泰拉菌素的合成工艺改进

Improving process of synthesis of Tulathromycin

摘要:

泰拉菌素是动物专用的新型大环内酯类抗生素。以阿奇霉素A为原料，经苄氧羰酰氯保护2’位羟基得到保护的阿奇霉素A(Ⅱ)，然后经Albright-Goldman方法氧化4’’位羟基得到Cbz保护的酮(Ⅲ)，酮通过Wittig-Horner反应得到保护的烯(Ⅳ)，烯经经双氧水氧化得到保护的环氧化合物(Ⅴ)，保护的环氧化合物在Pd/C催化下脱保护得到脱保护的环氧化合物(Ⅵ)，脱保护的环氧化合物与正丙胺反应开环得到泰拉菌素粗品，粗品泰拉菌素成磷酸盐纯化，最后解析得到泰拉菌素(Ⅶ)，总收率为42.0% ，经HPLC测定ω(Ⅶ)=98.0%。该方法改进了文献合成方法，不需采用极低温反应，可以有效的实现工业化生产。

Abstract:

Tulathromycin is a new-style macrolides antibiotic for animals. This study is intended to explore improved synthetic process route for trulathromycin using azithromycin-A as the raw material. First, protective azithromycin-A was prepared by reaction of azithromycin-A and Cbl-Cl, in this reacting the second hydroxide of azithromycin-A was protected in the presence of Cbl-Cl. Next, Cbz-protected ketone was prepared when the protective azithromycin-A was oxidized in the forth hydroxide by using Albright-Goldman method. Then protective alkene was prepared in the reacting of Witting-Horner when ketone group converted alkenyl. And then Cbz-protected epoxy compound was prepared with protective alkene was oxidized in the presence of hydrogen peroxide. After, deprotected epoxy compound was prepared with Cbz-protected epoxy compound deprotected by using Pd/C as the catalyst. Crude product of tulathromycin was prepared by reaction of deprotected epoxy compound and propylamine. Finally, the crude product was purified by phosphate and then tulathromycin was obtained in 42.0% yield with 98.0% purity determined by HPLC. This study proposed new improved preparing route, in the route, the reactions needn’t be at a low temperature compared with previous method. It can be effectively used in industrial production.