基于降低肾毒性的阿德福韦膦酸酯衍生物的设计与合成  

Design and synthesis of phosphonates derivatives of Adefovir with reduced nephrotoxicity

作　　者：裴健颖[1] 刘影[1] 傅晓钟[1] 欧瑜[1] 李靖[1] 董永喜[1] 王永林[1] 兰燕宇[1] 

机构地区：[1]贵阳医学院药学院,贵州贵阳550004

出　　处：《华西药学杂志》2012年第5期478-482,共5页West China Journal of Pharmaceutical Sciences

基　　金：国家自然科学基金资助项目(批准号:20962004);贵州省社会发展攻关计划(No.QKHSYZ-2009-3081);贵州省高层次人才科研特助基金(批准号:TZJF-2009-36)

摘　　要：目的合成具有较高抗HBV活性与较低肾细胞毒性的新型阿德福韦衍生物。方法低温下,硫代N-Boc-L-氨基酸与1,2-二溴乙烷在NaH条件下制备硫代N-Boc-L-氨基酸-3-溴-1-丙基酯;非甾体抗炎药(布洛芬、酮洛芬、氟比洛芬)与3-溴-1-丙醇在DCC/DMAP条件下转变为非甾体抗炎药-3-溴-1-丙基酯;以上两种原料与阿德福韦在缩合剂N,N'-二环己基-4-吗啉基-咪(DCMC)存在下通过"一锅法"制备目标化合物。结果合成了6个未见文献报道的阿德福韦单硫代L-氨基酸酯,单非甾体抗炎药羧酸酯前药5a～5f。结论目标化合物及重要中间体结构均经过1HNMR、ESI-MS以及HRMS确证。OBJECTIVE To synthesize novel Adefovir derivatives to improved anti - HBV activity and reduced nephrotoxicity. METHODS N - Boc - L - amino monothioacids was reacted with 1,2 - dibromoethane, using Nail as base, to obtain 3 - bromopropyl ester of N - Boc - L - amino monothioacids. Non - steroidal anti - inflammatory drugs （ ibuprofen, flurbiprofen and ketoprofen） were converted to 3 - bromopropyl esters by coupling with 3 - bromopropanol in the presence of DMAP/DCC. Then the above two materials were coupled with adefovir using ＇ one pot synthesis＇ method in the presence of N, N - dicyclohexyl -4 - morpholine carboxamidine （DCMC） as acid scavenger, and then the target compounds were obtained by removing the Boc - protecting group. RESULTS Six unreported mono- L- amino thioacid ester, mono non- steroidal anti -inflammatory drugs, carboxylic ester prodrugs of PMEA （Sa- 50 were synthesized. CONCLUSION The chemical structure of the target compounds and key intermediates were characterized by 1HNMR, ESI -MS and HRMS respectively.

关 键 词：阿德福韦 乙肝病毒 前药 非甾体药物 

分 类 号：R914[医药卫生—药物化学]