盐酸头孢吡肟合成工艺改进

发布时间：2018-05-21 18:01

本文选题：头孢菌素 + 盐酸头孢吡肟　；参考：《苏州大学》2014年硕士论文

【摘要】：盐酸头孢吡肟（Cefepime Hydrochloride）是20世纪90年代由美国Bristol-MyersSquibb公司研发，1993年上市，作为第一个上市的第四代头孢菌素，具有抗菌谱广，活性高的特点。文献报道的合成方法很多，从起始原料来看，主要有两种：第一种以GCLE（7-苯乙酰胺基-3-氯甲基头孢烷酸对甲氧基苄酯）为原料；第二种以7-ACA（7氨基头孢烷酸）为原料。以GCLE开始合成路线长，需要取代、脱保护等多步反应。以7-ACA为原料，，为了防止△-异构化的产生，需要使用极性小的氟利昂或环戊烷作为硅烷化和碘代化试剂，收率低，后处理麻烦，溶剂回收困难。本文对合成方法进行了优化，选择单一的二氯甲烷作为溶剂，控制特定的反应条件和控制体系水分的方法，保证在完成硅烷化保护和碘代反应后，加入N-甲基吡咯烷取代，不至于发生△-异构化。一步得到盐酸头孢吡肟关键中间体7-氨基-3-(1-甲基1--四氢吡咯)甲基-3-头孢-4-羧酸盐酸盐(7-MPCA),然后与AE-活性酯缩合得到盐酸头孢吡肟粗品，产品经重结晶得到盐酸头孢吡肟。高效液相色谱检测纯度大于99.5%，总收率可达70%以上。最后采用元素分析（EA）、红外色谱（IR）、核磁共振分析（1HNMR）和质谱分析（MS）等手段，确定了所得产物结构，证实了所得产品为盐酸头孢吡肟。所合成的产品通过质量研究，稳定性研究表明：工艺所得产品稳定，与对照品一致。
[Abstract]:Cefepime Hydrochloride (Cefepime Hydrochloride) was developed by Bristol-MyersSquibb Company in 1990s and listed in 1993. Cefepime Hydrochloride (Cefepime Hydrochloride) is the first fourth generation cephalosporin to be listed on the market with wide antibacterial spectrum and high activity. There are many synthesis methods reported in the literature. There are two kinds of raw materials: the first is GCLE7-phenylacetamide-3-chloromethyl-cephalosporic acid (p-methoxybenzyl ester) and the second is 7-ACA(7 amino-cephalosporic acid). The synthesis route is long with GCLE, which needs to replace, deprotect and other multistep reactions. In order to prevent the isomerization of 7-ACA, it is necessary to use low polarity freon or cyclopentane as silanization and iodination reagents. The yield is low, the post-treatment is troublesome and the solvent recovery is difficult. In this paper, the synthesis method has been optimized by selecting a single dichloromethane as the solvent, controlling the specific reaction conditions and controlling the water content of the system, so as to ensure the addition of N-methylpyrrolidine after the silane protection and the iodination reaction have been completed. Do not occur-isomerization. The key intermediates of cefepime hydrochloride (7- amino-3-methyl-1-methyl-tetrahydropyrrole) methyl -3-cef-4-carboxylate 7-MPCAN were obtained in one step, and then condensed with AE-active ester to obtain the crude product of cefepime hydrochloride. The product was recrystallized to obtain cefepime hydrochloride. The purity of HPLC was more than 99.5, and the total yield was over 70%. Finally, the structure of the product was determined by elemental analysis, IR, 1H NMR and MS, and the product was confirmed to be cefepime hydrochloride. Through the quality research and stability study, the synthesized product is stable and consistent with the reference substance.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.3

【参考文献】