恩替卡韦的合成及其质量评价

发布时间：2019-05-18 07:28

【摘要】：恩替卡韦是由美国布迈-百施贵宝(Bristol-Myers Squibb)公司在20世纪90年代研制开发的一种2’-戊环脱氧鸟嘌呤核苷类似物,其最初目的是用来治疗单纯疱疹病毒感染的,后来发现其有很强的抗HBV能力而毒性相对很低,因此作为治疗慢性乙型肝炎药物上市。本文研究的目的是在现有恩替卡韦合成方法的基础上进行改进,研究合成工艺,寻求新的适合于工业化生产合成条件,获得低成本高稳定性的恩替卡韦原料,为下一步恩替卡韦制剂的研究创造有利条件,生产出更廉价有效的治疗慢性乙型肝炎的药物造福广大患者。首先,综述了现有恩替卡韦的合成途径,在现有文献报道基础上以工业化生产为目的,选用简单易得的工业化生产对环境友好对人体低毒的产品作为起始原料,开发条件温和易于工业化生产合成路线,以α-哌烯、硼烷二甲基硫醚络合物和环戊二烯钠等为起始原料,经缩合反应得(1S-反式)-2-[(对甲基苯甲氧基)甲基]-3-环戊烯-1-醇,(1S-反式)-2-[(对甲基苯甲氧基)甲基]-3,5-环戊二烯-1-醇在乙酰丙酮氧钒和叔丁基过氧化氢作用下环氧化得到(1S-反式)-2-[(对甲基苯甲氧基)甲基]-氧杂双环[3.1.0]-环戊烷-1-醇。对甲基苄基保护羟基后与6-苄氧基鸟嘌呤偶合,再经过氧化、亚甲基化、脱保护基等反应得到恩替卡韦。对获得产品进行了元素分析、紫外光谱、红外光谱、核磁共振谱、质谱、差热分析和热重分析以确证其分子结构为恩替卡韦。其次,参考百世施贵宝恩替卡韦进口注册标准(JX20050113)和中国药典的要求,建立本品的质量标准。采用HPLC保留时间和红外吸收光谱法鉴别样品；测定了样品的性状、比旋度、水分；结合生产工艺用气相色谱法测定了残留溶剂；用高效液相色谱法测定了样品含量,并对可能存在的有关物质进行了检查。最后,根据《新药(化学药品)理化、质量标准研究的技术要求》和《中国药典二部》附录ⅪⅩ C“药物稳定性试验指导原则一制剂稳定性试验”的要求,进行本品光照、高温、高湿影响因素试验和长期加速稳定性试验,结果表明本品和原研恩替卡韦具有基本相同的稳定性。
[Abstract]:Enticavir was developed by Bristol-Myers Squibb in the 1990s. It was originally designed to treat herpes simplex virus (HSV) infection by using enecavir as a nucleosides analogues of 2-pentacyclodeoxyguanine, which was developed in the 1990s by Bumai-Pishibao (Bumai-Pishibao) Company of the United States. The original purpose of Entekawi is to treat herpes simplex virus infection. It was later found that it had strong anti-HBV ability and relatively low toxicity, so it was listed as a drug for the treatment of chronic hepatitis B. The purpose of this paper is to improve the existing Entekawi synthesis methods, to study the synthesis process, to find new synthesis conditions suitable for industrial production, and to obtain low cost and high stability entecavir raw materials. It creates favorable conditions for the next step of the study of entecavir preparation and produces cheaper and more effective drugs for the treatment of chronic hepatitis B. First of all, the existing synthetic ways of entecavir are reviewed. on the basis of the existing literature reports, for the purpose of industrial production, the products which are easy to obtain are environmentally friendly and low toxic to human body are selected as the starting materials. The development conditions are mild and easy to industrial production and synthesis route, with 伪-piperene, borane dimethyl sulfide complex and cyclopentadiene sodium as starting materials. (1s-trans)-2-[(p-methylbenzoxyl) methyl]-3-cyclopentene-1-ol was obtained by condensation reaction. (1S-trans)-2-[(p-methylbenzoxyl) methyl]-3, 5-cyclopentadiene-1-alcohol is cyclooxidized to (1S-trans)-2-[(p-methyl)-2-[(p-methyl)-2-alcohol under the action of vanadium acetylacetone oxide and tert-butylhydrogen peroxide Benzoxyl) methyl]-oxabicyclo [3.1.0]-cyclopentane-1-alcohol. After the hydroxyl group was protected by methyl benzylgroup, it was coupled with 6-benzyloxyguanine, and then reacted with 6-benzyloxyguanine to give entecavir by oxidation, methylene and deprotection. The obtained products were characterized by elemental analysis, ultraviolet spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry, differential thermal analysis and thermogravimetric analysis. Secondly, the quality standard of this product is established by referring to the standard of import registration (JX20050113) and the requirements of Chinese Pharmacopoeia. HPLC retention time and infrared absorption spectroscopy were used to identify the samples, the properties, specific curl and moisture of the samples were determined, and the residual solvents were determined by gas chromatography combined with the production process. The content of the sample was determined by high performance liquid chromatography (HPLC) and the related substances were examined. Finally, according to the Technical requirements of Physicochemical and quality Standard Research of New drugs (Chemicals) and Appendix XIX X C of Chinese Pharmacopoeia, "guiding principles of Drug Stability Test, preparation Stability Test", the light of this product is carried out. The influencing factors test of high temperature and high humidity and the long-term accelerated stability test show that the product has the same stability as the original Entekawi.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R914.5

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