Hydrochloric Acid → (R)-Methyl 2-amino-3-(4-nitrophenyl)propanoate hydrochloride

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A solution of 4-nitro-D-phenylalanine (25 g) in 300 mL of methanol is treated with dry hydrogen chloride gas for 10 minutes. The solution is stirred at room temperature overnight. The suspension is concentrated and triturated with 300 mL of ether. The solid is collected and dried to give 4-nitro-D-phenylalanine methyl ester hydrochloride. To a solution of 4-nitro-D-phenylalanine methyl ester hydrochloride (25 g, 96 mmol) in 500 mL of methylene chloride at 0° C. is added 3,5-dimethylbenzoyl chloride (19.3 g, 110 mmol) and triethylamine (29.4 mL, 211 mmol) in 100 mL of methylene chloride. The reaction mixture is warmed to room temperature and stirred overnight. The mixture is concentrated, 100 mL of ethyl acetate is added and the substance is passed through a pad of silica gel. The filtrate is concentrated and the residue is recrystallized from (1:1) toluene/heptane to give N-(3,5-dimethylbenzoyl)-4-nitro-D-phenylalanine methyl ester. To a solution of N-(3,5-dimethylbenzoyl)-4-nitro-D-phenylalanine methyl ester (35 g, 98 mmol) and methyl iodide (18.7 mL, 0.3 mol) in 600 mL of DMF is added in portions sodium hydride (4.2 g, 100 mmol, 60% dispersion) at 0° C. The reaction is warmed to room temperature and stirred overnight. The reaction mixture is poured into 1500 mL of ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated. Chromatography on silica gel with a gradient solvent system: methylene chloride, followed by 10% ethyl acetate/methylene chloride, followed by 20% ethyl acetate/methylene chloride gives the white solid N-(3,5-dimethylbenzoyl)-N-methyl-D-4-nitrophenylalanine methyl ester. A solution of N-(3,5-dimethylbenzoyl)-N-methyl-D-4-nitrophenylalanine methyl ester (5.0 g, 13.5 mmol) in 50 mL of methanol and 100 mL of ethyl acetate is added 1.6 g of 10% Pd/C. The suspension is hydrogenated at 50 psi overnight. The mixture is filtered and concentrated to give the crude amine. The amine is used as is without further purification. The above crude product of N-(3,5-dimethylbenzoyl)-N-methyl-D-4-aminophenylalanine methyl ester (5.15 g, 15.2 mmol) is dissolved in 150 mL of acetic acid. 2,5-Dimethoxytetrahydrofuran is added and the mixture is heated to 90° C. for 1 hour, then cooled and poured into ethyl acetate. The organic layer is washed with 1N HCl, H2O, sat. NaHCO3, brine, dried over MgSO4 and concentrated. Chromatography on silica gel with 1:2 ethyl acetate/hexane gives N-(3,5-dimethylbenzoyl)-N-methyl-D-4-(1-pyrrolyl)-phenylalanine methyl ester. To a solution of N-(3,5-dimethylbenzoyl)-N-methyl-4-(1-pyrrolyl)-phenylalanine methyl ester (3.3 g, 8.5 mmol) in 50 mL of methanol/THF (1:1) at room temperature is added 1N lithium hydroxide (10.14 ml, 10.1 mmol). The reaction is stirred overnight. The mixture is concentrated and washed with ether. The residue is acidified with 1N HCl and extracted with ethyl acetate, washed with H2O, brine, dried (MgSO4), filtered and concentrated giving N-(3,5-dimethylbenzoyl)-N-methyl-D-4-(1-pyrrolyl)-phenylalanine.

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