Study On The Synthetic Technology Of New Veterinary Drug Fluralaner

Fluralaner is a new broad-spectrum veterinary drug belonging to the isoxazoline insecticide,by interfering with the GABA-gated chloride ion channel to play a role,and it has significant differences in the molecular structure,site of action,selectivity and cross resistance,compared with phenyl pyrazoles,cyclopentadiene and macrolide insecticides,with the mammalian safety,higher insecticidal activity and other characteristics.This paper focuses on the design of a viable,easy-to-industrial route for the synthesis of fluralaner and the study on synthetic route technology the synthesis of three intermediates of fluralaner and target products.The molecular structure of the target product was analyzed,and it was split into three fragments,namely,Intermediate ?,Intermediate ?,and Intermediate ?,then assembled after synthesis.Firstly,1,3-dipolar cycloaddition reaction of 2-methyl-4-benzaldehyde methyl benzoate(Intermediate ?)with 2-trifluoromethyl-2-(3,5-dichlorophenyl)ethylene(Intermediate ?),then the resulting product was amidated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide(Intermediate ?)to give the desired product.Among them,the intermediate ? has not been reported in the literature.For the synthesis of fluralaner,a cheap "green" oxidant potassium persulfate and K? were used in this article.And 1,3-dipolar cycloaddition is first carried out to obtain an isoxazoline compound in the mixed solvent of water and methanol,followed by amidation reaction to obtain the product.?ts purity up to 98.9% and Calculated as Intermediate ?,the yield was 50.3%.In the synthesis of intermediate ?,this paper designs a synthetic process route which has not been reported in the literature.The target product was synthesized by the main synthetic steps such as amino protection,amidation reaction,deprotection and salt purification with glycine as the starting material,yield reached 88.2%,and it has the advantages of simple process,mild reaction conditions,easy availability of raw materials,low cost and suitable for industrialization.In the synthesis of intermediate ?,this paper also designs a synthetic process route which has not been reported in the literature.The product was obtained by esterification,nucleophilic substitution of trifluoromethyl and witting reaction,using 3,5-dichlorobenzoic acid as starting materials,yield reached 83.8% and the purity up to 96.8%.?t has raw materials acquire,simple operation.In this work,4-bromo-2-methyl benzoic acid methyl ester was synthesized with high yield by esterification,with 2-methyl-4-bromo-benzoic acid as starting material.And then substituted by cyano group,finally reaction with hydroxylamine to obtain 2-methyl-4-formaldehyde oxime-methyl benzoate(intermediate ?).The total yield reached 62.6% and the purity up to 98.1%.?ts advantages include simple process,mild reaction conditions,easy availability of raw materials and suitable for industrialization.Only one step reaction of hydroxylamine hydrochloride with cyano groups to produce oxime in aqueous sodium carbonate solution.Compared with the literature,this method is featured with high yileld and low cost.And it also provides a new and convenient method for the synthesis of important intermediate oximes in organic reactions.In this paper,the analysis of 1H-NMR and 13C-NMR were carried out for intermediate ?,intermediate ?,intermediate ? and target product fluralaner respectively and the structures of these compounds were confirmed.