Study On Synthesis Of Flonicamid

Flonicamid is a novel,highly selective and neurotoxic picricamide insecticide with new antifeeding mechanism of sucking mouthpart pests such as aphids.In the present article,the method for industrial synthesizing flonicamid based on the literature was proposed and operation technology was further optimized.The synthetic research was divided into two parts with one of the synthesis of the key intermediate 4-trifluoromethylnicotinic acid and the other of the synthesis of flonicamid.4-Trifluoromethylnicotinic acid was synthesized by using ethyl vinyl ether and trifluoroacetic anhydride as the starting materials,through trifluoroacetylation,ammonolysis,condensation and cyclization hydrolysis.An impurity was found during the condensation,it was isolated and characterized as 3-methoxy-3-(4,4,4-trifluoro-3-oxo-1-butenylamino)-propionic acid methyl ester.Later studies found that if the reaction conditions were changed,this impurity could be further transformed into the key intermediate 4-trifluoromethylnicotinic acid.Then the process conditions that can transform the impurities into the key intermediate were screened and determined.During the cyclization,the impurities of 4-hydroxy-6-methoxy-4-trifluoromethyl-1,5,5,6-tetrahydropyridine-3-carboxylic acid methyl ester and 4-hydroxy-4-trifluoromethyl-1-hydropyridine-3-carboxylic acid methyl ester were found and determined,the method for converting impurities to the key intermediate was established.Flonicamid synthesis including three methods had been reported in the literature,respectively,as direct method,indirect method and one-pot method.Direct method was simple but the yield was low,in our study,the key factor which affected the yield was the generation of impurity.After the enrichment and separation of impurity during the synthetic process,it was confirmed as N-cyanomethyl-bis(trifluoromethyl)nicotinamide,and reason for the impurity formation was found,the yield was improved by adjusting technology for converting impurities to the key intermediate.Synthesized flonicamid,key intermediate and the relative impurities were characterized by NMR,HRMS,HSQC and DSC,respectively.For easy to monitor the reaction,the detection methods by Gas Chromotagraphy or High Performance Liquid Chromotagraphy phase for each step were established.Synthesized flonicamid was tested in accordance with the pesticide guidelines and it was proved that it meet the requirements of the pesticide manual.The optimized synthetic technology was easy to operate with an overall yield of 42.5%(calculated based on vinyl ether)and is expected to be used in the industrial production.