Synthesis of 4-(N-Benzoylaminoacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane

This study aimed to develop an efficient synthesis of a new hexaazaisowurtzitane derivative, 4-(N-benzoylaminoacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane, which is a promising candidate for pharmacological screening. The synthesis was carried out in three steps: preparation of N-benzoylglycine by acylating glycine with benzoyl chloride under strictly controlled pH conditions with an extended holding period prior to acidification; synthesis of hippuryl chloride followed by dissolution in acetonitrile and removal of insoluble impurities; and acylation of 2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane with the resulting hippuryl chloride in refluxing acetonitrile for 3 h. The structures of the products were confirmed by infrared spectroscopy, 1 H and 13 C nuclear magnetic resonance spectroscopy, elemental analysis, and high-performance liquid chromatography. Optimization of the reaction conditions increased the yield of N-benzoylglycine by 3.0% relative to the literature value. An additional purification step increased the purity of hippuryl chloride by 6.9% and significantly simplified isolation of the final product. An acylation time of 3 h was optimal for the synthesis of 2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane; longer heating resulted in tar formation and reduced the product yield. The target compound was obtained in 60.6% yield with a chromatographic purity of 98%. Computational prediction of bioactivity indicated a high probability of anxiolytic properties and inhibition of polyamine-transporting ATPase. The resulting reproducible three-step synthesis provides the new compound in high yield and purity and establishes a foundation for scale-up and preclinical studies. The proposed approach may also be applicable to the targeted synthesis of aminoacyl derivatives of hexaazaisowurtzitane with desired pharmacological properties.