阿奇霉素二水合物的合成工艺研究

Study on the synthesis of azithromycin dihydrate

目的对阿奇霉素的合成工艺进行优化。方法以硫氰酸红霉素A为起始原料,经肟化、重排、还原、甲基化反应制得目标化合物。该制备工艺的关键步骤是红霉素肟硫氰酸盐在丙酮-水体系中与对甲苯磺酰氯发生重排反应制备红霉素A 6,9-亚胺醚(收率为85%左右),红霉素A 6,9-亚胺醚经硼氢化钾还原、连续多次酸水解、中和制得关键中间体9-脱氧-9a-氮杂-9a-高红霉素。结果与结论目标化合物经高效液相色谱检测纯度在98.5%以上,总收率为65%~70%,在丙酮-水中形成阿奇霉素二水合物晶型。该工艺路线提高了还原剂的利用率,控制了硼酸酯的逆反应,减少了不必要的分离过程,得到高质量的9-脱氧-9a-氮杂-9a-高红霉素可直接用于制备阿奇霉素。

An optimal process has been developed after summarizing all the synthetic methods in literatures and experiments. The target compound was produced by erythromycin thiocyanate via oximation, rearrangement,reduction, and methylation. The purity of the product was more than 98.5 % by HPLC, total yield was 65 % -70% and azithromycin dihydrate could be obtained in acetone-water. The paper emphasized on optimizing the rearrangement and reduction. As for the preparation of erythromycin A 6,9-imine ether, the erythromycin thiocyanate was reacted with p-toluenesulfonyl chloride at 0 - 5℃ in acetone-water and the yield was 85 %. Then erythromycin A 6,9-imine ether was reduced by potassium borohydride at pH 7.0 - 9. 0, after several consecutive hydrolysis by acid and neutralization. The amount of the reducing agent was reduced, and the reverse reaction of the borate was controlled. 9-Deoxo-9a-aza-9a-homoerythromycin which could be directly used to prepare azithromycin, was obtained in high quality.