奥贝胆酸合成工艺的研究

发布时间：2018-02-25 17:50

本文关键词： 鹅去氧胆酸奥贝胆酸肝病新型药物　出处：《南京理工大学》2017年硕士论文　论文类型：学位论文

【摘要】：目前,肝病已经成为威胁人类生存和社会发展的一种重大疾病,肝炎、脂肪肝等等肝类疾病依然无法得到有效治疗。因此,寻找一种更好的治疗肝病的药物迫在眉睫。奥贝胆酸(6-乙基鹅去氧胆酸)属法尼醇X受体激动剂,通过活化法尼醇X受体,间接抑制细胞色素7A1(CYP7A1)的基因表达。由于CYP7A1是胆酸生物合成的限速酶,因此奥贝胆酸可以促进胆酸合成,用于治疗原发性胆汁性肝硬化和非酒精性脂肪性肝病。本文以鹅去氧胆酸为原料合成奥贝胆酸,打通了经氧化、酯化、亲电加成、催化加氢、水解还原共5步反应得到奥贝胆酸(6-乙基鹅去氧胆酸)的新工艺,总收率达35%。其结构经1H-NMR、MS、IR等分析测试技术确认。通过考察各步反应条件,得出最佳工艺条件为:氧化反应中,使用N-溴代琥珀酰亚胺氧化鹅去氧胆酸,n(鹅去氧胆酸):n(N-溴代琥珀酰亚胺)=1:1.5;亲电加成中,先用叔丁基二甲基氯硅烷进行基团保护,再用乙醛进行加成,n(3α-羟基-7-酮-5β-胆烷酸-24-甲酯):n(三乙胺):n(叔丁基二甲基氯硅烷)=1:2:2.2;还原反应中,先进行加氢,后用硼氢化钠还原羰基,最后用氢氧化钠水解,n(3α-羟基-6-亚乙基-7-酮-5β-胆烷酸-24-甲酯):n(硼氢化钠)=1:6。该产物是用于治疗原发性胆汁性肝硬化和非酒精性脂肪性肝病的新型药物。本文研究的这种奥贝胆酸的新型合成工艺具有以下优点:(1)优化工艺路线,不使用LDA等危险物质,反应条件温和,改良了文献中的低温操作环境,且除催化加氢外都可在常压下进行,操作简便,设备要求低,适合实验室制备和工业化生产。(2)用三聚乙醛替换乙醛,作为乙醛前体,解决了乙醛纯度不高,不易保存的问题。(3)每一步反应产物的分离纯化操作较简便,单步产率与总产率均较高。(4)反应所需原料都可由工业化生产得到,价格低廉易获得。
[Abstract]:At present, liver disease has become a major disease threatening human survival and social development, hepatitis, fatty liver and other liver diseases are still unable to get effective treatment. It is urgent to find a better drug for the treatment of liver disease. Obercholic acid 6-ethyl chenodeoxycholic acid is a farnesol X receptor agonist, which activates the farnesol X receptor. Because CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, Obercholic acid can promote the synthesis of cholic acid. In this paper, Obercholic acid was synthesized from chenodeoxycholic acid, which was prepared by oxidation, esterification, electrophilic addition, and catalytic hydrogenation, and was used for the treatment of primary biliary cirrhosis and non-alcoholic fatty liver disease. The total yield was 35%. Its structure was confirmed by 1H-NMR-MSIR and other analytical techniques. The optimum reaction conditions were as follows: in the oxidation reaction, the optimum reaction conditions were as follows: 1 H-NMR-MSIR. N- bromosuccinimide was used to oxidize chenodeoxycholic acid (chenodeoxycholic acid) 1: 1.5; in electrophilic addition, the group was protected by tert-#china_person0# dimethyl chlorosilane, Then acetaldehyde was used to add 3 伪 -hydroxy-7-keto-5 尾 -cholanic acid--24 methyl ester (triethylamine: n (tert-#china_person0# dimethyl chlorosilane) 1: 2: 2.2). In the reduction reaction, the carbonyl group was first hydrogenated and then reduced by sodium borohydride. Finally, sodium hydroxide was used to hydrolyze nunz3 伪 -hydroxy-6-ethyl-7-keto-5 尾 -cholanic acid-methyl ester 1: 6. The product is a new drug used in the treatment of primary biliary cirrhosis and non-alcoholic fatty liver disease. The new synthetic process of Obercholic acid has the following advantages: 1. LDA and other dangerous substances are not used, the reaction conditions are mild, the low temperature operating environment in the literature is improved, and all but catalytic hydrogenation can be carried out under normal pressure. The operation is simple and the equipment requirement is low. Suitable for laboratory preparation and industrial production. Acetaldehyde is replaced by tripolyacetaldehyde as a precursor of acetaldehyde, which solves the problem of low purity of acetaldehyde, which is not easy to preserve. 3) the separation and purification of each reaction product is simple and convenient. Both single step yield and total yield are higher. 4) the raw materials needed for the reaction can be obtained from industrial production, and the price is low and easy to obtain.
【学位授予单位】：南京理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.6

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