The condensation of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (X) with 1,2,4-triazole-3-carboxylic acid methyl ester (VII) by means of PNPP at 160 C C gives 1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XI), which is finally treated with NH4OH in methanol.
The silylation of 1,2,4-triazole-3-carboxylic acid methyl ester (VII) with hexamethyldisylazane (HMDS) gives 1-(trimethylsilyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XII), which is condensed with 2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl bromide (XIII) by means of PNPP at 160 C to afford the previously described intermediate 1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XI).
The condensation of 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (XIV) with 1,2,4-triazole-3-carboxylic acid methyl ester (VII) by means of PNPP at 160 C gives 1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XV), which is finally treated with NH4OH in methanol. The condensation of 2,3,5-tri-O-acetyl-beta-D-ribofuranosyl bromide (XVI) with 1-(trimethylsilyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XII) in acetonitrile gives the previously reported intermediate 1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XV).
Viramidine can be synthesized by several related ways: 1) Reaction of triethyl orthoformate (I) with 1-cyanoformimidic acid hydrazide (II) by means of anhydrous HCl in dioxane gives 1,2,4-triazole-3-carbonitrile (III), which is condensed with tetra-O-acetyl-?D-ribofuranose (IV) by means of di-p-nitrophenyl phosphate (BNPP) at 150 oC to yield a mixture of the regioisomeric ribonucleosides (V) and (VI), easily separated by chromatography. Finally, the suitable regiosomer 3-cyano-1-(2,3,5-tri-O-acetyl-?D-ribofuranosyl)-1,2,4-triazole (V) is treated with anhydrous NH3 and NH4Cl at 85 oC in a pressure bomb (1, 2). 2) Alternatively, condensation of 2,3,5-tri-O-acetyl-?D-ribofuranosyl bromide (VII) with 1-(trimethylsilyl)-1,2,4-triazole-3-carbonitrile (VIII) - prepared by treatment of triazole (III) with hexamethyldisilazane in dry acetonitrile - in acetonitrile also gives the regioisomeric mixture of nucleosides (V) and (VI) (1). 3) Acylation of ribavirin (1-?D-ribofuranosyl-1,2,4-triazole-3-carboxamide) (IX) with Ac2O and pyridine gives the triacetate (X), which is dehydrated by means of POCl3 and triethylamine in chloroform to yield 3-cyano-1-(2,3,5-tri-O-acetyl-?D-ribofuranosyl)-1,2,4-triazole (V). Treatment of nucleoside (V) with NaOMe in methanol affords the methyl carboximidate (XI), which is finally treated with NH4Cl and dry NH3 gas in methanol (3).
The reaction of 2,3-O-isopropylidene-D-ribofuranose (I) with cyanoformidic acid hydrazone (II) and formic acid gives N1-(2,3-O-isopropyliene-D-ribofuranosyl)formamidrazone (III), which is cyclized with triethyl orthoformate (IV) by means of bis(p-nitrophenyl)phosphate (PNPP) yielding 1-(2,3-O-isopropylidene-D-ribofuranosyl)-1,2,4-triazole-3-carbonitrile (V). The amonolysis of the nitrile group of (V) with NH4OH in refluxing ethanol affords the corresponding carboxamide as a mixture of the alpha and beta isomers that are separated by column chromatography. The desired beta isomer (VI) is finally deprotected with 80% aqueous trifluoroacetic acid. The reaction of 1,2,4-triazole-3-carboxylic acid methyl ester (VII) with aqueous NH4OH gives the corresponding amide (VIII), which is condensed with D-ribofuranose-1-phosphate (IX) by digestion with the enzyme Nucleoside Phosphorylase (purified calf spleen).
The condensation of tetraacetyl-D-ribose (I) with 1H-1,2,4-triazole-3-carboxylic acid methyl ester (II) by means of SnCl4 in refluxing dichloromethane gives -(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester (III), which is hydrolyzed by means of NaOMe in methanol to yield the deacetylated ester (IV). Finally, this compound is treated with gaseous ammonia in methanol to afford the target amide.