奥芬达唑质控标准中关键杂质成分的合成

苯并咪唑氨基甲酸酯类化合物(Benzimidazolecarbamate,BZC)是一类广谱抗寄生虫抗菌剂,其广泛使用的典型代表药物为奥芬达唑。 但该药物中的杂质化合物不易获得,导致生产质控不足。 本文发现了奥芬达唑中4种主要杂质成分,包括芬苯达唑、5-苯磺酰基-1H-2-甲氧甲酰氨基苯并咪唑、5-苯亚磺酰基-1H-2-氨基苯并咪唑和2-二(5-苯亚磺酰基-1H-2-苯并咪唑基)-碳酰二胺的简单高效化学合成方法。 特别是通过两种不同的关环策略实现了关键吡唑环的有效合成,以及控制氧化条件得到硫醚的亚砜和砜的氧化产物。 该方法不仅可为奥芬达唑的质控提供标准品,而且为基于奥芬达唑类似物的新型杀虫、抗菌及抗肿瘤等药物的研发提供了一条简单高效的合成线路。

Synthesis of Key Impurities as Quality Control Standards of Oxfendazole

Oxfendazole, a benzimidazolecarbamate(BZC) compound, is a broad-spectrum antihelmintic and antimicrobial agent. The insufficient sources of its impurities affected the quality control of the product. Herein, a simple and efficient method for synthesis of four impurities, fenbendazole, methyl (5-(phenylsulfonyl)-1H-benzo[d]imidazol-2-yl)carbamate, 5-(phenylsulfinyl)-1H-benzo[d]imidazol-2-amine and 1,3-bis(5-(phenylsulfinyl)-1H-benzo[d]imidazol-2-yl)urea, is revealed. Especially, the key imidazole ring was constructed efficiently via two different strategies. Furthermore, oxidative products of sulfur ether, sulphone and sulfoxide were obtained by controlling oxidative conditions. This method not only increases the source of the standard substances for quality control of oxfendazole, but also provides an efficient synthetic strategy to prepare the novel antihelmintic, antimicrobial and antitumor agents based on oxfendazol.