贵州医科大学学报

2013, (01) 10-15

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6-取代嘌呤非环核苷膦酸双L-氨基酸酯类抗HBV前药的合成
Synthesis of 6-substituted Purine Acyclonucleoside Phosphonates Bis L-amino Acid Esters as Anti HBV Agents

傅胜;张顺;李零;刘香;傅晓钟;董永喜;
FU Sheng,ZHANG Shun,LI Ling,LIU Xiang,FU Xiaozhong,DONG Yongxi(School of Pharmacology,Guiyang Medical College,Guiyang 550004,Guizhou,China)

摘要(Abstract):

目的:合成具有较强抗乙型肝炎病毒(HBV)活性与较高口服吸收性的非环核苷膦酸双L-氨基酸酯衍生物(8a-d)。方法:以2-氯乙醇为原料,通过与多聚甲醛-氯化氢作用形成2-氯乙基-氯甲基醚,后者与亚磷酸三乙酯缩合形成2-氯乙氧甲基膦酸二乙酯,再与2-氨基-6-氯嘌呤缩合得到2-氨基-6-氯-9-[2-(二乙氧基膦酰甲氧基)乙基]嘌呤,所得产物分别与环丙胺或4-甲氧基苯硫酚缩合得到2-氨基-6-环丙胺基/(4-甲氧苯硫基)-9-[2-(二乙氧基膦酰甲氧基)乙基]嘌呤,再经三甲基溴硅烷脱去膦乙酯,得到6-取代嘌呤非环核苷膦酸,后者与N Boc L-氨基酸溴酯缩合,并经乙酰氯/甲醇体系脱去保护基得到目标化合物(8a-d)。结果:合成的化合物及中间体经核磁共振氢谱与质谱进行了结构鉴定,表明结构与目标产物一致。结论:该合成方法具有较好的实用性,能用于非环核苷膦酸双L-氨基酸酯衍生物的制备。
Objective: To synthesis acyclonucleoside phosphonates(8a-d) that has stronger anti-HBV activity and improved oral absorption properties.Methods: 2-chloroethanol was used as starting material,which reacted with paraformaldehyde/ hydrogen chloride to form 2-chloroethyl chloromethyl ether,which then was coupled with triethyl phosphite to form bis ethyl-(2-chloroethoxy)-methylphosphonate.The produced compound was then coupled with 2-amino-6-chloropurine and followed by condensation with substituted arylthiol or cyclopropylamine to afford 2-Amino-6-(arylthiol or cyclopropylamine)-9-[2-(phosphonomethoxy) ethyl] purine bis ethyl ester.The phosphonic acid ethyl ester of the obtained compounds was hydrolyzed in the presence of HCl/MeOH.The hydrolyzed compounds were then coupled with 3-bromo-1-propyl ester of N-Boc-L-amino acids and followed by removal of the N-protecting group in CH3COCl/MeOH ethyl acetate solution to give target compounds 8a-d.Results: The structure of target compounds 8a-d and its intermediates were confirmed by the methods of 1H NMR,ESI-MS.Conclusion: The synthetic method used in this study has preferable practicality and can be used in synthesizing 6-substituted purine acyclonucleoside phosphonates bis L-amino acid esters.

关键词(KeyWords): 非环核苷膦酸;前药;L-氨基酸;合成
acyclonucleoside phosphonates;prodrug;L-amino acid;synthesis

Abstract:

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基金项目(Foundation): 国家自然科学基金(No.20962004);; 贵州省科技厅攻关计划(No.黔科合SY字[2009]3028);; 贵州省高层人才科研条件特助基金(No.TZJF-2009-36)资助项目

作者(Author): 傅胜;张顺;李零;刘香;傅晓钟;董永喜;
FU Sheng,ZHANG Shun,LI Ling,LIU Xiang,FU Xiaozhong,DONG Yongxi(School of Pharmacology,Guiyang Medical College,Guiyang 550004,Guizhou,China)

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