Lithium Hydroxide → (R)-2-Acetylamino-3-methoxy-propionic acid

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Reaction Steps

Another method for the preparation of Lacosamide of Formula-I was described in the Journal Bioorganic & Medicinal Chemistry, 16(19), 8968-8975 (2008), wherein D-serine methyl ester is treated with diethoxytriphenylphosphorane to give 9:1 mixture of (R)-aziridine-2-carboxylic acid methyl and ethyl ester of Formula-XIV. The mixture of compound of Formula-XIV on acetylation with acetic anhydride in the presence of triethylamine and dimethylaminopyridine gives a mixture of (R)-1-acetylaziridine-2-carboxylic acid methyl and ethyl ester of Formula-XV. The mixture of compound of Formula-XV is treated with methanol in the presence of borontrifluoride etherate BF3.Et2O to give a mixture of (2R)-2-acetamido-3-methoxypropanic acid methyl and ethyl ester of Formula-XVI. The compound of Formula-XVI on hydrolysis with lithium hydroxide yields the compound (2R)-2-acetamido-3-methoxypropanoic acid of Formula- XVII; which on reaction with benzylamine in presence of tetrahydrofuran and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride followed by purification of the product using flash column chromatography (10:90 MeOH/CHCl3) yields compound Lacosamide of Formula-I. The reaction sequence is as given in Scheme-4;

Provenance & Evidence