Synthesis Of Ribavirin Derivatives

Ribavirin is a kind of Nucleoside drugs possessing antiviral activity, whose chemical name is 1-β-D-ribofuranose-1,2,4- triazole-3-carboxamide.However, recent preliminary pharmacological studies have suggested that by excess dosage and long term usage of ribavirin can lead to some adverse effects, such as hemolytic anemia. In order to find novel ribavirin analogues with wider range of application; efficient performance and low toxicity, structural modifications of ribavirin have become a hotspot of the research in ribavirin analogues.The main work of this study is the modifications of 5′-OH of ribofuranose ring, that is, the research on deoxy-halogenation and esterification of 5′-OH of ribofuranose ring.Firstly, the intermediate compound methyl 1-(β-D-ribofuranosyl)-1,2,4-triazole-3- carboxylate(c) was synthesized from methyl 1-(2,3,5-triacetyl-β-D-ribofuranosyl)-1,2,4- triazole-3-carboxylate(a) through alcoholysis reaction and protection of 2′,3′-hydroxyl reaction in the presence of acids. Effects of different reaction conditions of the alcoholysis reaction in the presence of base and the protection of 2′,3′-hydroxyl in the presence of acids were investigated. The experiments results suggested that in the condition of 5% sodium methoxide as catalyst, methanol as solven and room temperature, the yield of alcoholysis reaction was quantitative; In the condition of 10%TsOH as catalyst, acetone as solvent, trimethyl orthoformate as the dehydrating agent and room temperature, the yield of compound c was 94.0%.Secondly, 5′-deoxy-5′-iodoribavirin(f) was synthesized from compound c through Appel-Lee reaction, deprotection reaction and ammonolysis reaction, the total yield was 44.6%. 5′-deoxy-5′-chlororibavirin(i) was synthesized from the same intermediate, compound c, by two synthetic approaches: one is sequentially through aminolysis reaction, chlorination, deprotection of isopropylidene, the other is sequentially via chlorination, aminolysis, deprotection of isopropylidene, and the total yield of the two-step reaction of two approaches were 50.1% and 72.8% seperately. Effects of different reaction conditions of isopropylidene's deprotection were investigated. The experiments results suggested that in the condition of 20% TsOH as catalyst, water as solvent, 85℃as the reaction temperature, 2.5h as the reaction time and the yield was 90.0%.Finally, 1-[5-(4-nitrobenzoy)-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide(k1),1-[5- (3,4,5-tribenzyloxybenzoyl)-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide(k2) and 1-(5- benzoyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide(k3) were synthesized from 1-[2,3- O-(1-methylethylidene)-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide(g) through esterifica- tion reaction with three different acyl chloride by base catalyzing and hydrolysis reaction catalyzed by p-TsOH. 1-[5-(4-aminobenzoyl)-β-D-ribofuranosyl]-1,2,4-triazole-3- carboxamide(m1) and 1-[5-(3,4,5-trihydroxybenzoyl)-β-D-ribofuranosyl]-1,2,4-triazole-3- carboxamide(m2) were obtained via hydrogenation by Pd/C catalyzing under the solvent of MeOH. Different effect factors during the reaction were investigated, which are different bases and solvents of the condensation reaction, different acids of the deprotection reaction, and the different dosages of Pd/C on the reaction of catalytic hydrogenation. The result showed that the reaction of esterification in the presence of pyridiene as acid binding agent and solvent obtained high yield and good selectivity, the conversion was above 95%; p-TsOH was adopted as catalyst for the reaction of deprotection in order to make the conversion complete, and had a good result.Because of the multiple reactive sites existing in the structure of ribavirin and this reactive sites exhibiting high reaction activity or very sensitive to different reaction conditions, synthesis of ribavirin derivatives is much challengeable. This paper has the following advantages: the convenient synthesis approach, the simple aftertreatment, high yield of products, and the potential of industrial application. The structures of all the intermediates and title products were confirmed by IR and 1HNMR.