李零;傅晓钟;董永喜;
LI Ling;FU Xiaozhong;DONG Yongxi;School of Pharmacology,Guiyang Medical College;

• 1:贵阳医学院药学院

摘要(Abstract)：

目的:合成具有较强抗乙型肝炎病毒(HBV)活性与较高血浆稳定性的抗HBV前药——阿德福韦膦酸双L-异亮氨酸乙酯(YF-6)。方法:以三-(异丙氧基)磷为反应起始原料,通过与2-氯乙基氯甲基醚经Arbuzov重排得到二异丙基(2-氯乙氧基)甲基膦酸酯(1),而后(1)在四氯化碳溶液中经五氯化磷及三氯氧磷处理得到2-氯乙氧甲基二膦酰氯(2),(2)再与N-Boc L-异亮氨酸羟乙基酯缩合得到双N-Boc L-异亮氨酸-2-氯乙氧甲基膦酸乙酯(3),所得物在Cs2CO3/DMF条件下与腺嘌呤缩合得到阿德福韦膦酸双N-Boc L-异亮氨酸乙酯(4),后者经15%HCl/dioxane脱去Boc保护基得到目标化合物(YF-6),采用核磁共振氢谱和质谱鉴定。结果:根据探寻到的目标化合物合成的路线,获得了目标化合物(YF-6),且收率较高,合成的化合物及中间体均经过核磁共振氢谱与质谱进行了结构表征,确证结构与目标产物一致。结论:该合成方法具有较好的实用性。
Objective: To synthesis adefovir bis(L-isoleucine) ethyl ester with potent anti-HBV activity and higher stability.Methods: Triethyl phosphate was used as starting material which reacted with 2-chloroethyl chloromethyl ether by using Arbuzov rearrangement reaction to obtain bis isopropyl(2-chloroethoxyl) methyl phosphonate(1).(1) was then treated with phosphorus pentachloride and phosphorus oxychloride in carbon tetrachloride to afford 2-chloroethoxy methyl phosphonic acid chloride(2),which was then coupled with N-Boc L-isoleucine hydroxyl ethyl ester(3) to afford 2-chloroethoxy methyl phosphonic acid bis(N-Boc L-isoleucine) ethyl ester(4).The obtained compound was then coupled with adenine in the presence of Cs2CO3 / DMF to give adefovir bis(N-Boc L-isoleucine) ethyl ester,which was then treated by 15% HCl / dioxane to remove N-Boc group to produce the target compounds(YF-6).Results: The structure of target compounds YF-6 and its intermediates were confirmed by the methods of 1H NMR,MS and Elemental analysis.Conclusion: The synthetic method we used has preferable practicality and can be used in synthesizing adefovir bis L-amino acid esters.

关键词(KeyWords)： 阿德福韦;化学,药物;肝炎病毒,乙型
adefovir;chemistry,pharmaceutical;hepatitis virus,B

Abstract:

Keywords:

基金项目(Foundation): 贵州省高层人才科研条件特助基金资助项目(No.TZJF-2009-36)

作者(Author): 李零;傅晓钟;董永喜;
LI Ling;FU Xiaozhong;DONG Yongxi;School of Pharmacology,Guiyang Medical College;

Email:

DOI: 10.19367/j.cnki.1000-2707.2013.05.008

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