头孢硫脒新杂质的制备及结构解析

Preparation and structure analysis of new cefathiamidine impurities

目的对头孢硫脒的氧化杂质和双键转移杂质进行制备和结构分析。方法用适当的反应方法处理原料,目标杂质用HPLC定位,经分离纯化得到两个杂质的纯品,通过多级质谱和核磁共振确认其结构。结果对制备得到的两个杂质的结构做了解析,双键转移杂质为6R7R-3-[(乙酰氧基)甲基)]-7-[α-N,N’-二异丙基脒硫基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛_3-烯-2-甲酸内铵盐,氧化杂质为6R,7R-3-[(乙酰氧基)甲基)]-7-[α-(N,N>-二异丙基脒硫基)乙酰氨基]-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-甲酸内铵盐-5-氧化物,并推测出其降解路线。结论本研宄对头孢硫脒原料及其制剂的杂质分析和质量控制有重要参考价值。

Objective To prepare and analyze oxidized impurities and the double bond transfer impurities of cefathiamidine. Methods The cefotaxime material was dissolved in water, 3 0 % hydrogen peroxide was added, and the mixture was stirred at room temperature for two hours. The target impurity in the reaction solution was positioned by HPLC, and the retention time of the target impurity was 3.813min. The reaction solution was poured into an ODS separation column and eluted with acetonitrile-water to obtain an oxidized target impurity. The cefathiamidine was dissolved in DCM, an appropriate amount of triethylamine and trimethylchlorosilane was added, and the mixture was stirred at -10℃ for one hour. The reaction solution was extracted with water, the aqueous layer was taken, the target impurity was analyzed by HPLC, and the target impurity retention time was 5.44min. The extracted aqueous layer was poured into an ODS separation column and eluted with acetonitrile-water to obtain a double bond transfer impurity. The structures of the impurities were analyzed by multistage mass spectrometry and nuclear magnetic resonance. Results The structures of the impurities were confirmed. The double bond transfer impurity is (6R,7R)-3-(acetoxymethyl)-7-(2-(((E)-N,N'-diisopropylcarbamimidoyl)thio) acetamido)-8-oxo-5-thia-1 - azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid. The oxidation impurity is (6R,7R)-3-(acetoxymethyl)-7-(2-(((E)-N,N'- diisopropylcarbamimidoyl)thio)acetamido)-8-oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5-oxide, and the degradation route of the impurities were deduced. Conclusion This study is of considerable referential value for the impurity analysis and quality control of cefathiamidine and its preparations.