Optimization Of Synthesis Process Of The Important Intermediate Intermediate Of Bixafen

Bixafen is a pyrazole amide fungicide registered and marketed by Bayer in 2011.It has good therapeutic and protective effects against barley net blotch and apple powdery mildew,and its combination with prothioconazole has very good activity against diseases caused by Crustacea,with the advantages of high activity,broad antimicrobial spectrum,and low residue.In this paper,the synthesis of 1-methyl-3-（trifluoromethyl）-1H-4-carboxylic acid and3’,4’-dichloro-5-fluoro-（1,1’-biphenyl）-2-amine,two important intermediates for the synthesis of biphenyl pyrazole,were improved respectively,and finally,a relatively low cost,simple and environmentally friendly process route was developed.The target products were structurally characterized by IR,¹H NMR and ¹³C NMR.The synthetic process of 1-methyl-3-（trifluoromethyl）-1H-4-carboxylic acid was investigated and a total of three synthetic routes were identified.The first one is based on the chlorination of difluoroacetic acid raw material,the ring-off reaction with methyl hydrazine,and finally the hydrolytic acidification to obtain 1-methyl-3-（trifluoromethyl）-1H-4-carboxylic acid,with a total yield of 59.3%.The second synthetic route was the reaction of ethyl 4,4-difluoro acetoacetate with DMF and DMS at low temperature,followed by a ring closure reaction with methylhydrazine to give 1-methyl-3-（trifluoromethyl）-1H-4-carboxylic acid by hydrolytic acidification in 58.7%total yield.The third synthetic route was based on ethyl 4,4-difluoroacetoacetate,which underwent Claisen Condensation with triethyl orthoformate,followed by a ring-off reaction with methylhydrazine to give 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid by hydrolysis and acidification in 64.9%total yield.The synthesis of 3’,4’-dichloro-5-fluoro-（1,1’-biphenyl）-2-amine was investigated.3’,4’-dichloro-5-fluoro-（1,1’-biphenyl）-2-amine was synthesized by diazotization reaction with 3,4-dichloroaniline and then Gomberg-Bachmann reaction with 4-fluoroaniline under alkaline conditions with a yield of 58.3%.The synthesis process of its intermediate was investigated.2-bromo-4-fluoroaniline was obtained from 4-fluoroaniline by amino protection,bromination,and deprotection with acetic anhydride in 81.1%yield;4-bromo-1,2-dichlorobenzene was produced from 3,4-dichloroaniline by Grignard reaction in 74.8%yield.Through the study of the feasibility synthesis process of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid and 3’,4’-dichloro-5-fluoro-（1,1’-biphenyl）-2-amine,the conditions affecting the reaction yield in each step were optimized,and the more economical and reasonable process route were screened out,and the occurrence of side reactions was greatly reduced.The specific factors affecting the product yield were analyzed.The ideal process parameters were obtained.Most of the raw materials needed by this route are of low price and wide source.Because of their advantages of simple operation,high conversion rate and product selectivity,and suitable for industrial production,it lays a good foundation for industrial production.