Yaozh News Star Club Edu TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【药物名称】Tribavirin, Ribavirin, R-964, Ro-20-9963, ICN-1229, Copegus, Cotronak, Virazide, Rebetol, Viramid, Virazole

【化学名称】1-(beta-D-Ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide

【CA登记号】36791-04-5

【 分 子 式 】C8H12N4O5

【 分 子 量 】244.20864

【开发单位】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)

【药理作用】Anti-Hepatitis C Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Anti-Papilloma Virus Drugs, Anti-RSV Drugs, Antiviral Drugs, RESPIRATORY DRUGS, Severe Acute Respiratory Syndrome (SARS), Treatment of, Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitors
合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

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 中间体
【1】 Christensen, L.F.; Witkowski, J.T. (ICN Pharmaceuticals, Inc.); Process for preparing 1,2,4-triazole nucleosides. US 4138547 .
【2】 Witkowski, J.T.; Robins, R.K. (ICN Pharmaceuticals, Inc.); 1,2,4-Triazole-3-carboxamides as antiviral agents. US 3976545 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17718 (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol C8H14O5 详情 详情
(II) 33823 2-nitriloethanehydrazonamide C2H4N4 详情 详情
(III) 33824 N'-[(3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-nitriloethanehydrazonamide C10H16N4O4 详情 详情
(IV) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(V) 33825 1-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-1H-1,2,4-triazole-3-carbonitrile C11H14N4O4 详情 详情
(VI) 33826 1-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-1H-1,2,4-triazole-3-carboxamide C11H16N4O5 详情 详情
(VII) 33827 methyl 1H-1,2,4-triazole-3-carboxylate 4928-88-5 C4H5N3O2 详情 详情
(VIII) 33828 1H-1,2,4-triazole-3-carboxamide C3H4N4O 详情 详情
(IX) 33829 (3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl dihydrogen phosphate 58459-37-3 C5H11O8P 详情 详情

合成路线2

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.

参考文献 中间体
【1】 Witkowski, J.T.; et al.; Design, synthesis, and broad spectrum antiviral activity of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem 1972, 15, 11, 1150.
【2】 Laguna, N; Robins, R.K.; Witkowski, J.T. (ICN Pharmaceuticals, Inc.); 1,2,4-Triazole nucleosides. DE 2220246; US 3798209 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 33827 methyl 1H-1,2,4-triazole-3-carboxylate 4928-88-5 C4H5N3O2 详情 详情
(X) 26984 (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate C28H24O9 详情 详情
(XI) 33830 methyl 1-[(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl]-1H-1,2,4-triazole-3-carboxylate C30H25N3O9 详情 详情

合成路线3

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).

参考文献 中间体
【1】 Laguna, N; Robins, R.K.; Witkowski, J.T. (ICN Pharmaceuticals, Inc.); 1,2,4-Triazole nucleosides. DE 2220246; US 3798209 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 33827 methyl 1H-1,2,4-triazole-3-carboxylate 4928-88-5 C4H5N3O2 详情 详情
(XI) 33830 methyl 1-[(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl]-1H-1,2,4-triazole-3-carboxylate C30H25N3O9 详情 详情
(XII) 33831 methyl 1-(trimethylsilyl)-1H-1,2,4-triazole-3-carboxylate C7H13N3O2Si 详情 详情
(XIII) 33832 [(2R,3S,4R)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-furanyl]methyl benzoate C26H21BrO7 详情 详情

合成路线4

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 中间体
【1】 Witkowski, J.T.; et al.; Design, synthesis, and broad spectrum antiviral activity of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem 1972, 15, 11, 1150.
【2】 Laguna, N; Robins, R.K.; Witkowski, J.T. (ICN Pharmaceuticals, Inc.); 1,2,4-Triazole nucleosides. DE 2220246; US 3798209 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 33827 methyl 1H-1,2,4-triazole-3-carboxylate 4928-88-5 C4H5N3O2 详情 详情
(XII) 33831 methyl 1-(trimethylsilyl)-1H-1,2,4-triazole-3-carboxylate C7H13N3O2Si 详情 详情
(XIV) 33835 (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate 13035-61-5 C13H18O9 详情 详情
(XV) 33834 methyl 1-[(2R,3R,4S,5R)-4-(acetoxy)-5-[(acetoxy)methyl]-3-hydroxytetrahydro-2-furanyl]-1H-1,2,4-triazole-3-carboxylate C13H17N3O8 详情 详情
(XVI) 33833 (2R,3S,4R,5S)-4-(acetoxy)-2-[(acetoxy)methyl]-5-bromotetrahydro-3-furanyl acetate C11H15BrO7 详情 详情

合成路线5

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 中间体
【1】 Frigerio, M.; Banfi, A.; Dall'Oro, B.; Mancini, A. (Clariant Life Science Molecules SpA); Process for the preparation of ribavirin. EP 1281715; WO 0311883; WO 0311884 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 60541 (2R,3R,4R)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanyl acetate C13H18O9 详情 详情
(II) 33827 methyl 1H-1,2,4-triazole-3-carboxylate 4928-88-5 C4H5N3O2 详情 详情
(III) 60539 methyl 1-{(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-[(acetyloxy)methyl]tetrahydro-2-furanyl}-1H-1,2,4-triazole-3-carboxylate C15H19N3O9 详情 详情
(IV) 60540 methyl 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-1,2,4-triazole-3-carboxylate C9H13N3O6 详情 详情
Extended Information