【作者】 李士杰；

【导师】 章文军； 朱领地；

【作者基本信息】 河北工业大学 ， 化学工艺， 2004， 硕士

【摘要】 青霉烯属于新型β-内酰胺类抗生素。由于其具有较宽的抗菌谱，对需氧、厌氧革兰阳性菌和多数革兰阴性菌显示出广谱抗菌作用；此药物对β-内酰胺酶稳定，抗菌作用显著。与碳青霉烯类抗生素相比，该品安全性高，肾毒性及中枢神经毒性低，是新一类治疗感染症的首选药物。自从Woodward首次发现以来，该抗生素得以迅猛发展，成为抗生素药物研究热点。 具有手性的氮杂环丁酮是合成各种青霉烯和碳青霉烯的关键手性中间体。本研究工作致力于氮杂环丁酮的合成，以期建立合理可行的合成路线。并对合成路线进行了研究和探索，对涉及的反应进行了改进，优化了工艺条件，提高产品的收率，并对有关的反应机理进行了阐述。成功地实现了从廉价的6-氨基青霉烷酸(简称6-APA)为原料的立体控制合成，总收率37％。(以6～APA计)。 此工艺的优势是利用了河北省内资源优势，本工艺包括七步反应：(1)重氮化、二溴代反应；(2)酯化反应；(3)格利雅反应；(4)羟基保护；(5)还原反应；(6)开环反应；(7)氧化反应，并对其中的溴代、酯化反应进行了工艺优化和机理的探索，提高了产品的纯度和产率。根据金属—卤素交换的机理，适当的延长时间和降低温度，使格利雅合成的质量得到提高。在还原反应以甲醇作溶剂，锌粉作催化剂醋酸铵脱溴，提高了质量和收率。开环、氧化反应在保持收率不变的条件下，缩短了反应时间。至于后两步的条件优化和大量的手性分离还有待试验，氧化反应能否用氧气替代氧化剂还有待进一步的研究证实。更多还原

【Abstract】 Penem belongs to new-type beta-lactam antibiotics. Because these compounds which have both broad antibacterial spectra, including Gram-positive and Gram-negative species and stability to various beta-lactamases have received much attention as potential therapeutic agents. Its antibiotic function is remarkable. Compared with the antibiotic of carbapenem, it should have high security, its toxicity is low to kidney and central nervous system, and it is the first drug of being selected in curing the mediate bacterial infection. Since the first disclosure of penem antibiotic by Woodward, this kind of antibiotic has been developed rapidly, and become thefocus of the studies on antibiotic medicine.Chiral azetidinone is key medicament intermediate that synthesizes various kinds penem and carbapenem. The work of this research is devoted to the efficient synthesis of azetidinone, is in the hope of setting up rational and feasible synthetic route. The route of synthesis is studied and probed, the reaction that is involved has been improved, and we have optimized the process conditions, improved rate of the production, and have explained relevant response mechanism. We have succeed and realized in three-dimensional control and synthesize with 6-APA qua material, the total yield is 37% (at 6-APA count).The advantage of this technology is utilizing the resource advantage in Hebei province. This technology includes reaction of seven steps: [1] diazotized and brominates reaction; [2] esterifies reaction; [3] grignard reaction; [4] the hydroxyl is protected; [5] reduction reaction; [6] opening-ring reaction; [7] oxidation reaction. And replace reaction and esterifies reaction have been carried on condition optimizing and mechanism discussion. We have improved the purity of the products and rate of production. According to the mechanism of the exchange of metal-halogen, the time and temperature of reaction is proper extended, and the quality of reaction of grignard is improved. The rate of production of methyl 6-((lR)-hydroxyethyl)penicillanate has been improved in the reduction reaction, in which acetic acid ammonium take off the bromine using methanol as solvent and zinc powder as catalyst. Make it a condition that opening-ring reactionand oxidize reaction in keeping rate of production is not change, the time of reaction is shorten. Optimizing conditions of reaction and vast chiral-separate of the last step need further study. Oxygen instead of oxidant whether or not needs further research and confirmation also in the oxidation reaction更多还原