泰拉菌素的合成工艺改进

Improvement of the Synthesis Process of Tulathromycin

以阿奇霉素A(Ⅰ)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w(Ⅶ)=98.0%。该法改进了文献合成方法,不需采用极低温反应。

Tulathromycin is a new-type macrolide antibiotic for animals. This study is intended to explore the improved synthetic process route for tulathromycin using azithromycin-A as the raw material. First, protective azithromycin-A was prepared by reaction of azithromycin-A with Cbz-C1 ; in this stage of reaction the second hydroxide of azithromycin-A was protected in the presence of Cbz-C1. 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 Witting-Horner reaction when ketone group converted alkenyl. And then Cbz-protected epoxy compound was prepared with protective alkene being oxidized in the presence of hydrogen peroxide. In the next step, deprotected epoxy compound was prepared with Cbz-protected epoxy compound deprotected by using Pd/C as catalyst. The 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 a yield of 42.0% with a purity of 98.0% determined by HPLC. This study proposed a new and improved preparation route in which the reaction needn＇t be carried out at an extremely low temperature compared with previous methods. It can be effectively applied in industrial production.