Hydrochloride Amphetamine Ketone Synthesis Technology And Process Optimization Study

This paper study on the new technique of two-step synthesis of bupropion hydrochloride .In the first step, the key intermediate ,m-chloro-a-bromopropiophenone, was synthesized from m-chloropropiophenone by use of bromine or cupric bromide as brominating agent.In the second step, m-chloro-a-bromopropiophenone reacted with t-butyl amine at the low temperature in the presence of tetrabutylammonium iodide as catalyst and then acidified by hydrochloride to prepare for bupropion hydrochloride. The optimal process conditions of every reaction were obtained through optimizing test separately,and quantitative and qualitative analyse were carried out on products.When brominating agent was bromine , adding anhydrous aluminium chloride to tetrachloromethane as catalyst and reacting at low temperature would accelerate the velocity of reaction ,and decreased the content of by-product.In comparison with the traditional synthesis,this process could obtain good purity and yield of m-chloro-a-bromopropiophenone at the same time ,however the former could not.m-Chloropropiophenone undergo bromination in high yield and selectivity on refluxing with cupric bromide in ethyl acetate-chloroform. The reaction can carried out calmly, and its by-product, cuprous bromide, can be separated readily by filtration and recovered.The animation of m-chloro-a-bromopropiophenone with t-butyl amine which use tetrabutylammonium iodide as catalyst and acidified by hydrochloride instead of its hydrous solution greatly increased the yield of bupropion hydrochloride.Moreover, recrystaUization is omitted for its high purity,which simplified the operation.The optimum operation conditions of bromination which use bromine as brominating agent were obtained through experiments.When the mole ratio of m-chloropropiophenone to bromine was 1:1, the temperature was 10℃, the amount of catalyst was 1%(mass fraction), and bromine charging-up in Ih, the purity of m-chloro-a-bromopropiophenone was 98.83% and the yield of pure product was 96.1%.Through uniform test and regression analysis,the optimal process conditions of bromination, in which cupric bromide was brominating agent, were obtained asfollows: the mole ratio of m-chloropropiophenone to cupric bromide was 1:1.86, the volume of solvent was 100ml , and the feeding time of m-chloropropiophenone was 1h.In this reaction,the purity of m-chloro-a-bromopropiophenone was over 97% and its yield up to 99.3%(based on the consumption of cupric bromide)or 91.9%(based on the consumption of m-chloropropiophenone).After cany out uniform test design and simplex optimization,the optimum reaction conditions of amination were obtained. When the mole ratio of m-chloro-a-bromopropiophenone to t-butylamine was 1:5, the temperature was 0~5 ℃, the amount of catalyst was 4%, and the reacting time was 24h, the yield of bupropion hydrochloride was up to 94.2%, and its purity was 99.86%.