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【结 构 式】 
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【药物名称】Fozivudine tidoxil, BM-21.1290 【化学名称】3'-Azido-3'-deoxy-5'-O-[2-decyloxy-3-(dodecylthio)propoxy-hydroxyphosphoryl]thymidine 【CA登记号】141790-23-0 【 分 子 式 】C35H64N5O8PS 【 分 子 量 】745.96683 |
【开发单位】Roche (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors |
合成路线1
Treatment of 2-decyloxy-3-(dodecylmercapto)-1-propanol (I) with phosphorus oxychloride in the presence of Et3N gave the intermediate dichlorophosphate ester (II). This was subsequently condensed with 3'-deoxy-3'-azidothymidine (AZT) (III) to produce, after aqueous hydrolysis, the target phosphate diester. The title diester was alternatively obtained by the phospholipase D-catalyzed condensation of AZT (III) with the choline monophosphate ester (IV).
| 【1】 Zilch, H.; Leinert, H.; Mertens, A.; Herrmann, D. (Roche Diagnostics GmbH); New phospholipid derivs. of nucleosides, their preparation and their use as antiviral drugs. DE 4026265; EP 0545966; JP 1994500546; WO 9203462 . |
| 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) | 59212 | 2-(decyloxy)-3-(dodecylsulfanyl)-1-propanol | C25H52O2S | 详情 | 详情 | |
| (II) | 59213 | C25H51Cl2O3PS | 详情 | 详情 | ||
| (III) | 25317 | 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | 101703-35-9 | C10H13N5O4 | 详情 | 详情 |
| (IV) | 59214 | 9-(decyloxy)-2,2-dimethyl-6-oxo-5,7-dioxa-11-thia-2-azonia-6lambda~5~-phosphatricosan-6-olate | C30H64NO5PS | 详情 | 详情 |
合成路线2
In a further procedure, the monophosphate ester of 3-dodecylmercapto-2-decyloxy-1-propanol (V) was directly condensed with AZT employing DCC as the coupling reagent. A related method involved previous activation of (V) as the mixed anhydride with benzenesulfonyl chloride or triisopropylbenzenesulfonyl chloride in the presence of pyridine.
| 【1】 Zilch, H.; Leinert, H.; Mertens, A.; Herrmann, D. (Roche Diagnostics GmbH); New phospholipid derivs. of nucleosides, their preparation and their use as antiviral drugs. DE 4026265; EP 0545966; JP 1994500546; WO 9203462 . |
| 【2】 Zilch, H.; Kiegel, E. (Boehringer Ingelheim GmbH); Method of preparing unsymmetrical phosphoric acid diesters. WO 9520596 . |