过敏性疾病是非常常见的多发性疾病，而且在过去几十年里过敏性疾病发病率显著上升，早已成为举世瞩目的公众卫生问题，世界变态反应组织调查了大约30个国家一共12亿人，结果显示大约有22%（2.6亿人）患有过敏性疾病，如哮喘、食物过敏、过敏性鼻炎、结膜炎、湿疹、药物过敏和严重过敏反应等。

盐酸苯海拉明是一种非常有效的抗过敏类药物，1943年辛辛那提大学的教授Dr. George Rieveschl在研究合成东莨菪碱时发现的盐酸苯海拉明。在1946年，它是由McNeil-PPC药业（后成为强生药业的一员）最先上市。它是美国第一个被批准的抗组胺药。现在盐酸苯海拉明已经可以制作为各种剂形，用来方便临床使用，充分发挥药物的治疗作用，降低或避免不良反应。盐酸苯海拉明适用皮肤粘膜的过敏性疾病，如枯草热、荨麻疹、过敏性鼻炎等。还可用于预防晕船、晕飞机、晕车等晕动病。

吉林博大伟业制药因为其他公司的委托，展开了盐酸苯海拉明制药的研发生产工作，本文着重介绍了盐酸苯海拉明原料药的合成和工艺优化。

纵观国内外文献报道的多种盐酸苯海拉明合成路线，都存在一些缺点，我们根据现有文献方法，结合自身实验及生产条件，并规避了某些专利限制，设计出了一条合理的工艺合成路线研究方案。

本研究方案分为两个部分。一是通过文献调研设计盐酸苯海拉明的合成路线，纯化原材料，并对原材料进行质量监控，开展相应的合成工作，得到各个中间体化合物并进行结构表征，打通该路线得到目的产物进行结构表征；二是对反应中收率和纯度较低的反应进行工艺优化，优化效果不好的尝试其他的合成路线或在现有的基础上设计新的合成路线，力求得到低成本、绿色环保、操作简单、后处理方便、适于工业化生产的工艺路线。

在查阅大量文献的基础上，对盐酸苯海拉明合成路线进行了优化及改进：由二苯基溴甲烷和二甲基乙醇胺经过高温反应得到生成醚，在用强碱中和氢溴酸，得到苯海拉明游离碱，游离碱在盐酸的作用下得到目的产物盐酸苯海拉明。

因为二苯基溴甲烷为工业级，纯度过低，本论文通过摸索条件对其进行纯化，并制定了纯化后二苯基溴甲烷的检验标准和原材料二甲基乙醇胺的检验标准。本论文通过大量实验进行了优化，使反应条件温和，操作简便，适用于工业大生产。并且通过进行中试实验验证了本实验路线的稳定性和可重复性。

所得的中间体及目的产物均通过HPLC、¹H-NMR、¹³C-NMR等的结构确证。而且经过工艺优化，本实验的每步反应收率均有所提高。目标产物盐酸苯海拉明的纯度为99.6%以上，已达到原材料标准，总杂小于0.5%，单杂小于0.1%。

Allergic diseases are very common multiple diseases, and the incidence of allergic diseases has risen significantly in the past few decades and has long been a public health issue of worldwide concern.The World Allergy Organization surveyed a total of 1.2 billion people in approximately 30 countries and found that approximately 22% (260 million people) had allergic diseases such as asthma, food allergies, allergic rhinitis, conjunctivitis, eczema, drug allergies, and serious allergic reactions.

Diphenhydramine hydrochloride is a very effective anti-allergic drug.In 1943, Dr. George Rieveschl, a professor at the University of Cincinnati, studied diphenhydramine hydrochloride in the synthesis of scopolamine.In 1946， it was first listed by McNeil-PPC Pharmaceuticals (later became a member of Johnson & Johnson Pharmaceuticals).It is the first approved antihistamine in the United States.Now diphenhydramine hydrochloride can be made into various dosage forms to facilitate clinical use, give full play to the therapeutic effect of drugs, and reduce or avoid adverse reactions.Diphenhydramine hydrochloride is suitable for allergic diseases of the skin and mucous membranes, such as hay fever, urticaria, and allergic rhinitis. It can also be used to prevent motion sickness such as seasickness, motion sickness.

Jilin Broadwell Pharmaceutical Co., Ltd. initiated the research, development and production of diphenhydramine hydrochloride as commissioned by other companies. This article focuses on the synthesis and process optimization of diphenhydramine hydrochloride raw materials.

Looking at various synthetic routes of diphenhydramine hydrochloride reported in domestic and foreign literature, there are some shortcomings. According to the existing literature methods, we have combined our own experiments and production conditions and circumvented certain patent restrictions to design a reasonable  research scheme of process synthesis route.

This research plan is divided into two parts.The first is to design a synthetic route for diphenhydramine hydrochloride through literature research, purify raw materials, monitor the quality of raw materials, carry out corresponding synthesis work, obtain each intermediate compound and perform structural characterization, and open the route to obtain the target product for structural characterization.The second is to optimize the process of the reaction with low yield and purity, try other synthesis routes with poor optimization results or design new synthetic route on the basis of the existing, and strive to obtain low cost, environmental protection, and simple operation. Convenient post-processing, suitable for industrial production process route.

On the basis of reviewing a large amount of literature, the synthetic route of diphenhydramine hydrochloride was optimized and improved: the ether was generated from the reaction of diphenyl methyl bromide and dimethyl ethanolamine at high temperature, and the hydrobromic acid was neutralized with a strong base. Diphenhydramine free base, free base in the role of hydrochloric acid to obtain the target product diphenhydramine hydrochloride.Because the diphenyl methyl bromide is industrial grade and its purity is too low, this paper purifies it by exploring the conditions, and has established the test standard of purified diphenyl methyl bromide and the inspection standard of raw material dimethyl ethanol amine.This paper has been optimized through a large number of experiments to make the reaction conditions mild, easy to operate, and suitable for industrial production.And through the pilot test to verify the stability and repeatability of the experimental route.

The obtained intermediate and the desired product were confirmed by HPLC, 1H-NMR and 13C-NMR.And after process optimization, the yield of each step of the experiment has been improved. The target product, diphenhydramine hydrochloride, has a purity of 99.6% or more, has reached the standard for raw materials, total impurities less than 0.5%, and single impurities less than 0.1%.

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