Synthesis of alkyl 2-aminomethyl-5-(1,2,3-thiadiazol-4-yl)furan-3-carboxylate and pseudopeptides on its basis

Abstract

Cyclization of alkyl 2-methyl-5-acetylfuran-3-carboxylate carbethoxyhydrazone according to Hurd-Mori reaction afforded alkyl 2-methyl-5-(1,2,3-thiadiazol-4-yl)-3-carboxylate. Its bromination with Nbromosuccinimide yielded 2-bromomethyl derivative. The latter was involved in the Delepine reaction to form alkyl 2-aminomethyl-5-(1,2,3-thiadiazol-4-yl)-3-carboxylate. Acylation of the product synthesized with chloroacetyl chloride and subsequent treatment with morpholine or 4-methylpiperidine gave the corresponding pseudopeptides. In the course of these transformations the furylthiadiazole fragment retained its stability.γ-Aminoacetoacetic acid and its derivatives for a long time attract the attention of neurophysiologists as the participants of metabolism of glutamate in brain, and also due to the role played by ketone bodies in the process of epilepsy [1-5]. 2-Aminomethylfuran-3-carboxylic acid is the isostere of Z-enol form of γ-aminoacetoacetic acid. Therefore the search of new pharmaceuticals among the compounds containing this structural fragment seems promising.cule and permits performing a considerably broad range of chemical transformations [8]. Considering the above-mentioned data, in this work the synthesis of the derivatives of 2-aminomethyl-5-(1,2,3-thiadiazol-4-yl)-furan-3-carboxylic acid was carried out. In the first stage it was necessary to establish whether the introduction of an ester group in the position 3 of the furan ring which is not conjugated with the thiadiazole fragment can provide the thermal stability of the system.Easily available ethyl 2-methyl-5-acetylfuran-3-carboxylate I was chosen as the starting substance. It was reacted with carbethoxyhydrazine to give the corresponding hydrazone II. Under the action of thionyl chloride in chloroform the latter underwent cyclization according to Hurd-Mori reaction [9, 10] to form thiadiazolylfuran III in 87% yield. Its structure was established by 1 H and 13 C NMR spectroscopy and mass spectrometry. In the 1 H NMR spectrum of this compound the signal of thiadiazole proton in the position 5 of the thiadiazole ring is observed at 8.58 ppm what coincides with the value of chemical shift of corresponding proton in 4-substituted 1,2,3-thiadiazoles [11]. In the mass spectrum of thiadiazole III an intense peak of molecular ion and the peaks of fragments arising from its decomposition with the elimination of a nitrogen molecule are observed. The isotope composition of such ions corresponds to the calculated one (Scheme 1).