The synthesis of bisphosphonate analogues of nucleotides – derivatives of (α-phenyl)(α-fluoro)methylenebisphosphonic acids

Abstract

The synthetic methods of fluorine-containing mimetics of nucleozide-diphosphates based on the derivatives of (α-fluoro)(α-phenyl) methylenebisphosphonic acid containing the residues of 2-{1-[4-(toluene-4-sulfonyl)-5-per-fluoroalkyl-[1,2,3]triazol-2-yl]-ethoxy}-ethelene and {2,2-dimethyl-6-[4(toluene-4-sulfonyl)-5-pentafluoroethyl-[1,2,3] triazol-2-yl]-tetrahyro-furo[3,4-d][1,3]dioxol-4-yl}-methylene as ester groups have been developed. Selective mono-and bisdealkylation of methoxy-groups in the tetramethyl ester of (α-fluoro)(α-phenyl)methylenebisphosphonic acid allows to prepare in high yields the corresponding trimethyl or symmetrical dimethyl esters containing one or two free reactive phosphonic acids groups. These compounds are convenient starting materials for the synthesis of mixed esters of (α-fluoro)(α-phenyl)methylenebisphosphonic acid by esterefication of acidic functionalities using simple aliphatic alcohols (n-butanol) and such analogues of nucleosides as 2-{1-[4-(toluene-4-sulfonyl)-5-perfluoroalkyl-[1,2,3]triazol-2-yl]-ethoxy}-ethanols and {2,2-dimethyl-6-[4(toluene-4-sulfonyl)-5-pentafluoroethyl-[1,2,3]triazol-2-yl]-tetrahyro-furo[3,4-d][1,3]dioxol-4-yl}-methanol. The structure of the compounds obtained has been proven using the methods of IR, NMR (1H, 13C, 19F, 31P) spectroscopy, mass-spectra, and elemental analysis. The cytotoxicity and antiviral activity of the compounds synthesized have been studied on the model of the Epstein-Barr virus. The compound possessing a significant inhibitory effect on the Epstein-Barr virus reproduction has been found.