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【结 构 式】 
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【分子编号】11867 【品名】5-Iodo-2,4(1H,3H)-pyrimidinedione 【CA登记号】696-07-1 |
【 分 子 式 】C4H3IN2O2 【 分 子 量 】237.98457 【元素组成】C 20.19% H 1.27% I 53.32% N 11.77% O 13.45% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(I)This compound has been obtained by two similar ways: 1. The reaction of 5-iodouracil (I) with trimethylsilylacetylene (II) by means of PdCl2(PPh3)2 and CuI2 in TEA/DMF gives 5-(trimethylsilylethynyl)uracil (III), which is then desilylated with sodium methoxide or NaOH in methanol. 2. The reaction of 5-iodouracil (I) with POCl3 at 120 C catalyzed by N,N-diethylaniline gives 2,4-dichloro-5-iodopyrimidine (IV), which by reaction with NaOMe in methanol is converted into 2,4-dimethoxy-5-iodopyrimidine (V). The condensation of (V) with trimethylsilylacetylene by means of PdCl2(PPh3)2 and CuI2 in TEA/DMF yields 2,4-dimethoxy-5-(trimethylsilylethynyl)pyrimidine (VI), which is treated with NaI and Tms-Cl in refluxing acetonitrile to afford 5-(trimethylsilylethynyl)uracil (III).
| 【1】 Cooke, J.W.B.; et al.; Process research and development of a dihydropyrimidine dehydrogenase inactivator: Large-scale preparation of eniluracil using a Sonogashira coupling. Org Process Res Dev 2001, 5, 4, 383. |
| 【2】 Spector, T.; Porter, D.J.T.; Rahim, S.G. (Glaxo Wellcome plc); Uracil reductase inactivators. EP 0550580; JP 1994504263; JP 1998045623; WO 9204901 . |
| 【3】 Spector, T.; Porter, D.J.T.; Rahim, S.G. (Glaxo Wellcome plc); Enzyme inactivators. EP 0539442; EP 0711555; JP 1994502619; JP 2000297076; WO 9201452 . |
| 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) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (III) | 47911 | 5-[2-(trimethylsilyl)ethynyl]-2,4(1H,3H)-pyrimidinedione | C9H12N2O2Si | 详情 | 详情 | |
| (IV) | 11868 | 2,4-Dichloro-5-iodopyrimidine | C4HCl2IN2 | 详情 | 详情 | |
| (V) | 11869 | 5-Iodo-2-methoxy-4-pyrimidinyl methyl ether; 5-Iodo-2,4-dimethoxypyrimidine | 52522-99-3 | C6H7IN2O2 | 详情 | 详情 |
| (VI) | 47912 | 2,4-dimethoxy-5-[2-(trimethylsilyl)ethynyl]pyrimidine; 2-methoxy-5-[2-(trimethylsilyl)ethynyl]-4-pyrimidinyl methyl ether | C11H16N2O2Si | 详情 | 详情 |