SYNTHESIS OF AZACROWN ETHER DERIVATIVES WITH ADAMANTANE FRAGMENTS

摘要

As a result of the wide application of adamantane containing medicines for the treatment of influenza some mutations took place in the virus genome which caused the resistance of most influenza viruses strains for the traditional medicines. One of the method of their activity restoration is the introduction of the additional functional groups into the adamantine molecule, these groups being able to bind the proteins of the M2 virus channel. Synthesis of the supramolecular compounds on the base of adamantane and azacrown ethers may result in making the antiviral agents to which at the moment some strains of influenza virus have no resistance.We have worked out the efficient methods of the synthesis of the potential antiviral agents – the adamantane-containing derivatives of azacrown ethers of the amide type and their reduction to the corresponding adamantane alkyl azacrown ethers. It has been shown that among the studied acylation methods the most effective method of the synthesis of macrocyclic derivatives in which the substitute is added to azacrown ether using the amide fragment is the chloroanhydride method. The acylation with adamantane carboxylic acids in the presence of DCC and HOBT gives low yields (up to 25%), evidently due to the steric hindrances of the reaction centre which are connected with a large volume of the adamantane skeleton. Reduction of the macrocyclic amides with adamantane fragments using diborane in tetrahydrofurane resulted in macrocyclic amines with the yields 92–97%. Combination of the developed methods of acylation and reduction allows to increase the total yeilds of adamantine alkyl containing azacrown ethers up to 87–92%. As a result of the investigation the below products have been synthesized: adamantanacyl- and adamantanalkyl derivatives of aza-12-crown-4, aza-15-crown-5, aza-18-crown-6, diaza-12-crown-4, diaza-15-crown-5 and diaza-18-crown-6. The compounds synthesized have been handed over to the laboratory in order to study their antiviral activity.