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【结 构 式】 
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【分子编号】17718 【品名】(3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol 【CA登记号】 |
【 分 子 式 】C8H14O5 【 分 子 量 】190.19616 【元素组成】C 50.52% H 7.42% O 42.06% |
合成路线1
该中间体在本合成路线中的序号：(I)The synthesis of RFCNU from 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide (III) has been described, as well as the preparation of 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide from 2,3-O-isopropylidene-D-ribosyl-furanose (I). Briefly, the synthesis is as follows: A cold solution of 2,3-O-isopropylidene-D-ribofuranose (I) in dry pyridine is stirred and treated with p-nitrobenzoyl chloride (A). Workup gives 2,3-O-isopropylene-1,5-di-O-p-nitrobenzoyl-D-ribofuranose (II), which is crystallized from methylene chloride/ether. (II) is added in portions to a dry solution of methylene chloride saturated with HBr at 0 C and stirred for 0.5 h. It is warmed to room temperature, the precipitated p-nitrobenzoic acid removed by filtration (under argon) and the filtrate concentrated. Addition of petroleum ether/diethyl ether and partial concentration by vacuum gives crystals of 2,3-isopropylidene-5-O-p-nitrobenzoyl-beta-ribosyl bromide (III). (III), dissolved in toluene, is reacted with silver isocyanate and refluxed under nitrogen. Silver bromide is filtered off and the filtrate concentrated by evaporation, yielding an oil. Dissolution of the oil in acetonitrile and cooling to -40 C yields crystals of isocyanato-1-O-isopropylidene-2,3-O-p-nitrobenzoyl-5-D-ribofuranose (IV). (IV) is reacted with an aqueous solution of 2-chloroethylamine (B) and the solution extracted with benzene. The organic base is separated, dried and refrigerated. Warming gives a yellow oil, which is treated with ethanol to give crystalline (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-urea (V). (V) is dissolved in methylene chloride, cooled to -40 C and an excess of liquid nitrosyl chloride (NOCl) is added with stirring. Addition of a mixture of chloroform and petroleum ether gives crystals of (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-nitrosourea (RFCNU). The synthesis may be modified to yield either the alpha or beta anomer. Both anomeric forms have shown the same antitumor activity.
| 【1】 Weigele, M.; De Bernado, S.; A synthesis of pyrazomycins. J Org Chem 1976, 41, 287-290. |
| 【2】 Imbach, J.L.; Montero, J.L.; Rodriguez, M.; Sur une nouvelle voie de synthese de la R.F.C.N.U. Eur J Med Chem - Chim Ther 1977, 12, 408-412. |
| 【3】 Eastland, G.; Bofumustine. Drugs Fut 1984, 9, 9, 641. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16170 | 1,2-dichloroethane | 107-06-2 | C2H4Cl2 | 详情 | 详情 |
| (A) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (I) | 17718 | (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol | C8H14O5 | 详情 | 详情 | |
| (II) | 34287 | [(3aR,4R,6aR)-2,2-dimethyl-6-[(4-nitrobenzoyl)oxy]tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate | C22H20N2O11 | 详情 | 详情 | |
| (III) | 34288 | [(3aS,4R,6aR)-6-bromo-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate | C15H16BrNO7 | 详情 | 详情 | |
| (IV) | 34289 | [(3aR,4R,6aR)-6-isocyanato-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate | C16H16N2O8 | 详情 | 详情 | |
| (V) | 34290 | [(3aR,4R,6aR)-6-([[(2-chloroethyl)amino]carbonyl]amino)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-nitrobenzoate | C18H22ClN3O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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).
| 【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3
该中间体在本合成路线中的序号：(XXXV)The reaction of 2,3-O-isopropylidene-D-ribofuranose (XXXV) with 4-methylbenzoyl chloride (XXXVI) by means of pyridine in butyl acetate gives 2,3-O-isopropylidene-5-O-(4-methylbenzoyl)-D-ribofuranose (XXXVII), which is methylated by means of NaH and dimethylsulfate in THF to yield the expected methyl ribofuranoside (XXXVIII). The hydrolysis of the acetonide group of (XXXVIII) with trifluoromethanesulfonic acid in acetonitrile affords 1-O-methyl-5-O-(4-methylbenzoyl)-alpha-D-ribofuranose (XXXIX), which is treated with SO2Cl2/triethylamine in butyl acetate to give the cyclic sulfate (XL). The reduction of (XL) with NaBH4 in THF yields 3-deoxy-1-O-methyl-5-O-(4-methylbenzoyl)-alpha-D-ribofuranose (XLI), which is treated with trifluoromethanesulfonic anhydride and tetrabutylammonium fluoride in dichloromethane/pyridine to afford 2,3-dideoxy-2-fluoro-1-O-methyl-alpha-D-arabinofuranose (XLII). The reaction of (XLII) with HBr in acetic acid as before gives the bromosugar (XLIII), which is condensed with 6-chloro-9-(trimethylsilyl)purine (XLIV) in dichloromethane to yield 6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(4-methylbenzoyl)-beta-D-arabinofuranosyl]purine (XLV). Finally, this compound is treated with ammonia in methanol at 90 C.
| 【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189. |
| 【2】 Saischek, E.; Dax, K.; Braun, W.; Fuchs, F.; Saischek, G. (Chevron Research Co.); D-Xylofuranose derivs., method of preparing them, their use, and novel intermediate compounds for the method. WO 9606851 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXL) | 17722 | [(2R,3S,4R,5S)-3,4-dihydroxy-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate | C14H18O6 | 详情 | 详情 | |
| (XXXV) | 17718 | (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol | C8H14O5 | 详情 | 详情 | |
| (XXXVI) | 17719 | p-Toluoyl chloride; 4-methylbenzoyl chloride | 874-60-2 | C8H7ClO | 详情 | 详情 |
| (XXXVII) | 17720 | [(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-methylbenzoate | C16H20O6 | 详情 | 详情 | |
| (XXXVIII) | 17721 | [(3aR,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-methylbenzoate | C17H22O6 | 详情 | 详情 | |
| (XL) | 17723 | [(3aR,4R,6S,6aR)-6-methoxy-2,2-dioxotetrahydro-2lambda(6)-furo[3,4-d][1,3,2]dioxathiol-4-yl]methyl 4-methylbenzoate | C14H16O8S | 详情 | 详情 | |
| (XLI) | 17724 | [(2S,4R,5S)-4-hydroxy-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate | C14H18O5 | 详情 | 详情 | |
| (XLII) | 17725 | [(2S,4S,5S)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate | C14H17FO4 | 详情 | 详情 | |
| (XLIII) | 17726 | [(2S,4S,5S)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C13H14BrFO3 | 详情 | 详情 | |
| (XLIV) | 17727 | 6-chloro-9-(trimethylsilyl)-9H-purine | C8H11ClN4Si | 详情 | 详情 | |
| (XLV) | 17728 | [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate | C18H16ClFN4O3 | 详情 | 详情 |