Tribavirin, Ribavirin, R-964, Ro-20-9963, ICN-1229, Copegus, Cotronak, Virazide, Rebetol, Viramid, Virazole
利巴韦林Chemical Name: 1-(beta-D-Ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide
CAS No. 36791-04-5
项目整合开发状态: Launched-1986
项目研究机构: Ribapharm (Orphan Drug), Schering-Plough (Orphan Drug), Valeant (Orphan Drug), Ribapharm (Originator), Valeant (Originator), Chugai (Not Determined), National Institutes of Health (Not Determined), Roche (Not Determined), Schering-Plough (Licensee)
合成路线: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.
合成路线: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).
合成路线: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).
合成路线: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).
📌 参考资料/链接：
参考文献标题:1,2,4-Triazole nucleosides
文献作者:Laguna,N.; Robins,R.K.; Witkowski,J.T.(ICN Pharmaceuticals,Inc.)
参考来源:DE 2220246; US 3798209
📄 详细内容
合成路线: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).
参考文献标题:1,2,4-Triazole-3-carboxamides as antiviral agents
文献作者:Witkowski,J.T.; Robins,R.K.(ICN Pharmaceuticals,Inc.)
参考来源:US 3976545
合成路线: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).
参考文献标题:Process for preparing 1,2,4-triazole nucleosides
文献作者:Christensen,L.F.; Witkowski,J.T.(ICN Pharmaceuticals,Inc.)
参考来源:US 4138547
合成路线: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.
参考文献标题:Process for the preparation of ribavirin
文献作者:Frigerio,M.; Banfi,A.; Dall'Oro,B.; Mancini,A.(Clariant Life Science Molecules SpA)
参考来源:EP 1281715; WO 0311883; WO 0311884
合成路线: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.
合成路线: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).
参考文献标题:Design,synthesis,and broad spectrum antiviral activity of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides
文献作者:Witkowski,J.T.; Robins,R.K.; Sidwell,R.W.; Simon,L.N.
参考来源:J Med Chem 1972,15(11),1150
产品链接: CAS No. 36791-04-5››