Sedative Diazepam Synthesis Process Research

Diazepam is developed for treatment of anxiety,phobia,muscle tension headache and insomnia,which also exhibits good clinical efficacy and safety compared to other sleeping drugs.In this study,5-Chloro-3-phenyl-2,1-benzisoxazole as a starting material,obtained5-Chloro-2-(methylamino)benzophenone by comparing two different routes,namely,methylation before reduction and reduction before methylation,and determining the one-pot method of methylation before reduction,after acylation reaction and cyclization reaction,we got diazepam experimentally.And for the key step,it has been optimized the yield and purity of the methylation reaction before reduction and cyclization reaction.(1)Using 5-Chloro-3-phenyl-2,1-benzisoxazole as raw material and dimethyl sulfate as methylation reagent,5-Chloro-2-(methylamino)benzophenone was synthesized by quaternization in methylbenzen solution and reduction reaction under the acidic condition with iron powder or stannous chloride,which significantly avoided consecutive reaction in the traditional process.By comparing the reduction processes of iron powder or stannous chloride,the reduction process of iron powder has the advantages of short reaction time and high yield.Therefore,the feed ratio,reaction time,reaction temperature and iron powder specification were optimized by single factor experiment.The optimized process conditions were as follows: the feed ratio was 1:4.25,reaction time was 1.5h,the reaction temperature was 75℃ and iron powder specification was 0.25-0.35 mm.The yield of 5-Chloro-2-(methylamino)benzophenone was 97.3% and the purity was 98.80%.(2)N-(2-benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide was synthesized using5-Chloro-2-(methylamino)benzophenone as raw material and as chloroacetyl chlorideacylation reagent,and dichloromethane as solvent,which avoided low yield and high energy consumption of acylation reaction of primary amine.The process conditions including feed ratio,reaction time,different feed ways and reaction temperature were optimized by single factor experiment.The optimized process conditions were as follows: the feed ratio was 1:1.5,reaction time was 12 h and the reaction temperature was 26℃.The yield of N-(2-benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide was 90.7% and the purity was99.55%.(3)Diazepam was synthesized from N-(2-benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide by cyclization with hexamethylenetetramine,ammonium bicarbonate and ammonium carbonate as cyclization reagents.By comparing three cyclization reagents,ammonium bicarbonate as cyclization reagent has the advantages of high product purity and simple process.Single factor experiment and orthogonal experiment were used to optimize the cyclization process.Diazepam was refined by medicinal activated carbon adsorption and anionic ion exchange resins with the type of two-zero-one.The optimized process conditions were as follows: the feed ratio was 1:6,reaction time was 7h and the reaction temperature was53℃.The yield of diazepam was 84.8% and the purity was 99.10%.Through the research of this paper,the problem of low yield in methylation of primary amine can be improved.Ammonium bicarbonate was used as cyclization reagent in cyclization,which avoided the high energy consumption and high cost.At the same time,this process was simplified,which has guiding significance to industrial production.