O. S. Vasil'eva, E. S. Ostroglyadov, A. A. Nikonorov
Jun 1, 2016
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Journal
Russian Journal of Organic Chemistry
Abstract
Compounds exhibiting high pharmacological activity have been found among β-substituted γ-aminobutyric acid derivatives. For example, 4-amino-3phenylbutanoic acid hydrochloride (Phenibut) is used in medical practice as nootropic agent [1, 2], and 4-amino-3-(4-chlorophenyl)butanoic acid (Baclofen) is a myorelaxant and analgesic [2]. There are limited published data on the synthesis of 3,4-disubstituted aminobutyric acids [3–5]. The first representative of this series, 4-amino-3,4-diphenylbutanoic acid, was synthesized for the first time in our laboratory [3], and it was later obtained by other authors using different methods [4, 5]. γ-Aminobutyric acid derivatives containing both phenyl and other pharmacophoric (het)aryl substituents attract considerable interest as promising pharmacologically active substances. Substituted aminobutyric acids can be synthesized by various methods, each being characterized by its own advantages and disadvantages related to required equipment, number of steps, and yields of final products [6, 7]. In this connection, acid hydrolysis of oxopyrrolidinecarboxylic acids is undoubtedly interesting; this method is experimentally simple, and it ensures direct preparation of targeted γ-aminobutyric acid hydrochlorides in quite satisfactory yields. Herein, we report the synthesis and analysis of the structure of a series of 3,4-disubstituted aminobutyric acids. The hydrolysis of methyl 4-R-2-oxo-5-phenylpyrrolidine-3-carboxylates 1–4 on heating in 6 N aqueous HCl for 9 h was accompanied by decarboxylation of pyrrolidine-3-carboxylic acids formed in the first step and subsequent opening of the lactam ring. As a result, we isolated in good yields 4-amino-3-R-4phenylbutanoic acid hydrochlorides 5–8. Initial esters 1–4 were prepared as described in [8].