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【结 构 式】 
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【分子编号】33835 【品名】(2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate 【CA登记号】13035-61-5 |
【 分 子 式 】C13H18O9 【 分 子 量 】318.28052 【元素组成】C 49.06% H 5.7% O 45.24% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (I) with dry HCl in ether-acetic anhydride gives 1-chloro-2,3,5-tri-O-acetyl-beta-D-ribofuranose (II), which by reaction with silver isocyanate in dry xylene is converted into 2,3,5-tri-O-acetyl-beta-D-ribofuranosylisocyanate (III). The reaction of (III) with 2-methylisourea (IV) in dry CHCl3 affords 1-(2,3,5-tri-O-acetyl-3-D-ribofuranosyl)-4-methylisobiuret (V), which is cyclized by reaction with ethyl orthoformate at 135 C yielding 1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-4-methoxy-2-oxo-1,2-dihydro-1,3,5-triazine (VI). Finally, this compound is treated with ammonia in dry methanol.
| 【1】 Sorm, F.; Piskala, A.; Nucleic acid components and their analogues. LI. Synthesis of 1-glycosyl derivatives of 5-azauracil and 5-azacytosine. Coll Czech Chem Commun 1964, 29, 2060-76. |
| 【2】 Von Hoff, D.D.; Azacitidine. Drugs Fut 1980, 5, 8, 392. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 12304 | N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide | C21H20FN3O2S | 详情 | 详情 | |
| (I) | 33835 | (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate | 13035-61-5 | C13H18O9 | 详情 | 详情 |
| (II) | 39189 | (2R,3S,4R,5S)-4-(acetoxy)-2-[(acetoxy)methyl]-5-chlorotetrahydro-3-furanyl acetate | C11H15ClO7 | 详情 | 详情 | |
| (III) | 39190 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-isocyanatotetrahydro-3-furanyl acetate | C12H15NO8 | 详情 | 详情 | |
| (IV) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (V) | 39191 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[([[(E)-amino(methoxy)methylidene]amino]carbonyl)amino]tetrahydro-3-furanyl acetate | C14H21N3O9 | 详情 | 详情 | |
| (VI) | 39192 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[4-methoxy-2-oxo-1,3,5-triazin-1(2H)-yl]tetrahydro-3-furanyl acetate | C15H19N3O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)This compound has been obtained by two similar ways: 1) The condensation of 1-O-acetyl-2,3,5-O-tribenzoyl-beta-D-ribofuranose (I) with N6-benzoyl-9-(trimethylsilyl)adenine (II) by means of trimethylsilyl perchlorate or trimethylsilyl trifluoromethanesulfonate in dichloroethane gives the tetrabenzoyladenosine (III), which is finally debenzoylated with ammonia in methanol. 2) The reaction of tetraacetyl-D-ribofuranose (IV) with dry HCl in ethyl ether gives the 1-chloro derivative (V), which is condensed with the silver salt of 2,8-dichloroadenine (VI) in refluxing xylene yielding the acetylated dichloroadenosine (VII). The hydrolysis of (VII) with ammonia in methanol affords 2,8-dichloroadenosine (VIII), which is finally dechlorinated by hydrogenation with H2 over Pd/BaSO4 in aqueous NaOH.
| 【1】 Davoll, J.; et al.; Experiments on the synthesis of purine nucleosides. Part XIX. A synthesis of adenosine. J Chem Soc 1948, 967. |
| 【2】 Krolikiewicz, K.; Vorbrueggen, H.; New catalysts for the synthesis of nucleosides. Angew Chem. Int Ed Engl 1975, 14, 6, 421. |
| 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) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (II) | 34914 | N-[9-(trimethylsilyl)-9H-purin-6-yl]benzamide | C15H17N5OSi | 详情 | 详情 | |
| (III) | 34915 | (2R,3R,4R,5R)-2-[6-(benzoylamino)-9H-purin-9-yl]-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C38H29N5O8 | 详情 | 详情 | |
| (IV) | 33835 | (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate | 13035-61-5 | C13H18O9 | 详情 | 详情 |
| (V) | 34916 | (2R,3S,4R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-chlorotetrahydro-3-furanyl acetate | C11H15ClO7 | 详情 | 详情 | |
| (VI) | 34917 | C5H2AgCl2N5 | 详情 | 详情 | ||
| (VII) | 34918 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-amino-2,8-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17Cl2N5O7 | 详情 | 详情 | |
| (VIII) | 34919 | (2R,3R,4S,5R)-2-(6-amino-2,8-dichloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H11Cl2N5O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)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).
| 【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4
该中间体在本合成路线中的序号：(V)This compound has been obtained by several related ways: The acylation of Ribavirin (1-(beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide) (I) with Ac2O gives the triacetate (II), which is anhydrized by means of POCl3 and TEA in chloroform to yield the carbonitrile (III). The reaction of (III) with NaOMe in methanol affords the methyl carboximidate (IV), which is finally treated with NH4Cl and NH3 in methanol to provide the target carboxamidine. Alternatively, the intermediate carbonitrile (III) can be treated with NH4Cl and NH3 in methanol at 85 C in a steel bomb to give the target carboxamidine. Finally, the condensation of 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (V) with 1,2,4-triazole-3-carbonitrile (VI) by means of bis-(4-nitrophenyl)phosphate (BNPP) at 150 C also gives the intermediate triacetyl carbonitrile derivative (III).
| 【1】 Laguna, N; Robins, R.K.; Witkowski, J.T. (ICN Pharmaceuticals, Inc.); 1,2,4-Triazole nucleosides. DE 2220246; US 3798209 . |
| 【2】 Robins, R.K.; Kini, G.D.; Synthesis and anti-leukemic activity of alkyl-1-(beta-ribofuranosyl)[1,2,4]triazole-3-carboximidates. US 4925930 . |
| 【3】 Ramasamy, K.; Hong, Z.; Tam, R.; Lau, J. (ICN Pharmaceuticals, Inc.); Nucleoside analogs with carboxamidine modified monocyclic base. WO 0160379 . |
| 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) | 48598 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-1,2,4-triazole-3-carboxamide | C8H12N4O5 | 详情 | 详情 | |
| (II) | 48599 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[3-(aminocarbonyl)-1H-1,2,4-triazol-1-yl]tetrahydro-3-furanyl acetate | C14H18N4O8 | 详情 | 详情 | |
| (III) | 48600 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(3-cyano-1H-1,2,4-triazol-1-yl)tetrahydro-3-furanyl acetate | C14H16N4O7 | 详情 | 详情 | |
| (IV) | 48601 | methyl 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-1,2,4-triazole-3-carboximidoate | C9H14N4O5 | 详情 | 详情 | |
| (V) | 33835 | (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate | 13035-61-5 | C13H18O9 | 详情 | 详情 |
| (VI) | 48602 | 1H-1,2,4-triazole-3-carbonitrile | C3H2N4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The silylated 5-fluorocytosine (I) is coupled with D-ribofuranose tetraacetate (II) in the presence of SnCl4 in acetonitrile to afford the triacetyl 5-fluorocytidine (III). Acylation of (III) with allyl chloroformate (IV) yields carbamate (V). Then, methanolysis of the acetate ester groups of (V) provides 5-fluoro-N-(allyloxycarbonyl)cytidine (VI). Finally, selective oxidation of the primary alcohol group of (VI) with oxygen and PtO2 gives the target carboxylic acid
| 【1】 Kim, K.-H.; Kim, J.-Y; Lee, K-H; Noh, M.-J.; Kim, Y.-C.; Park, H.-J.; Synthesis and biological activity of the new 5-fluorocytosine derivatives, 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-carboxylic acid. Bioorg Med Chem Lett 2002, 12, 3, 483. |
| 【2】 Lee, K.-H.; Kim, J.-Y.; Kim, Y.-C.; Kim, K.-H.; Park, H.-J.; Noh, M.-J.; Park, Y.-S.; Cho, S.-M. (Kolon Industries, Inc.); 5'-Deoxy-N-(substd. oxycarbonyl)-5-fluorocytosine and derivs. thereof, method of preparing same, and anticancer compsn. comprising same as active ingredients. WO 0211668 . |
| 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) | 36959 | 5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine | C10H20FN3OSi2 | 详情 | 详情 | |
| (II) | 33835 | (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-3-furanyl acetate | 13035-61-5 | C13H18O9 | 详情 | 详情 |
| (III) | 60387 | (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C15H18FN3O8 | 详情 | 详情 | |
| (IV) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (V) | 60388 | (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-[4-{[(allyloxy)carbonyl]amino}-5-fluoro-2-oxo-1(2H)-pyrimidinyl]tetrahydro-3-furanyl acetate | C19H22FN3O10 | 详情 | 详情 | |
| (VI) | 60389 | allyl 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2-oxo-1,2-dihydro-4-pyrimidinylcarbamate | C13H16FN3O7 | 详情 | 详情 |