Diphenhydramine Hydrochloride Synthesis And Process Optimization

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 caralso 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 cf 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%.