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【结 构 式】 
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【分子编号】11876 【品名】1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5,6-diiododihydro-2,4(1H,3H)-pyrimidinedione 【CA登记号】 |
【 分 子 式 】C9H12I2N2O5 【 分 子 量 】482.0137 【元素组成】C 22.43% H 2.51% I 52.66% N 5.81% O 16.6% |
合成路线1
该中间体在本合成路线中的序号：(X)Idoxuridine can be obtained by several related ways: 1) The reaction of 5-iodouracil (I) with refluxing POCl3 and dimethylaniline gives 2,4-dichloro-5-iodopyrimidine (II), which by reaction with NaOCH3 in refluxing methanol, is converted into 2,4-dimethoxy-5-iodopyrimidine (III). The reaction of (III) with 2-deoxy-3,6-di-O-p-toluoyl-D-ribofuranosyl chloride (IV) in acetonitrile yields the ribofuranosyl pyridone (V), which is demethylated with acetic anhydride - dry HCl to afford 2'-deoxy-5-iodo-3',6'-di-O-p-toluoyluridine (VI). Finally, this compound is hydrolyzed with NaOCH3 in methanol. 2) The acetylation of 5-iodouracil (I) with refluxing acetic anhydride gives 1-acetyl-5-iodouracil (VII), which by reaction with mercuric acetate in refluxing methanol is converted into the corresponding mercurium salt (VIII). The condensation of (VIII) with the ribofuranosyl chloride (IV) in chloroform affords the protected 2'-deoxy-5-iodouridine (VI), already obtained. 3) The iodination of 2'-deoxyuridine (IX) with iodine, iodic acid, acetic anhydride, CCl4 and water gives 2'-deoxy-5,6-diiodo-5,6-dihydrouridine (X), which is then treated with NaOH to eliminate HI. 4) By direct iodination of 2'-deoxyuridine (IX) with iodine and nitric acid in refluxing chloroform.
| 【1】 Castaner, J.; Robinson, C.; Idoxuridine. Drugs Fut 1995, 20, 7, 670. |
| 【2】 Prystas, M.; Sorm, F.; Nucleic acid components and their analogues.XLIII. Synthesis of anomeric 5-iodo-2'-deoxyuridines. Coll Czech Chem Commun 1964, 29, 121-9. |
| 【3】 Chang, P.K.; Welch, A.D.; Iodination of 2'-deoxycytidine and related substances. J Med Chem 1963, 6, 428-30. |
| 【4】 Cheong, L.; Rich, M.A.; Eidinoff, M.L.; Introduction of the 5-halogenated uracil moiety into deoxyribonucleic acid of mammalian cells in culture. J Biol Chem 1960, 235, 5, 1441-7. |
| 【5】 Prusoff, W.H.; Synthesis and biological activities of iododeoxyuridine, an analog of thymidine. Biochim Biophys Acta 1959, 32, 295-6. |
| 【6】 Amiard, G.; Torelli, V. (Aventis Pharma SA); New method for the preparation of a uridine deriv. and products used in this method. FR 1336866; GB 1024156 . |
| 【7】 Trivedi, M.A.; A rapid method for the synthesis of 5-iodo-2'-deoxyuridine (IDR) and optimisation of the parameters. J Label Compd Radiopharm 1993, 33, 7, 607-12. |
| 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) | 11867 | 5-Iodo-2,4(1H,3H)-pyrimidinedione | 696-07-1 | C4H3IN2O2 | 详情 | 详情 |
| (II) | 11868 | 2,4-Dichloro-5-iodopyrimidine | C4HCl2IN2 | 详情 | 详情 | |
| (III) | 11869 | 5-Iodo-2-methoxy-4-pyrimidinyl methyl ether; 5-Iodo-2,4-dimethoxypyrimidine | 52522-99-3 | C6H7IN2O2 | 详情 | 详情 |
| (IV) | 11870 | (2R,3S,5S)-5-Chloro-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | C21H21ClO5 | 详情 | 详情 | |
| (V) | 11871 | (2R,3S,5R)-5-[5-iodo-4-methoxy-2-oxo-1(2H)-pyrimidinyl]-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | C26H25IN2O7 | 详情 | 详情 | |
| (VI) | 11872 | (2R,3S,5R)-5-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-[[(4-methylbenzoyl)oxy]methyl]tetrahydro-3-furanyl 4-methylbenzoate | C25H23IN2O7 | 详情 | 详情 | |
| (VII) | 11873 | 1-Acetyl-5-iodo-2,4(1H,3H)-pyrimidinedione | C6H5IN2O3 | 详情 | 详情 | |
| (VIII) | 11874 | 6-Iodo-8,8a-dihydro-7H-[1,4,2]oxazamercurolo[4,5-a]pyrimidin-7-one | C5H5HgIN2O2 | 详情 | 详情 | |
| (IX) | 11875 | 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione; 2'-Deoxyuridine | 951-78-0 | C9H12N2O5 | 详情 | 详情 |
| (X) | 11876 | 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5,6-diiododihydro-2,4(1H,3H)-pyrimidinedione | C9H12I2N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)L-Gulono-gamma-lactone (I) was reduced with DIBAL and then protected as the diisopropylidene ketal (III). This was converted to 1,6-anhydrogulopyranose (IV) upon treatment with 0.5N HCl. Subsequent oxidative cleavage of (IV) with NaIO4, followed by reduction with NaBH4 provided triol (V), which was protected as the isopropylidene derivative (VI) with acetone and TsOH. Condensation of (VI) with benzoyl chloride in the presence of pyridine yielded benzoate ester (VII). Then, ketal deprotection of (VII) afforded diol (VIII). Oxidative treatment with NaIO4/RuO2 produced acid (IX), and further oxidative decarboxylation with Pb(OAc)4 furnished dioxolanyl acetate (X). 5-Iodouracil (XI) was silylated using hexamethyldisilazane and a catalytic amount of (NH4)2SO4. The resulting silylated uracil (XII) was coupled with dioxolanyl acetate (X) in the presence of trimethylsilyl triflate to afford an anomeric mixture of nucleosides (XIII). Title compound was then obtained by deprotection of the benzoate ester of the mixture (XIII) with methanolic ammonia, followed by chromatographic isolation of the desired L-anomer.
| 【1】 Kim, H.O.; et al.; L-beta-(2S,4S)- and L-alpha-(2S,4R)-dioxolanyl nucleosides as potential anti-HIV agents: Asymetric synthesis and structure - Activity relationships. J Med Chem 1993, 36, 5, 519. |
| 【2】 Lin, J.-S.; et al.; Structure-activity relationships of L-dioxolane uracil nucleosides as anti-epstein barr virus agents. J Med Chem 1999, 42, 12, 2212. |
| 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) | 25836 | (3S,4R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3H)-furanone | C6H10O6 | 详情 | 详情 | |
| (II) | 25837 | (3S,4R)-5-[(1S)-1,2-dihydroxyethyl]tetrahydro-2,3,4-furantriol | C6H12O6 | 详情 | 详情 | |
| (III) | 25838 | (3aS,6aS)-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol | 14131-84-1 | C12H20O6 | 详情 | 详情 |
| (IV) | 25839 | (1S,2S,3S,4S,5S)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol | C6H10O5 | 详情 | 详情 | |
| (V) | 25840 | (1S)-1-[(2S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]-1,2-ethanediol | C6H12O5 | 详情 | 详情 | |
| (VI) | 25841 | 4-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-1,3-dioxqlan-2(S)-ymethanol | C9H16O5 | 详情 | 详情 | |
| (VII) | 25842 | Benzoic acid 4-(2,2-dimethyl-1,3-dioxolan-4(S)-yl)-1,3-dioxolan-2(S)-ylmethyl ester | C16H20O6 | 详情 | 详情 | |
| (VIII) | 25843 | [(2S)-4-[(1S)-1,2-dihydroxyethyl]-1,3-dioxolan-2-yl]methyl benzoate | C13H16O6 | 详情 | 详情 | |
| (IX) | 25844 | (2S,4S)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylic acid | C12H12O6 | 详情 | 详情 | |
| (X) | 25845 | [(2S)-4-(acetoxy)-1,3-dioxolan-2-yl]methyl benzoate | C13H14O6 | 详情 | 详情 | |
| (XI) | 11876 | 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5,6-diiododihydro-2,4(1H,3H)-pyrimidinedione | C9H12I2N2O5 | 详情 | 详情 | |
| (XII) | 25846 | 5-iodo-2,4-bis[(trimethylsilyl)methyl]pyrimidine | C12H23IN2Si2 | 详情 | 详情 | |
| (XIII) | 25847 | [(2S)-4-[5-iodo-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1,3-dioxolan-2-yl]methyl benzoate | C15H13IN2O6 | 详情 | 详情 |