N-carbobenzyloxyalanine → benzyloxycarbonyl-L-alanyl-2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl] glycine methyl ester

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Reaction Steps

In 20 ml of dimethylformamide were dissolved 1 g of 2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl]glycine methyl ester and 1.5 g of N-hydroxysuccinimide ester of benzyloxycarbonyl-L-alanine, and the solution was stirred at room temperature for 50 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium hydrogen carbonate, and dried over sodium sulfate and concentrated under reduced pressure. To the residue was added petroleum ether to give benzyloxycarbonyl-L-alanyl-2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl]glycine methyl ester as a white powder. This powder was dissolved in a mixture of 50 ml of methanol and 10 ml of acetic acid and stirred with 500 ml of palladium black in a stream of hydrogen at room temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dried in a desiccator overnight and dissolved in 50 ml of methanol. With adjusting pH to 9-10 with 1 N sodium hydroxide, the solution was stirred at room temperature for 3 hours. This reaction mixture was adjusted to pH 5 and concentrated under reduced pressure. The residue was dried in a desiccator overnight, dissolved in 10 ml of a 30% solution of hydrogen bromide in acetic acid, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and adjusted to pH 4 with saturated sodium hydrogen carbonate. It was chromatographed on a column (200 ml) of MCI gel CHP-20P, and water to 50% aqueous methanol-water gradient elution was carried out. The eluate was concentrated under reduced pressure and lyophilized to give L-alanyl-2-(2,5-dioxopyrrolidin-3-yl)glycine as a white powder.

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