Setmelanotide的制备工艺改进

Improvements in the Preparation Process of Setmelanotide

采用固相合成法,以Rink Amide MBHA树脂为载体、Fmoc保护的氨基酸为原料、1-羟基苯并三唑(HOBt)/N,N'-二异丙基碳二亚胺(DIC)为缩合试剂、三氟乙酸(TFA)体系为裂解液,按照减肥药setmelanotide(1)的氨基酸序列制得还原型1粗肽,后采用双氧水氧化法环化还原型1,用RP-HPLC技术进行分离纯化,得到纯度98%以上的1精制品,总收率约47%;并对其制备过程中的相关工艺参数进行了探讨和优化,明确了关键工艺参数,为工业化生产奠定基础,也为其他多肽药物研究提供了技术参考。

In this paper,using Rink Amide MBHA resin as the carrier,Fmoc-protected amino acids as the raw materials,1-hydroxybenzotriazole(HOBt)/N,N'-diisopropylcarbodiimide(DIC)as the condensation reagents,and trifluoroacetic acid(TFA)system as the lysis solution,the prototype setmelanotide(1)crude peptide was synthesized by a solid-phase synthesis method according to the amino acid sequence of 1,a weight loss agent.Then the oxidative type 1 was obtained by hydrogen peroxide oxidation method.After separation and purification by the RP-HPLC method,the 1 purified product with a purity of more than 98%was obtained.The total yield of this process was about 47%.The related process parameters in the preparation process of 1 were discussed and optimized.In line with the principle of improving yield and reducing cost,the process parameters of each link were clarified and kept within a controllable range,which laid the foundation for its industrialized large-scale production and also provided a technical reference for other peptide drug researches.