The Improvement Of The Synthesis Method Of Clobazam And The Synthesis Of The Related Substances

As an antiepileptic drug,Clobazam has a good therapeutic effect on intractable epilepsy and Lennox Gastaut syndrome in children aged?2 years.There is no legal source of active pharmaceutical ingredients in China now.The research and development of domestic Clobazam is listed on the market,which has good social and economic benefits for the whole country.A synthetic route of Clobazam was suitable for industrialization in this paper,it is synthesized from 4-Chloro-2-fluoronitrobenzene by the substitution reaction with aniline,acylation reaction with Ethyl hydrogen malonate,reduction reaction of nitro,cyclization reaction and methyl substitution reaction.The synthesis process of Clobazam was improved and optimized through solvents,reaction time,reaction temperature,the dosage of raw material and catalysts,so that the total yield was up to 48.4%,the purity of intermediates and Clobazam were tested by HPLC,the purity of Clobazam was 99.83%,and the purity of single related substance is less than 0.1%.The chemical structure of Clobazam had been characterized by means of ¹H-NMR,¹³C-NMR and MS.In addition,the sources of four related impurities were analyzed,and the synthesis route was designed by referring to the literature and their structural characteristics,and four related impurities were successfully obtained.Their structure was confirmed by means of ¹HNMR and MS.On the basis of the optimization and improvement of the small-scale process,three batches of pilot scale-up were carried out for the Clobazam.The results show that the yield is about 3%higher than that of the small-scale test,and the quality of Clobazam can be controlled within the allowable range,which proves that the synthesis route has good stability and feasibility.