Study On The Synthesis Process Of The Key Intermediate Of Neostigmine Methyl Sulfate

Neostigmine methosulfate,often administered as an injection,is a commonly used isochretic anticholinesterase drug,clinically used in myasthenia gravis,antagonizing residual muscle relaxation after surgery,and urine retention.The drug has a unique advantage in clinical application due to its rapid effect after administration.During the preparation of neostigmine methosulfate,the synthesis route of neostigmine is obtained by esterification of m-dimethylaminophenol and N,N-dimethylcarbamoyl chloride,followed by quaternization of dimethyl sulfate.M-Dimethylaminophenol is a key intermediate of neostigmine methosulfate and an important chemical raw material.It has important uses in the pharmaceutical and dye industries.However,the market price of m-dimethylaminophenol is expensive,and it can be seen from the literature that the existing synthesis methods of m-dimethylaminophenol generally have the disadvantages of harsh conditions,difficult post-processing,low yield,and environmental pollution.Therefore,it is of great academic and application value to study the synthesis process of m-dimethylaminophenol in line with the concept of green chemistry and suitable for large-scale preparation.Based on the synthetic route reported in the literature,this study selected p-aminosalicylic acid as the raw material to obtain m-aminophenol through decarboxylation reaction,and then obtained m-dimethylaminophenol through N-alkylation reaction.And after determining the synthesis route,the synthesis process conditions were optimized.Specific research includes:(1)Study on the synthesis process of m-aminophenolUsing para-aminosalicylic acid as raw material,water as reaction solvent,and copper powder as catalyst,decarboxylation reaction was carried out to synthesize m-aminophenol.The better process conditions obtained are: p-aminosalicylic acid: copper powder is 5: 1(mass ratio),reflux time is 3.5h,and the target substance aminoaminophenol can be obtained by quantitative reaction.The reaction uses water as a solvent,is green and pollution-free,and selects copper powder as a catalyst,which accelerates the reaction speed and improves the reaction yield.The post-processing is simple and the product yield can be increased to 99%.This process has not been reported in the literature by the method of copper powder catalysis.(2)Research on the synthesis process of m-dimethylaminophenolUsing m-aminophenol as the raw material,methyl iodide as the alkylating agent,Aluminosilicate molecular sieve as the catalyst,and acetonitrile as the solvent,m-dimethylaminophenol is prepared through the alkylation reaction.The better process conditions obtained are: m-aminophenol: methyl iodide: anhydrous potassium carbonate: acetonitrile is 1.0: 2.2: 3.0: 18(molar ratio),M-aminophenol: Aluminosilicate molecular sieve is 1: 1(mass ratio),the reaction temperature is 25 ℃,the reaction time is 20 h.In this process,Aluminosilicate molecular sieve was proposed as the reaction catalyst for the first time,which significantly improved the reaction yield.This step also improves the post-treatment purification method,and directly uses the recrystallization method to obtain a purer product,avoiding the vacuum distillation method reported in the literature,and the obtained product can be directly used for the preparation of neostigmine mesylate.After optimization,the reaction yield increased from 51.1% to 65.0% compared with the literature.The process is catalyzed by Aluminosilicate molecular sieve,which has not been reported in the literature.In summary,this article explores the synthesis process of meta-dimethylaminophenol,a key intermediate of neosmethyl methionate,and the obtained process conditions have two significant improvements.The decarboxylation reaction of m-aminophenol yields m-aminophenol.The second is the first use of Aluminosilicate molecular sieve to catalyze the N-alkylation of m-aminophenol and obtain the target compound.The improved process conditions have the advantages of simple operation,effective cost reduction,green and pollution-free,higher yield,and can be prepared in kilograms.