Alternative Methods of Synthesis of Novel Heterosynthones – Functionalized Hypoxanthine Pyrimidines

Abstract

It has been known that derivatives of dihydropyrimidine and xanthine possess the physiological activity of the wide spectrum of action. The combination of the specified heterocyclic fragments within one molecule can lead to the increase of its known types of biological activity as well as to the discovery of novel types of activity. We have previously reported the synthesis of intermediates, which consist of functionalized dihydropyrimidines, connected via a methylene bridge with the halogen substituted derivatives of the ophylline, 3-methylxanthine and imidazole. It was also observed that these compounds would react with N‑nucleophiles with the formation of various branched and cyclic products. The aim of this work was to determine the optimal conditions for obtaining heterocyclic products as a result of conjugation of bromomethyldihydropyrimidine and hypoxanthine at the positions C6 and C1 via a methylene bridge. It is important to note, that the latter can be widely modified by using structurally diverse aromatic aldehydes during the synthesis of dihydropyrimidine core by using Biginelli reaction, which explains structural diversity of the reaction products. After having tried various reaction conditions, we have concluded that the optimal method for obtaining the products entailed keeping equimolar ratios of bromomethyl substituted dihydropyrimidines and 1-potassium‑2-chloro‑7-methylhypoxanthine in dry ethanol for 4 hours. The ester group at the C5 of dihydropyrimidine ring and a chlorine leaving group at C2 of hypoxanthine fragments of the molecule allow to consider these structures as pro missing synthons for farther synthesis of condensed pyrimidine and xanthine systems. The structures of novel compounds have been confirmed with the methods such as HPLC/MS, 1H, and 13C NMR spectroscopy.