Study On The Synthesis Of Diclofenac Sodium

Diclofenac sodium is a non-steroidal anti-inflammatory analgesic that has strong anti-inflammatory effects and high safety compared to other non-steroidal anti-inflammatory drugs.In this paper,combined with the requirements of green,safe and economical industrial production,the existing synthetic routes of diclofenac sodium were compared and analyzed,and the aniline method suitable for industrial production was determined to carry out experimental research,which provided a theoretical basis for the industrial production of diclofenac sodium.Firstly,the solvent for the synthesis of the intermediate dichlorodiphenylamine was screened and the optimization of the synthesis conditions was studied.Toluene,xylene mixture,n-butanol,cyclohexane,petroleum ether,N,N-dimethylformamide were used as solvents,and the yield of dichlorodiphenylamine was used as an indicator to compare several solvents.The effect is determined by the preferred solvent and the optimum process conditions.Next,the screening experiment was carried out on the alcoholysis agent after the dichlorodiphenylamine acylation reaction.Using methanol,ethanol,n-propanol,isopropanol and n-butanol as alcohol decomposers,the yield of the target product N-(2,6-dichlorophenyl)-phenyl-chloroacetamide was investigated.The indicator identifies a better alcoholysis agent.Finally,the process conditions for the synthesis of the intermediate 1-(2,6-dichlorophenyl)-2-indanone and the final target product diclofenac sodium were optimized.Mainly on the basis of single factor experiment,the response surface method was used to optimize the design of the experimental scheme,and the yield of the target product was used as the evaluation index to optimize the synthesis process conditions.The target products of the experimental synthesis were qualitatively analyzed by infrared spectrometer.The important intermediates were also qualitatively analyzed by NMR spectroscopy,and quantitative analysis was carried out by ultraviolet spectrophotometry.The solvent for synthesizing the intermediate dichlorodiphenylamine is a mixed solution of xylene.The optimum synthesis conditions are as follows: the reaction time is 24 hours,the ratio of catalyst to aniline is 0.18,and the molar ratio of raw material 2,6-dichlorophenol to aniline is 1.20.Calculate the yield of 2,6-dichlorodiphenylamine to 90.05 % based on aniline.The optimum synthesis conditions of the intermediate 1-(2,6-dichlorophenyl)-2-indanone are as follows: reaction time 2 hours,reaction temperature 140 ?,catalyst and N-(2,6-dichloro The mass ratio of phenyl)-phenyl-chloroacetamide was 1.20,and the yield of the product was 97.24 %.The results of response surface methodology showed that the linear effect of reaction temperature on the yield of the product was extremely significant,and the linear effect of reaction time and catalyst dosage was significant,but the interaction between the three had no significant effect on the yield,while the reaction temperature and The secondary effect of the reaction time is extremely significant.The correlation coefficient of the calibration model is 0.9646,and the coefficient of determination is 0.9191,which indicates that the selected experimental mathematical model fits well with the actual situation and can better reflect the correlation between the factor variable and the experimental index.Within the design range of factor variables,the influence of factor variables on product yield is from reaction temperature,reaction time and catalyst dosage.The optimal conditions for the synthesis of the target product diclofenac sodium were as follows: the reaction time was 8 hours,the lye concentration was 0.18 g/ml,and the yield of diclofenac sodium was 87.15 %.The results of response surface methodology showed that the linear effect of reaction time on product yield was very significant,and the linear effect of lye concentration on product yield was significant,but the interaction between the two was not significant,while the secondary effect was significant.The correlation coefficient of the calibration model is 0.9285,and the coefficient of determination is 0.8774,which indicates that the selected experimental mathematical model fits well with the actual situation and can better reflect the correlation between the factor variable and the experimental index.Within the design range of factor variables,the influence of factor variables on product yield from large to small is reaction time and alkali concentration.In the above-mentioned optimized experimental conditions,a confirmatory experiment was carried out.Based on the calculation of aniline,the final yield of diclofenac sodium was 63.88 %,and the product containing diclofenac sodium was 98.51%,which met the requirements of the 2015 edition of the Chinese Pharmacopoeia.The feasibility and reliability of the research results.