amide (0.108 g, 0.76 mmol) gives the title compound.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.0 grams of N, N-dicyclohexylcarbodiimide was added to a solution of 5.6 grams of proline ethylamide and 9.0 grams of benzyloxycarbonyl alanine in a mixture of 5 ml. of dimethylformamide and 60 ml. of tetrahydrofuran cooled to -5 degrees C. After 1 hour of stirring at 0 degrees C., the reaction mixture was permitted to stand for 12 hours at room temperature, so resulting in the separation of N, N-dicyclohexylurea which was filtered off. The filtrate was evaporated; the evaporation residue dissolved in a mixture of ethyl acetate and water. The organic phase formed was gradually shook with 1M hydrochloric acid, water, 5% sodium hydrogen carbonate, with water, dried with anhydrous sodium sulphate and evaporated. The evaporation residue was crystallized from a mixture of 30 ml. of ether and 30 ml. of petroleum ether. 5.4 g of a product having a melting point of 99 to 101 degrees C. was obtained. to stand for 12 hours at room temperature

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

Procedure: 40 ml. of 36% hydrogen bromide in acetic acid was added to 11 grams of a solution of benzyloxycarbonyl proline ethylamide in 10 ml. of acetic acid. After 1 hour 300 ml. of ether was added to the reaction solution, so resulting in the separation of a non-crystalline hydrobromide. The hydrobromide was dried for 2 hours in desiccator over phosphorus pentoxide and sodium hydroxide, and then suspended in 60 ml. of a saturated amoniacal solution of chloroform at 0 degrees C. The resultant suspension was permitted to stand at 3 degrees C. for 20 minutes and then filtered, the filtrate being evaporated. 5.7 g of a non-crystalline product was obtained. Rf 0.25/S1 ; 0.56/S2.

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

Procedure: 7.33 g (29.7 mmoles) of Z-Arg(NO2)-OH and 1.034 g of N-hydroxy-benzotriazole are added to a solution containing 3.24 g (22.8 mmoles) of proline ethylamide in 70 ml of THF. The reaction mixture is cooled in an iced water bath and 5.34 g (25.8 mmoles) of DCC dissolved in 50 ml of THF are portionwise added under stirring. The mixture is stirred under cooling with ice for 5 hours, at room temperature for additional 20 hours, then filtered and washed with THF. The filtrate is evaporated under reduced pressure, the residue is dissolved in chloroform and successively washed 3 times with 35 ml of an 1:5 mixture of ammonium hydroxide with water each, twice with 20 ml of water each, 3 times with 35 ml of 1N hydrochloric acid each and finally twice with 20 ml of water each. The chloroformic solution is dried over anhydrous sodium sulfate, filtered, washed with chloroform, then the filtrate is evaporated. The residue is dissolved in a mixture of 35 ml of THF and 50 ml of ethyl acetate, filtered and washed with 30 ml of an 1:2 mixture of THF with ethyl acetate. After evaporating the solution, 100 ml of ethyl ether are added to the solid foamy residue. The thus-obtained product is filtered, washed with ether and dried under reduced pressure to afford 9.69 g (98% yield) of the aimed compound, m.p.: 125° C. The reaction mixture is cooled in an iced water bath are portionwise added The mixture is stirred filtered washed with THF The filtrate is evaporated under reduced pressure the residue is dissolved in chloroform successively washed 3 times with 35 ml of an 1:5 mixture of ammonium hydroxide with water each, twice with 20 ml of water each, 3 times with 35 ml of 1N hydrochloric acid each and finally twice with 20 ml of water each The chloroformic solution is dried over anhydrous sodium sulfate filtered washed with chloroform the filtrate is evaporated The residue is dissolved in a mixture of 35 ml of THF and 50 ml of ethyl acetate filtered washed with 30 ml of an 1:2 mixture of THF with ethyl acetate After evaporating the solution, 100 ml of ethyl ether are added to the solid foamy residue The thus-obtained product is filtered washed with ether dried under reduced pressure

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

Procedure: Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (S)-proline ethyl amide (0.108 g, 0.76 mmol) gives the title compound.