ethyl 1-aminocyclopentane-1-carboxylate

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cycloleucine ethyl ester ##STR155## A solution of cycloleucine (8.94 g, 69.2 mmol) in EtOH (100 mL) was saturated with HCl gas, and the mixture was stirred at 23° C. for 2 d. The solvents were evaporated in vacuo, the residue was dissolved in water (200 mL) and the solution basified with solid NaHCO3. The aqueous solution was extracted with EtOAc (3×100 mL) and the combined extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was dissolved in hexane-Et2O (1:1) and a solution of HCl in Et2O-dioxane (0.5 M, 1:1) was added which gave a precipitate. This off-white solid was collected by filtration and dried to give cycloleucine ethyl ester hydrochloride (6.57 g, 33.9 mmol). The solvents were evaporated in vacuo the residue was dissolved in water (200 mL) The aqueous solution was extracted with EtOAc (3×100 mL) the combined extracts were washed with brine dried (MgSO4) evaporated in vacuo The residue was dissolved in hexane-Et2O (1:1) a solution of HCl in Et2O-dioxane (0.5 M, 1:1) was added which gave a precipitate This off-white solid was collected by filtration dried

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cycloleucine ethyl ester ##STR155## A solution of cycloleucine (8.94 g, 69.2 mmol) in EtOH (100 mL) was saturated with HCl gas, and the mixture was stirred at 23° C. for 2 d. The solvents were evaporated in vacuo, the residue was dissolved in water (200 mL) and the solution basified with solid NaHCO3. The aqueous solution was extracted with EtOAc (3×100 mL) and the combined extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was dissolved in hexane-Et2O (1:1) and a solution of HCl in Et2O-dioxane (0.5 M, 1:1) was added which gave a precipitate. This off-white solid was collected by filtration and dried to give cycloleucine ethyl ester hydrochloride (6.57 g, 33.9 mmol). The solvents were evaporated in vacuo the residue was dissolved in water (200 mL) The aqueous solution was extracted with EtOAc (3×100 mL) the combined extracts were washed with brine dried (MgSO4) evaporated in vacuo The residue was dissolved in hexane-Et2O (1:1) a solution of HCl in Et2O-dioxane (0.5 M, 1:1) was added which gave a precipitate This off-white solid was collected by filtration dried

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

Procedure: To a dimethylformamide (25 ml) solution of ethyl 1-amino-1-cyclopentanecarboxylate liberated from its hydrochloride (1.0 g, 5 mmoles) with N-ethylpiperidine (0.7 ml) there was portionwise added benzyloxycarbonylalanyl-glycine p-nitrophenyl ester (2.1 g, 5 mmoles). After 3 hours of stirring and 12 hours of standing at room temperature the solution was evaporated, the residue was taken into ethyl acetate and extracted successively with 1% ammonia and water, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from ethyl acetate-petroleum ether to give 1.4 g (67%) of the title product, m.p. 119° to 121° C. An analytical sample was crystallized similarly, m.p. 137° to 139° L C. [α]D20 -3.4°. of standing at room temperature was evaporated extracted successively with 1% ammonia and water dried over anhydrous sodium sulfate evaporated The residue was crystallized from ethyl acetate-petroleum ether

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

Procedure: Ethyl N-acetyltyrosyl-alanyl-1-amino-1-cyclopentanecarboxylate, by the procedure of Example 1 from the preceding compound and ethyl-1-amino-1-cyclopentanecarboxylate, yield 88%, m.p. 168° to 171° C., [α]D20 -3.1° (c 0.2, MeOH).

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of benzyloxycarbonylleucyl-alanine (6.72 g, 20 mmoles) in dimethylformamide (70 ml) was added N-hydroxysuccinimide (2.3 g. 20 mmoles) and on cooling to -5° C. N,N'-dicyclohexyl-carbodiimide (4.4 g) was admixed. After 1 hour of stirring and cooling (-5° C.) there was added a dimethylformamide (40 ml) solution of ethyl 1-amino-1-cyclopentanecarboxylate liberated from its hydrochloride (3.86 g, 20 mmoles) with N-ethylpiperidine (2.8 ml) and the reaction mixture was stirred for further 2 hours at room temperature. After subsequent 12 hours of standing, the N,N'-dicyclohexylurea precipitate was filtered off, washed with dimethylformamide and the filtrate was evaporated. The residue was dissolved in an ethyl acetate-water mixture and the organic phase was shaken successively with 1M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from ethyl acetate (25 ml) and petroleum ether (200 ml) to give 7.6 g (80%) of the title compound, m.p. 102° to 104° C., after similar recrystallization 104° to 106° C. [α]D20 -35.9° (c 0.2, methanol). cooling (-5° C.) there the reaction mixture was stirred for further 2 hours at room temperature After subsequent 12 hours of standing the N,N'-dicyclohexylurea precipitate was filtered off washed with dimethylformamide the filtrate was evaporated The residue was dissolved in an ethyl acetate-water mixture the organic phase was shaken successively with 1M hydrochloric acid, water, 5% sodium hydrogencarbonate and water dried over anhydrous sodium sulfate evaporated The residue was crystallized from ethyl acetate (25 ml) and petroleum ether (200 ml)