克利贝特相转移催化法合成研究

发布时间：2018-02-25 22:29

本文关键词： 克利贝特降血脂药物相转移催化合成研究　出处：《山东大学》2015年硕士论文　论文类型：学位论文

【摘要】：克利贝特(clinofibrate),化学名：2,2'-(4,4'-亚环己基二苯氧基)-2,2’-二甲基二丁酸,是一种治疗高血脂症的苯氧芳酸衍生物降血脂药物,能够有效地降低极低密度脂蛋白和甘油三酯,同时在升高高密度脂蛋白方面有着显著的作用。克利贝特1981年由日本住友公司(Sumitomo Pharmaceutical Co.Ltd)研制开发并在日本上市,已在日本药典16版收录。甘油三酯较高是我国高血脂患者的主要病症,克利贝特能够显著地降低极低密度脂蛋白和甘油三酯,是我国高血脂患者比较理想的治疗药物。本论文参考文献资料对克利贝特合成反应步数较少的合成路线进行工艺改进,利用相转移催化法对关键的缩合反应进行研究。本论文的合成过程有二步：(1)苯酚和环己酮在酸性溶剂条件下通过亲电反应生成中间体1,1-二-(4-羟基苯基)环己酮；(2)三氯甲烷在相转移催化条件下与浓NaOH溶液发生反应生成二氯卡宾,二氯卡宾与丁酮发生加成反应生2-氯-2-甲基丁酸,2-氯-2-甲基丁酸与1,1-二-(4-羟基苯基)环己烷发生缩合反应生成克利贝特。克利贝特的相转移催化法合成反应路线简短、操作简易、经济成本、安全环保,此种相转移催化法合成的产品质量优异,产品收率较常规的溴代物缩合法提高近10%(以环己酮计)。产品经过紫外、红外、氢谱、碳谱和质谱检测,结构确证与文献报道一致,产品主要质量指标符合日本药局方质量要求。试验研究重点明确了克利贝特相转移催化法的合成工艺参数,为大生产化相转移催化法的应用提供参考,也将促进克利贝特的临床应用。
[Abstract]:Klebeter is a hyperlipidemic derivative of phenoxyaromatic acid, which can effectively reduce very low density lipoprotein and triglyceride. Krebert was developed in 1981 by Sumitomo Pharmaceutical Co. Ltd, a Japanese Sumitomo Pharmaceutical Co., and went on sale in Japan. It has been recorded in Japanese Pharmacopoeia 16 edition. High triglyceride is the main disease in hyperlipidemia patients in China. Klebete can significantly reduce very low density lipoprotein and triglyceride. It is an ideal therapeutic drug for hyperlipidemia patients in China. The key condensation reaction was studied by phase transfer catalysis. In this thesis, the synthesis process of phenol and cyclohexanone was two-step: 1: 1) in acidic solvent, the intermediate 1 ~ (1) -di-di-4-hydroxyphenyl) cyclohexanone was synthesized by electrophilic reaction in acidic solvent. Under the condition of phase transfer catalysis, dichlorocarbene was formed by the reaction of trichloromethane with concentrated NaOH solution. The addition reaction of dichlorocarbene and butanone resulted in the condensation of 2-chloro-2-methylbutyric acid with 1-di-4-hydroxyphenyl) cyclohexane. The phase transfer catalysis method for the synthesis of Krebette was brief. Simple operation, economic cost, safety and environmental protection. The product quality of this phase transfer catalytic method is excellent. The yield of the product is nearly 10% higher than that of the conventional bromine condensation method (measured by cyclohexanone). The main quality indexes of the products are in line with the quality requirements of the Japanese Drug Bureau. The key points of the study are the synthesis process parameters of Krebeit phase transfer catalysis method, and the results show that the main quality indexes of the products are consistent with those reported in the literature. It provides reference for the application of phase transfer catalysis in mass production, and will also promote the clinical application of Krebert.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R914

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