罗红霉素相关物的制备

引言罗红霉素(roxithromycin)又名9-O-甲氧乙氧甲基肟红霉素,是红霉素的衍生物,是20世纪80年代初开发的十四元环口服用大环内酯类抗生素,1988年首次在法国上市。它是广谱抗生素,除了对敏感的革兰阳性菌、革兰阴性菌和厌氧菌有效,对军团菌、支原体、衣原体等也有效[1-3],并且对胃酸稳定、吸收率高、疗效好、不良反应小,

Preparation of roxithromycin related substances

N-Demethyl roxithromycin,3-decladinosyl roxithromycin and roxithromycin Z are specified related substances to be controlled in European Pharmacopoeia 7.0,which are derived from roxithromycin.These compounds are required for its routine assay,however cannot be commercially available in China.The related substances were synthesized according to a new procedure developed from previous methods.In the producing process,erythromycin A 9-(Z)-oxime was produced from erythromycin A 9-(E)-oxime in the presence of a strong base.Roxithromycin Z was synthesized by the reaction between erythromycin A 9-(Z)-oxime and methoxyethoxy methyl chloride ether in ethyl acetate at a low temperature,such as lower than 5℃.Roxithromycin Z was then separated with silica chromatography and purified by semi-preparative HPLC.N-Demethyl roxithromycin was prepared by N-demethylation of roxithromycin with iodine and sodium acetate in aqueous solution of sodium hydroxide(pH=8—9),and was purified by two-stage recrystallization.And 3-decladinosyl roxithromycin was obtained through a process of acidic hydrolysis catalyzed by aqueous hydrochloride at room temperature,and was also purified by silica chromatography and semi-preparative HPLC.All three compounds,N-demethyl roxithromycin,3-decladinosyl roxithromycin and roxithromycin Z were determined by HPLC to high purity of over 95%.Their structures were identified by MS,1H NMR and 13C NMR.In this paper,three producing routes of the compounds have been established successfully.The obtained compounds would provide a new standard reference of roxithromycin for drug assay in Chinese Pharmacopieia.