(3R)-3-aminoazepan-2-one;hydrochloride

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (1.396 g=1.91 ml, 13.8 mmol) is added to a stirred mixture of (R)-3-amino-azepan-2-one hydrochloride (7) in N,N-dimethylformamide (12 ml) at 18-22° C., then stirring is continued for approx. 1 hour. 1-Hydroxybenzotriazole hydrate (2.113 g, 13.8 mmol) is added at 18-22° C. to the stirred mixture, followed by the solution of (3R,4R)-4-tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-3-hydroxy-pentanoic acid (6) in N,N-dimethyl-formamide. N,N-dimethylformamide (2 ml) is used for rinsing. The mixture is cooled to 0-5° C., then 1,3-dicyclohexylcarbodiimide (2.847 g, 13.8 mmol) is added, followed by N,N-dimethylformamide (1.5 ml), used for rinsing. Stirring at approx. 0-5° C. is continued for approx. 1 hour, then the mixture is warmed to approx. 18-22° C. and stirred at that temperature for approx. 20 hours. The precipitated solids are removed by filtration and the filter cake is rinsed with N,N-dimethylformamide (12 ml). The filtrate is concentrated at a mantle temperature of approx. 60° C. under reduced pressure, until a concentrate of approx. 19.5 g is obtained. The resulting suspension is cooled to approx. 20-25° C., then an aqueous solution of potassium hydrogencarbonate (1.92 g, 19.17 mmol) in water (32 ml) is added over a period of approx. 20 minutes under evolution of carbon dioxide to give a suspension. The precipitated solids are isolated by filtration, rinsed with water (24 ml) and dried in vacuo at approx. 60° C. to constant weight to yield crude [(1R,2R)-1-(3,4-dichloro-benzyl)-2-hydroxy-3-((R)-2-oxo-azepan-3-ylcarbamoyl)-propyl]-methyl-carbamic acid tert-butyl ester (8) (6.019 g, 99.8% of theory based on (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3,4-dichloro-phenyl-propionic acid (1). for rinsing for rinsing Stirring at approx. 0-5° C. is continued for approx. 1 hour the mixture is warmed to approx. 18-22° C. stirred at that temperature for approx. 20 hours The precipitated solids are removed by filtration the filter cake is rinsed with N,N-dimethylformamide (12 ml) The filtrate is concentrated at a mantle temperature of approx. 60° C. under reduced pressure until a concentrate of approx. 19.5 g is obtained The resulting suspension is cooled to approx. 20-25° C. to give a suspension The precipitated solids are isolated by filtration rinsed with water (24 ml) dried in vacuo at approx. 60° C. to constant weight

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

Procedure: To a stirred suspension of 173 g of (R)-α-amino-ε-caprolactam hydrochloride, 266 g of triethylamine and 1,700 ml of chloroform, 293 g of chlorotriphenylmethane was added portionwise under ice-cooling. The resulting mixture was stirred for an hour under the same conditions, and then for two hours at room temperature. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and to the resultant oily residue 600 ml of n-hexane-ethyl acetate (2:1) mixture was added under heating and stirring. The crystalline precipitates obtained were collected by filtration, washed with 1,000 ml of n-hexane-ethyl acetate (10:1) mixture and dried to provide 290 g of (R)-α-triphenylmethylamino-ε-caprolactam, m.p. 189° C. was added portionwise under ice- cooling The reaction mixture was washed with water dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure to the resultant oily residue 600 ml of n-hexane-ethyl acetate (2:1) mixture was added under heating stirring The crystalline precipitates obtained were collected by filtration washed with 1,000 ml of n-hexane-ethyl acetate (10:1) mixture dried