摘要
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 cyclopropyl- amine）-9-[2- （phosphonomethoxy） ethyl] purine bis ethyl ester. The phosphonic acid ethyl ester of the obtained compounds was hydrolyzed in the presence of HC1/MeOH. The hydrolyzed compounds were then coupled with 3-bromo-l-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.
出处
《贵阳医学院学报》
CAS
2013年第1期10-15,共6页
Journal of Guiyang Medical College
基金
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
关键词
非环核苷膦酸
前药
L-氨基酸
合成
acyclonucleoside phosphonates
prodrug
L-amino acid
synthesis
