Studies On The Synthetic Method Of Alverine Citrate

Alverine Citrate is a synthetic derivative of the poppy base,is a highly selective calcium channel regulator developed by Norgine UK.Alverine citrate has been used in clinic for more than 20 years.It acts directly on the human smooth muscle.It can also be selectively applied to the smooth muscle of the gastrointestinal tract 、the uterus and genitourinary organs.It has the antispasmodic effect.It is used to treat irritable bowel syndrome,intestinal cramps,abdominal pain,which caused by diverticular disease,biliary spasm,and spasmodic pain caused by urinary calculi or infection.Since it’s listing,its market share has been increasing year by year,and it is one of the most widely used antispasmodic drugs in clinical application.However,there are several problems in the synthesis of alverine citrate in the current research: 1.The reaction conditions are harsh,not suitable for large-scale factory production;2.Low yield;3.Special reaction devices are needed;4.Solvents are poisonous,corrosive or controlled reagents;5.Some key starting materials that are not high-purity industrial products and requires special production.In view of the above many deficiencies,this study is based on a large number of previous studies.The synthesis process of alverine citrate was also studied systematically.A new synthetic route of alverine citrate was developed.To some extent,this research has laid a foundation for the synthesis of raw materials for alverine and its capsules.This article reviews the development history,clinical application,action mechanism and main synthesis methods of alverine citrate.The synthesis technology of alverine citrate is described in detail.The main parameters of the synthetic process were systematically investigated and optimized.Finally,the following best synthetic route is determined:1.Hydrochloride is used as the raw material.N-butanol is the solvent.In the presence of anhydrous potassium carbonate,the reaction with chloro-phenylpropane,we can get intermediate 1.Intermediate 1 is purified by reduced pressure distillation.The purity of the intermediate 1 is more than 99.5%,and the yield of pure product is more than 75%.2.Intermediate 1 as raw material.N-butanol is the solvent.With the effect of anhydrous potassium carbonate and six hydrated sodium iodide,the reaction with chloro-phenylpropane is "one pot".We get the intermediate 2.Intermediate 2 is purified by decompression distillation,and the purity of intermediate 2 is more than 99.8%,and the yield of pure intermediate 2 is more than 78%.3.Through the reaction of intermediate 2 and citric acid in ethanol solution,we can obtain alverine citrate.Its purity is more than 99% by HPLC.The yield is over 95%.The total yield of the synthetic process can reach up to 50%(in ethylamine hydrochloride).This synthetic route has high yield,good purity,simple and mild reaction conditions,easy to operate,friendly environment and suitable for industrial production.