固液结合法合成醋酸亮丙瑞林  

Synthesis of leuprorelin acetate using solid-liquid combination method

作　　者：李新宇 张利香 钟祥龙 付玉清 LI Xinyu;ZHANG Lixiang;ZHONG Xianglong;FU Yuqing(Shenzhen JYMed Technology Co.,Ltd.,Shenzhen 518118,China)

机构地区：[1]深圳市健元医药科技有限公司,广东深圳518118

出　　处：《中国药物化学杂志》2025年第1期10-17,共8页Chinese Journal of Medicinal Chemistry

基　　金：2023年度深圳高新区发展专项计划坪山区创新平台项目(29853M-KCJ-2023-068-02)。

摘　　要：目的解决目前醋酸亮丙瑞林合成方法中存在的偶联不稳定,以及因发生二酮哌嗪副反应(DKP副反应)使合成终止而导致的粗肽合成收率低及纯度低等问题。方法采用固液结合策略合成醋酸亮丙瑞林,以HMBA Linker为连接链,将其偶联至AM Resin,得到HMBA Linker AM Resin,再将液相合成的二肽引入固相合成体系中,逐步构建得到全保护的肽树脂。肽树脂经乙胺胺解、三氟乙酸脱保护后,通过RP-HPLC纯化,得到醋酸亮丙瑞林。结果终产品醋酸亮丙瑞林的纯度为99.88%,总收率46.20%。结论该合成方法操作简单、成本低、收率高,易达到产业化要求。In the current synthetic methods for leuprorelin acetate,there are problems such as unstable coupling,low synthetic yield and low purity of crude peptide due to the side reaction of diketopiperazine.To solve the problems above,leuprorelin acetate was synthesized by solid-liquid combination method in this paper.The HMBA Linker AM Resin was obtained by coupling AM Resin with a HMBA Linker.A dipeptide synthesized through liquid-phase method was then integrated into solid-phase synthesis to prepare a fully protected peptide resin.Subsequent aminolysis with an ethylamine solution yielded the terminally ethylaminated,fully protected peptide.After deprotection with trifluoroacetic acid,crude peptides were obtained.After purification by RP-HPLC,the total yield of leuprorelin acetate was 46.2%and the purity was 99.88%(HPLC).The synthetic method has the advantages of simple operation,low cost,high yield and feasibility for industrial-scale production.

关 键 词：醋酸亮丙瑞林 固液结合法 多肽合成 

分 类 号：R914[医药卫生—药物化学]