本文選題：鹽酸右哌甲酯 + 原研路線��； 參考：《吉林大學(xué)》2013年碩士論文

【摘要】：哌甲酯是一種人工合成藥,其化學(xué)結(jié)構(gòu)與交感胺類藥物苯丙胺相似,具有興奮精神、減輕疲乏、活躍情緒、消除困意及緩解抑郁癥狀的作用,在臨床實踐中主要被用于治療兒童注意力缺乏或者多動綜合征及其他注意力障礙疾病。哌甲酯化合物分子內(nèi)含有2個手性中心,因此存在著4種異構(gòu)體。哌甲酯異構(gòu)體混合物于1955年被批準(zhǔn)上市,商品名為Ritalin;而其D-threo單體藥物(藥效最好的異構(gòu)體)于2002年獲準(zhǔn)進(jìn)入市場,商品名Focalin。長期以來,哌甲酯類藥物一直是應(yīng)用最廣泛的面向兒童的治療精神異常的藥物。數(shù)據(jù)顯示,在2011年全美藥物銷售排行中,Ritalin排名第20,Focalin排名85。美國諾華公司長期壟斷著哌甲酯藥物的生產(chǎn)工藝和銷售渠道,使國內(nèi)制藥公司無法涉足。然而,諾華公司對于單體藥物鹽酸右哌甲酯的專利保護(hù)將在2-3年內(nèi)失效的事實,以及國內(nèi)制藥公司越來越多投入于研發(fā)的大背景,為我們研發(fā)自主的鹽酸右哌甲酯合成工藝提供了強(qiáng)勁的動力。本篇論文的工作以吉林大學(xué)組化中心-上海藥物基團(tuán)中央研究院的合作為基礎(chǔ),目的是最終形成擁有自主知識產(chǎn)權(quán)的鹽酸右哌甲酯生產(chǎn)工藝。本篇論文的主要工作內(nèi)容分為兩個部分,第一部分是鹽酸右哌甲酯原研路線部分。在這一部分中,通過文獻(xiàn)總結(jié)我們首先確定了鹽酸右哌甲酯的原研路線,繼而對原研路線的每一步反應(yīng)進(jìn)行了細(xì)致地重復(fù),優(yōu)化了原專利中不合理部分,制定了符合自身實驗條件的工藝流程和操作規(guī)范,得到了物質(zhì)純度和手性純度均達(dá)標(biāo)的終產(chǎn)品,總產(chǎn)率與原研路線近似。與此同時,通過制備目標(biāo)產(chǎn)物的其他三個異構(gòu)體,為質(zhì)量標(biāo)準(zhǔn)的建立做了充分的準(zhǔn)備。在成功重復(fù)和優(yōu)化原研路線并詳細(xì)分析其缺陷的基礎(chǔ)上,我們開展了論文的第二部分工作：鹽酸右哌甲酯新工藝路線的開發(fā)。在新穎性和可行性的前提下,我們設(shè)計并打通了以工業(yè)原料3,4-二氫-2H-吡喃為起始原料,以N,O-縮醛開環(huán)加成反應(yīng)為核心的,經(jīng)歷加成開環(huán)、取代關(guān)環(huán)、脫保護(hù)基、差向異構(gòu)和手性拆分的新工藝路線。在打通實驗路線之后,我們又從成本控制、重金屬殘留控制、原料循環(huán)使用以及綠色化學(xué)等角度對工藝路線的一些細(xì)節(jié)問題進(jìn)行了進(jìn)一步的優(yōu)化,力圖使之成為一條更合理的、更實用的成熟工藝。優(yōu)化后的新工藝路線成本相比原研路線降低了60%,而且具有條件溫和、操作簡便、安全環(huán)保、試劑溶劑可循環(huán)使用等諸多優(yōu)勢。新路線的成功開發(fā)為日后建立擁有自主知識產(chǎn)權(quán)的鹽酸右哌甲酯生產(chǎn)專利提供了保障。
[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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：TQ463

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相關(guān)期刊論文 前2條

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本文編號：2028838