一种单分散聚乙二醇药物修饰剂的合成和杂质分析方法研究

Synthesis and impurity analysis of a monodisperse polyethylene glycol drug modifier

以三甘醇为起始物料,丙烯酸叔丁酯和叠氮磷酸二苯酯为端基衍生化试剂,经多步反应制得N_(3)-PEG_(3)-SPA(叠氮-三聚乙二醇-琥珀酰亚胺丙酸酯)。通过改进纯化方法控制单杂,得到含量和纯度分别高达98.16%和97.92%,并且单杂低于1%的单分散N_(3)-PEG_(3)-SPA,其结构经^(1)H NMR和HPLC进行表征。通过实验研究了N_(3)-PEG_(3)-SPA制备过程中缩合剂对产品纯度及含量的影响。N,N′-二环己基碳酰亚胺(DCC)为缩合剂得到的产品纯度好,含量高,中间产物纯化简便,收率较高。针对高纯度单分散N_(3)-PEG_(3)-SPA这种重要的药物修饰剂,开发出的廉价、简便、高效和通用的合成和纯化方法具有重要的理论意义和实用价值。

With triethylene glycol as starting material,tertiary butyl acrylate and azide diphenyl phosphate ester as derivatization reagent for the end-group,N_(3)-PEG_(3)-SPA(azo-tripolyethylene glycol-succinimidyl propionate)was prepared by a four-step synthetic sequence.The monodisperse N_(3)-PEG_(3)-SPA with up to 98.16%content and 97.92%purity and less than 1%single impurity was obtained by improved purification method.The structure of monodisperse N_(3)-PEG_(3)-SPA was confirmed by 1H NMR and HPLC.The effect of condensating agent on product purity and content in the preparation of N_(3)-PEG_(3)-SPA was studied experimentally.The results showed that N,N′-dicyclohexylcarbodiimide(DCC)was a condensating agent with good purity and high content,and the purification of intermediate product was simple and the yield was high.For the high purity monodisperse N_(3)-PEG_(3)-SPA,which is an important drug modifier,the development of a cheap,simple,efficient and universal synthesis and purification method has important theoretical significance and practical value.