本文關(guān)鍵詞： 鵝去氧膽酸 奧貝膽酸 肝病 新型藥物　出處：《南京理工大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目前,肝病已經(jīng)成為威脅人類生存和社會(huì)發(fā)展的一種重大疾病,肝炎、脂肪肝等等肝類疾病依然無(wú)法得到有效治療。因此,尋找一種更好的治療肝病的藥物迫在眉睫。奧貝膽酸(6-乙基鵝去氧膽酸)屬法尼醇X受體激動(dòng)劑,通過(guò)活化法尼醇X受體,間接抑制細(xì)胞色素7A1(CYP7A1)的基因表達(dá)。由于CYP7A1是膽酸生物合成的限速酶,因此奧貝膽酸可以促進(jìn)膽酸合成,用于治療原發(fā)性膽汁性肝硬化和非酒精性脂肪性肝病。本文以鵝去氧膽酸為原料合成奧貝膽酸,打通了經(jīng)氧化、酯化、親電加成、催化加氫、水解還原共5步反應(yīng)得到奧貝膽酸(6-乙基鵝去氧膽酸)的新工藝,總收率達(dá)35%。其結(jié)構(gòu)經(jīng)1H-NMR、MS、IR等分析測(cè)試技術(shù)確認(rèn)。通過(guò)考察各步反應(yīng)條件,得出最佳工藝條件為:氧化反應(yīng)中,使用N-溴代琥珀酰亞胺氧化鵝去氧膽酸,n(鵝去氧膽酸):n(N-溴代琥珀酰亞胺)=1:1.5;親電加成中,先用叔丁基二甲基氯硅烷進(jìn)行基團(tuán)保護(hù),再用乙醛進(jìn)行加成,n(3α-羥基-7-酮-5β-膽烷酸-24-甲酯):n(三乙胺):n(叔丁基二甲基氯硅烷)=1:2:2.2;還原反應(yīng)中,先進(jìn)行加氫,后用硼氫化鈉還原羰基,最后用氫氧化鈉水解,n(3α-羥基-6-亞乙基-7-酮-5β-膽烷酸-24-甲酯):n(硼氫化鈉)=1:6。該產(chǎn)物是用于治療原發(fā)性膽汁性肝硬化和非酒精性脂肪性肝病的新型藥物。本文研究的這種奧貝膽酸的新型合成工藝具有以下優(yōu)點(diǎn):(1)優(yōu)化工藝路線,不使用LDA等危險(xiǎn)物質(zhì),反應(yīng)條件溫和,改良了文獻(xiàn)中的低溫操作環(huán)境,且除催化加氫外都可在常壓下進(jìn)行,操作簡(jiǎn)便,設(shè)備要求低,適合實(shí)驗(yàn)室制備和工業(yè)化生產(chǎn)。(2)用三聚乙醛替換乙醛,作為乙醛前體,解決了乙醛純度不高,不易保存的問(wèn)題。(3)每一步反應(yīng)產(chǎn)物的分離純化操作較簡(jiǎn)便,單步產(chǎn)率與總產(chǎn)率均較高。(4)反應(yīng)所需原料都可由工業(yè)化生產(chǎn)得到,價(jià)格低廉易獲得。
[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 偽 -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 偽 -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.
【學(xué)位授予單位】：南京理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：TQ460.6

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