本文關(guān)鍵詞： 克利貝特 降血脂藥物 相轉(zhuǎn)移催化 合成研究　出處：《山東大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

【摘要】：克利貝特(clinofibrate),化學(xué)名：2,2'-(4,4'-亞環(huán)己基二苯氧基)-2,2’-二甲基二丁酸,是一種治療高血脂癥的苯氧芳酸衍生物降血脂藥物,能夠有效地降低極低密度脂蛋白和甘油三酯,同時在升高高密度脂蛋白方面有著顯著的作用。克利貝特1981年由日本住友公司(Sumitomo Pharmaceutical Co.Ltd)研制開發(fā)并在日本上市,已在日本藥典16版收錄。甘油三酯較高是我國高血脂患者的主要病癥,克利貝特能夠顯著地降低極低密度脂蛋白和甘油三酯,是我國高血脂患者比較理想的治療藥物。本論文參考文獻(xiàn)資料對克利貝特合成反應(yīng)步數(shù)較少的合成路線進(jìn)行工藝改進(jìn),利用相轉(zhuǎn)移催化法對關(guān)鍵的縮合反應(yīng)進(jìn)行研究。本論文的合成過程有二步：(1)苯酚和環(huán)己酮在酸性溶劑條件下通過親電反應(yīng)生成中間體1,1-二-(4-羥基苯基)環(huán)己酮；(2)三氯甲烷在相轉(zhuǎn)移催化條件下與濃NaOH溶液發(fā)生反應(yīng)生成二氯卡賓,二氯卡賓與丁酮發(fā)生加成反應(yīng)生2-氯-2-甲基丁酸,2-氯-2-甲基丁酸與1,1-二-(4-羥基苯基)環(huán)己烷發(fā)生縮合反應(yīng)生成克利貝特。克利貝特的相轉(zhuǎn)移催化法合成反應(yīng)路線簡短、操作簡易、經(jīng)濟(jì)成本、安全環(huán)保,此種相轉(zhuǎn)移催化法合成的產(chǎn)品質(zhì)量優(yōu)異,產(chǎn)品收率較常規(guī)的溴代物縮合法提高近10%(以環(huán)己酮計)。產(chǎn)品經(jīng)過紫外、紅外、氫譜、碳譜和質(zhì)譜檢測,結(jié)構(gòu)確證與文獻(xiàn)報道一致,產(chǎn)品主要質(zhì)量指標(biāo)符合日本藥局方質(zhì)量要求。試驗(yàn)研究重點(diǎn)明確了克利貝特相轉(zhuǎn)移催化法的合成工藝參數(shù),為大生產(chǎn)化相轉(zhuǎn)移催化法的應(yīng)用提供參考,也將促進(jìn)克利貝特的臨床應(yīng)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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R914

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本文編號：1535427