【作者】 梁建军；

【导师】 赵临襄；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2004， 硕士

【摘要】 寻找对耐药菌株具有良好作用的药物是抗感染药物领域关注和研究的热点之一。现已开发出多个对耐药菌株有效的β-内酰胺类、喹诺酮类等传统抗菌药的新衍生物。基于多个可供抗菌药物设计的新型靶标，设计开发具有新作用机制的抗菌药，更能有效地解决细菌的耐药性问题。 头孢匹胺（Cefpiramide）属于第三代头孢菌素，半衰期长，血清蛋白结合率高，在体内几乎不代谢，主要以原型药物经胆汁排泄，适用于敏感G⁺和G^-菌引起的肺炎、支气管炎、胆囊炎等疾病。 本文对头孢匹胺的合成路线进行了研究，在文献的基础上总结出了3条路线，并进行了可行性分析，着重对其中的两条路线进行了实验考察。以4-羟基-6-甲基-2-吡喃酮为原料经缩合和重排得到关键中间体4-羟基-6-甲基吡啶-3-甲酸；吡啶酸与（R）-2-氨基-（4-羟基苯基）乙酸乙酯盐酸盐进行酰化和水解生成（2R）-2-[（4-羟基-6-甲基-3-吡啶）甲酰胺基]-2-（4-羟基苯基）乙酸，其中（R）-2-氨基-（4-羟基苯基）乙酸乙酯盐酸盐由（R）-2-[1-（乙氧基酰基）丙-1-烯-2-基]氨基-2-（4-羟基苯基）乙酸钾经水解和酯化反应得到；侧链酸与（6R，7R）-3-[（1-甲基-1H-四唑-5-基）硫甲基]-7-氨基-8-氧代-5-硫杂-1-氮杂双环[4．2．0]辛-2-烯-2-羧酸（简称7-ACA-MMT）酰化制得头孢匹胺，共六步反应，总收率为18.1％。 通过优化反应条件，使4-羟基-6-甲基吡啶-3-甲酸的收率提高至62.3％；改进了实验方法，简化了实验操作，使侧链酸的收率达80.9％；改进最后一步酰化反应的溶剂系统使头孢匹胺的收率提高至51.2％。头孢匹胺的化学结构经IR、¹H-NMR和¹³C-NMR确证。更多还原

【Abstract】 Drugs that can cope with bacterial resistance will play an important role in the field of antibacterial research. Many derivatives of traditional antibiotics and new chemical entities with novel structures or targets have been reported abroad. Novel drugs can settle bacterial resistance more efficaciously by new antibacterial mechanism, which are designed on the basis of novel targets.Cefpiramide, a third-generation cephalosporin, has a relatively long half-life of 4.5 hours, plasma protein binding extensively and high biliary excretion with prototype. Cefpiramide can be used to treat the disease caused by susceptive Gram-positive and Gram-negative bacterias.Synthetic technology of cefpiramide is studied in this paper. Three synthetic routes were designed on the basis of relevant references, then their feasibilities were analysed. 4-Hydroxy-6-methylpyridine-3-carboxylic acid was gained from 4-hydroxy-methyl-2-pyrone by the reaction of condensation and rearrangement. (2R)-2-[[(4-hydroxy-6-methyl-3-pyridinyl)carboyl]amino]-2-(4-hydroxyphenyl)acetic acid was synthesized from 4-Hydroxy-6-methylpyridine-3-carboxylic acid and ethyl (R)-ethyl 2-amino-2-(4-hydroxyphenyl)acetate hydrochloride by the reaction of acylation. (R)-ethyl 2-amino-2-(4-hydroxyphenyl)acetate hydrochloride was gained from potassium (R)-2-[l-(ethoxycarbonyl)prop-l-en-2-ylamino]-2-(4-hydroxyphenyl)acetate by the reaction of hydrolyzation and esterification. Cefpiramide was produced from更多还原