4乙酰氧基氮杂环丁酮的合成工艺分析.docx

优秀毕业论文 精品参考文献资料 摘 要 随着抗生素的大量使用，细菌耐药日趋严重，而碳青霉烯类抗生素作为一组新 型的β-内酰胺类广谱抗生素，对绝大多数的β-内酰胺酶耐受，对各种细菌感染疗效 优异，毒副反应少，使其在临床治疗严重感染中具有难以替代的作用，成为开发抗 感染药物的研究热点。本课题是关于碳青霉烯类抗生素培南类原料药中间体4-乙酰氧 基氮杂环丁酮（4-AA）的合成工艺研究。 本课题在印度Arch酶法工艺和日本高砂不对称合成工艺的研究成果基础之上， 以苯甲酰胺为起始原料经羟甲基化得到N-羟甲基苯甲酰胺，与乙酰乙酸甲酯缩合， 经酶促还原、脱保护、甲酯保护，酒石酸成盐纯化后，叔丁基二甲基氯硅烷保护羟 基，然后用格式试剂闭环、过氧乙酸氧化得到4-AA。工艺总收率达18%以上，产品 纯度大于98.2%，含量高于96.7%。 本课题将酶还原工艺用于4-AA手性中间体的合成研究中，为后续4-AA的合成工 艺研究提供了基础数据和新的研究方向。本课题还针对于文献步骤合成工艺进行部 分改进，减少了三乙胺调pH步骤，并且降低了过氧化反应中过氧乙酸浓度等，为4-AA 的工业化生产提供了数据依据，并在一定程度上降低了工业化生产中存在的危险。 关键词 4-乙酰氧基氮杂环丁酮；合成工艺；苯甲酰胺；酶还原；手性中间体 II II Abstract With the extensive use of antibiotics, bacterial resistance increases seriously. Carbapenems, as a group of new broad-spectrum β-lactam antibiotics, have an irreplaceable role in the clinical research because of its resistance for the vast majority of the β-lactamase, and the excellent efficacy for the treatment of a variety of bacterialinfections along with fewer side effects. So Carbapenems become a research hotspot in the development of anti-infective drugs. This topic is about the synthetic process of the4 - acetoxy azetidinone (4-AA), which is a drug Intermediates of imipenem API belonging to the carbapenem antibiotic. The subject is carried out basing on the process of enzymatic reduction from India Arch and asymmetric synthesis from Japan Takasago. The benzamide as starting material is transformed into N-hydroxymethyl benzamide by hydroxymethyl reaction. And then 4-AA is synthesized by condensation reaction with methyl acetoacetate, enzymatic reduction, deprotection, ester protection, purification with tartrate salt, protection reaction of hydroxy with t-butyl dimethyl chlorosilane, closed loop with a Grignard reagent and oxidation of peracetic acid .The overall yield of processes in above is more than 18%, and the purity of product is greater than 98.2%, the content of 4-AA is higher than 96.7%. The enzymatic reduction is applied in the synthesis of 4-AA as chiral intermediates in the subject. It p