Synthesis Study For Flunarizine Hydrochloride And Propafenone Hydrochloride

Flunarizine hydrochloride is a class of selective calcium antagonists that can slow down calcium overload caused by hypoxia or ischemia in brain tissue,thereby reducing neuronal damage.It has anti-histamine and central nervous system(CNS)inhibition,but is mainly used as an inhibitor of central and peripheral vasoconstriction.Therefore,it has a good effect in the treatment of cerebral vasospasm headache,dizziness and cerebral arteriosclerosis.The product was first synthesized by Janssen in 1970 and,after a series of clinical trials,was launched in many European countries in the early 1980s.Propafenone hydrochloride is an antiarrhythmic drug developed by Helopharm,Germany.It is a sodium channel blocker.It was first marketed in Germany in 1979.It is mainly used for the prevention and treatment of ventricular or supraventricular ectopic beats.Ventricular or supraventricular tachycardia,pre-excitation syndrome,and post-ventricular ventricular fibrillation episodes are also used to treat ischemic and refractory arrhythmias.This thesis mainly studies the synthesis of flunarizine hydrochloride and propafenone hydrochloride.At present,there are many reports on the synthesis of flunarizine hydrochloride,but there are still many problems such as complicated operation,high toxicity of reagents and high cost.In order to solve the above problems and obtain a process more suitable for industrial production,this paper improves on the basis of the existing process:1)In the preparation of the intermediate cinnamylpiperazine,the literature uses toluene as the reaction solvent,and the reaction time is long.The yield is low.After improvement,the use of dichloromethane as a solvent increased the yield by 10.7%and the reaction time by 2 hours.2)In the preparation of flunarizine and its salt formation,the literature uses dichloroethane as solvent and phase transfer catalyst tetrabutylammonium bromide.The operation is complicated,and the solid precipitation amount of the solution is adjusted by salt.less.After an attempt,in the step of preparing flunarizine,acetonitrile is used as a solvent,and the treatment method is simple,and flunarizine is directly precipitated by cooling.The mixed solution of anhydrous ethanol and 18%hydrochloric acid solution is used as a reaction solvent for preparing flunarizine hydrochloride.After the salt is formed,the crude product can be directly obtained by filtration,and the filter cake can be washed with ethyl acetate to obtain flunarizine hydrochloride.More than 99%,the yield is 43.8%.The raw materials of this route are cheap and easy to obtain,the intermediates are easy to prepare,the yield is high,the reagents used are all common reagents,the reaction conditions are mild,and the post-treatment is simple,which lays a foundation for industrial production.There are several synthetic routes for propafenone hydrochloride,but there are problems of cumbersome operation and low yield.There is still a need for optimization,and improvements have been made on the basis of existing processes:in the literature,2’-hydroxyl The-3-phenylpropiophenone is first reacted with sodium methoxide in methanol,and then the methanol is distilled off,and then reacted with epichlorohydrin,the operation is complicated,and the yield is not high.Improved,2’-hydroxy-3-phenylpropiophenone,potassium hydroxide,was reacted in epichlorohydrin.The operation steps are simplified,the yield is increased by 8.2%,the purity is over 99%,and the total yield is 64.0%.This route is easy to operate,low in raw materials,and suitable for industrial production.