着重探讨大位阻氨基酸Fmoc-Arg(Pbf)-OH与NH2-Arg(Pbf)-Rink Amide-AM之间的缩合反应，同时对缩合反应进行动力学实验，以期能够获得一条最佳的醋酸阿基瑞林合成路线并对工业化生产进行指导。采用自制新型多肽固相合成反应器，集成过滤、搅拌、控温、鼓泡四重功能。通过对缩合过程中各反应条件的优化，确立了一条最佳的醋酸阿基瑞林合成路线：NMP/DCM(V：V=2：1)为反应溶剂，HBTU/HOBt/DIEA为缩合试剂，氨基酸与树脂摩尔比3：1，40℃下反应2.5 h，粗肽产率高达90.2%。经RP-HPLC分析，醋酸阿基瑞林粗品纯度为83.5%。同时采用微分法对大位阻氨基酸Fmoc-Arg(Pbf)-OH 与NH2-Arg(Pbf)-Rink Amide-AM之间的缩合反应进行动力学研究，测定了温度变化对反应速率的影响，并获得了活化酯方法下缩合反应的宏观动力学参数：反应级数为1.67，表观活化能为37.4 kJ×mol-1。%In order to obtain a best synthetic route of Argireline Acetate and the guidance of its industrial production, this paper focuses on the condensation reaction between sterically hindered amino acid Fmoc-Arg (Pbf)-OH and NH2-Arg(Pbf)-Rink Amide-AM with self-designed reactor, and its kinetic experiments were carried out at the same time. In self-designed reactor, the four functions of filtration, stir, temperature control and bubbling were combined. By optimizing the reaction conditions in the condensation process, a best synthetic route of Argireline Acetate was established, and its optimum reaction conditions were found as follows:the molar ratio of amino acid to resin 3:1, reaction time 2.5 h, temperature 40℃, NMP/DCM (2:1, V/V) as the solvent and HBTU/HOBt/DIEA as coupling reagents. Under above conditions, the highest yield of Argireline Acetate is 90.2%, and its purity is 83.5% by RP-HPLC analysis. The macroscopic kinetics of condensation reaction of Fmoc-Arg-(Pbf)-OH and NH2-Arg(Pbf)-Rink Amide-AM resin were studied by using the differential method. The effect of reaction temperature on reaction rate was determined, and the macroscopic kinetic parameters of condensation reaction under activated ester method were obtained. The results show that the reaction order is 1.67 and the activation energy is 37.4 kJ×mol-1.
展开▼
