【作者】 侯秀梅；

【导师】 陈兴娟；

【作者基本信息】 哈尔滨工程大学 ， 应用化学， 2007， 硕士

【摘要】 β-内酰胺类抗生素选择性好，是很重要的一类抗感染药物。但在此类抗生素的主体结构中，均有一个具有一定外张力的β-内酰胺环，该环对外界环境极为敏感，易水解开环，导致β-内酰胺类抗生素抗菌活性下降，甚至完全丧失抗菌作用。因此，细菌的耐药性已成为临床治疗中的严重问题。在对待耐药菌的感染时，使用β-内酰胺酶抑制剂，将其与β-内酰胺类抗生素结合，保持甚至加强β-内酰胺类抗生素的抗菌活性，不失为一种快捷、有效的方法。舒巴坦是具有抑酶作用的典型的β-内酰胺酶抑制剂，与β-内酰胺环类抗生素联合应用，通过对酶的抑制，保护抗生素免受破坏，提高抗菌活性。因而研究和优化舒巴坦钠的工艺路线具有十分重要的现实意义。舒巴坦钠的合成分重氮化、取代、氧化、还原、成盐共五步。其传统合成路线大致分二种。第一种为：取代反应是在乙酸乙酯有机相中进行，用硫酸保持酸性条件，高锰酸钾作为氧化反应的氧化剂，在高压釜中以镍催化还原，总收率为66.5％。第二种为：取代反应是在二氯甲烷有机相中进行，用硫酸保持酸性条件，高锰酸钾作为氧化反应的氧化剂，甲醇为溶剂以镁粉还原，总收率为65％。本论文在传统工艺基础上，主要研究了以6-氨基青霉烷酸（6-APA）为原料经由重氮化、双溴化、氧化、还原、成盐制得舒巴坦钠的工艺优化。其中，取代反应的采用氢溴酸，氧化反应中氧化剂采用高锰酸钾与磷酸混合液，还原反应中还原剂采用锌粉。在实验过程中考虑了温度、物料配比、反应时间、反应液pH值、氧化剂混合液的配比、还原剂的种类、萃取次数及催化剂等因素的影响，进行大量实验，进而确定最佳合成工艺路线：取代反应中6-APA：NaNO₂：HBr：Br₂的比例为1：1：13：4（物质的量比），在0℃时，以十六烷基三甲基溴化铵为催化剂，反应3.5h；氧化反应中，溴代青霉烷酸（Ⅱ）：磷酸：高锰酸钾的比例为1：1.5：1.5（物质的量比）在0～5℃、pH值为6.5的条件下反应1h；还原反应中，采用锌粉作为还原剂，溴代青霉烷砜酸（Ⅲ）：锌粉的比例为1：6，pH值为4.0，后处理过程用乙酸乙酯萃取三次；成盐反应中，属巴坦（Ⅳ）：异辛酸钠的比例为1：1（物质的量比），反应1h。反应的总收率可达69.67％（以（Ⅰ）计）。反应收率较传统工艺（收率为65～66％）提高了将近4％。优化后的工艺简便易行、成本低、收率高、适合工业化生产。最后用熔点仪、红外光谱仪、核磁共振氢谱、液相色谱及质谱对产物结构进行分析和鉴定。更多还原

【Abstract】 With fine selectivity,β-lactam antibiotics are very important anti-infective drugs. But, in the main structure of such antibiotics, there is aβ-lactam ring of a certain tension outside. Theβ-lactim is extremely sensitive to the external environment, and it is easy to hydrolysis and part, which may degrade the antibacterial activity ofβ-lactam antibiotics, even lead to loss of antibacterial effect completely. Therefore, clinical treatment of bacterial resistance has become a serious problem. Combiningβ-lactamase inhibitors withβ-lactam antibiotics in the treatment of resistant bacteria infections, which maintaining or even strengthening antibacterial activity of theβ-lactam antibiotics, is a rapid and effective method. Sulbactam was proved to be the penicillin sulfoxide possessing inhibiting effect. Penicillin sulfoxide is a typical beta-lactamase inhibitor. It was combined withβ-lactam ring antibiotics to protect antibiotics against damaging and improve its antibacterial activity by the way of inhibition of the enzyme. Thus, the process study of sulbactam sodium has great practical significance.Generally, the traditional synthesis routes of sulbactam sodium have two types. At the first route, substitution reaction is carried out in the organic phase of ethyl acetate, with sulfuric acid as medium; oxidation reaction is carried out permanganate of potash as oxidant; using nickel as catalyst at the reduction in autoclave. The total yield is 66.5%.At the second route, substitution reaction is carried out in the organic phase of dichloromethane, sulfuric acid as medium; oxidation reaction is carried out using permanganate of potash as oxidant; in the reduction, methanol was used as a solvent and magnesium as reducing medium. The total yield is 65%.In this dissertation, the process of sulbactam sodium based on the traditional process was researched, optimizing produce procedure of sulbactam sodium using 6-aminopenicillanic acid （6-APA） as raw materials by diazotization, di-bromidation, oxidation and reduction. Substitution reaction is carried out in inorganic phase of hydrobromic acid medium. Mixture of potassium permanganate with phosphoric acid was used as oxidant in oxidation reaction, and zinc powder as reductant in reduction reaction.In the course of experiment, consideration the influence of factors such as temperature, the ratio of reactive substances, reaction time, pH value, the ratio of oxidant mixture, reductant, the times of extraction and catalyst. Through a lot of experiments, the optimum route of preparation sulbactam sodium was determined: substitution reaction lasted 3.5h with cetyl trimethyl ammonium bromide as catalyst at 0°C when 6-APA: NaNO₂: HBr: Br₂ was 1:1:13:4 （mole ratio）, oxidation reaction lasted 1h at 0～5°C when （II）: permanganate of potash: phosphoric acid was 1:1.5:1.5 （mole ratio） and pH was 6.5; reduction react with zinc powder as reductant when （III）: zinc was 1:6 （mole ratio） ,and extracted for three times with ethyl acetate; The final reaction lasted for 1h when （IV）: CH₃ （CH₂） 4CH （CH₃） COONa was 1:1 （mole ratio）.The total yield of reaction is of 69.67% （to （I） subtotal）, which increased by nearly four percent than conventional processes （yield 65～66%）. The process is simple, low cost, high yield, and suitable for industrial production.Finally, structure of the product was analyzed and investigated by melting point equipment, IR, ¹HNMR, HPLC and MS.更多还原