盐酸右哌甲酯合成工艺的研究

发布时间：2018-06-17 00:53

本文选题：盐酸右哌甲酯 + 原研路线　；参考：《吉林大学》2013年硕士论文

【摘要】：哌甲酯是一种人工合成药,其化学结构与交感胺类药物苯丙胺相似,具有兴奋精神、减轻疲乏、活跃情绪、消除困意及缓解抑郁症状的作用,在临床实践中主要被用于治疗儿童注意力缺乏或者多动综合征及其他注意力障碍疾病。哌甲酯化合物分子内含有2个手性中心,因此存在着4种异构体。哌甲酯异构体混合物于1955年被批准上市,商品名为Ritalin;而其D-threo单体药物(药效最好的异构体)于2002年获准进入市场,商品名Focalin。长期以来,哌甲酯类药物一直是应用最广泛的面向儿童的治疗精神异常的药物。数据显示,在2011年全美药物销售排行中,Ritalin排名第20,Focalin排名85。美国诺华公司长期垄断着哌甲酯药物的生产工艺和销售渠道,使国内制药公司无法涉足。然而,诺华公司对于单体药物盐酸右哌甲酯的专利保护将在2-3年内失效的事实,以及国内制药公司越来越多投入于研发的大背景,为我们研发自主的盐酸右哌甲酯合成工艺提供了强劲的动力。本篇论文的工作以吉林大学组化中心-上海药物基团中央研究院的合作为基础,目的是最终形成拥有自主知识产权的盐酸右哌甲酯生产工艺。本篇论文的主要工作内容分为两个部分,第一部分是盐酸右哌甲酯原研路线部分。在这一部分中,通过文献总结我们首先确定了盐酸右哌甲酯的原研路线,继而对原研路线的每一步反应进行了细致地重复,优化了原专利中不合理部分,制定了符合自身实验条件的工艺流程和操作规范,得到了物质纯度和手性纯度均达标的终产品,总产率与原研路线近似。与此同时,通过制备目标产物的其他三个异构体,为质量标准的建立做了充分的准备。在成功重复和优化原研路线并详细分析其缺陷的基础上,我们开展了论文的第二部分工作：盐酸右哌甲酯新工艺路线的开发。在新颖性和可行性的前提下,我们设计并打通了以工业原料3,4-二氢-2H-吡喃为起始原料,以N,O-缩醛开环加成反应为核心的,经历加成开环、取代关环、脱保护基、差向异构和手性拆分的新工艺路线。在打通实验路线之后,我们又从成本控制、重金属残留控制、原料循环使用以及绿色化学等角度对工艺路线的一些细节问题进行了进一步的优化,力图使之成为一条更合理的、更实用的成熟工艺。优化后的新工艺路线成本相比原研路线降低了60%,而且具有条件温和、操作简便、安全环保、试剂溶剂可循环使用等诸多优势。新路线的成功开发为日后建立拥有自主知识产权的盐酸右哌甲酯生产专利提供了保障。
[Abstract]:Methylphenidate is an artificial synthetic drug. Its chemical structure is similar to that of amphetamine, a sympathetic amine drug. It has the effect of stimulating spirit, reducing fatigue, active mood, eliminating sleepiness and relieving depression symptoms. In clinical practice, it is mainly used to treat children with attention deficit or hyperactivity syndrome and other attention disorder. There are two chiral centers in the molecules of methylphenidate compounds, so there are four isomers. The mixture of methylphenidate isomers was approved for sale in 1955 under the trade name of Ritalin.The D-threo monomers (the most effective isomers) were approved to enter the market in 2002 under the trade name of Focalin. For a long time, methylphenidate has been the most widely used drugs for the treatment of mental disorders in children. In 2011, Ritalin ranked 20th and Focalin 85th in the U. S. drug sales rankings, according to data. Novartis has long monopolized the production process and marketing channels of methylphenidate drugs, which makes domestic pharmaceutical companies unable to get involved. However, the fact that Novartis's patent protection for the monomer drug dexphenidate hydrochloride will expire within 2-3 years, and the background in which domestic pharmaceutical companies are increasingly investing in research and development, It provides a strong impetus for us to develop our own synthesis process of dexphenidate hydrochloride. The work of this paper is based on the cooperation of the Center of Chemistry of Jilin University-Shanghai Institute of Pharmaceutical Group. The aim of this paper is to form a production process of dexdromethyl hydrochloride with independent intellectual property rights. The main work of this thesis is divided into two parts. The first part is the original route of dexamphenidate hydrochloride. In this part, by summarizing the literature, we first determine the original research route of dexphenidate hydrochloride, then repeat each step of the original research route in detail, and optimize the unreasonable part of the original patent. The process flow and operation standard according to the experimental conditions were established, and the final product with both purity and chiral purity was obtained, and the total yield was similar to that of the original research route. At the same time, the other three isomers of the target product were prepared for the establishment of quality standard. Based on the successful repetition and optimization of the original research route and the detailed analysis of its defects, we developed the second part of the thesis: the development of a new process route for dexdromethylphenidate hydrochloride. On the premise of novelty and feasibility, we have designed and opened the starting material of industrial raw material 3O- 4- dihydro-2H-pyran, and the core of the ring-opening addition reaction of NNO-acetal, which has gone through addition opening, replacing closed ring, deprotecting group. A new process of differential isomerization and chiral separation. After opening the experimental route, we have further optimized some details of the process from the aspects of cost control, heavy metal residue control, recycling of raw materials, and green chemistry, in an effort to make it a more reasonable one. More practical mature process. Compared with the original route, the cost of the optimized new process is reduced by 60%, and has many advantages, such as mild conditions, simple operation, safety and environmental protection, reagents, solvent recycling and so on. The successful development of the new route provides a guarantee for the establishment of the patent for the production of dexamphenidate hydrochloride with independent intellectual property rights.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：TQ463

【参考文献】