Synthesis Of 2-(2-chloro-4-(Trifluoromethyl)Phenylamino)-3-methylbutanoic Acid

The preparation for 2-(2-chloro-4-(trifluoromethyl)phenylamino)-3-methylbutanoic acid which is an important intermediate of fluvalinate is emphatically discussed. By reading a lot of literature, two methods are elaborated for the synthesis of the intermediate. (1) Ethyl 2-bromo-3-methylbutanoate as raw material, 2-(2-chloro-4-(trifluorome-thyl)phenylamino)-3-methylbutanoic acid was prepared through three step reactions including hydrolysation, condensation with 4-(trifluoromethyl)benzenamine, chlorination with NCS. (2) It was also obtained from isopropanol via bromination, Grignard reaction, addition, reduction, hydrolysation and chlorination. And an optimization of preparation technique was obtained in this paper, by wich could reach a high yield.In the first synthesis route, without solvent and catalyst, 2-(4-(trifluoromethyl)phe-nylamino)-3-methylbutanoic acid was prepared through the nucleophilic substitution reaction of 4-(trifluoromethyl)benzenamine with potassium 2-bromo-3-methylbutanoate which was obtained from ethyl 2-bromo-3-methylbutanoate via hydrolysation. Then NCS as the chlorination reagent, 2-(2-chloro-4-(trifluor omethyl)phenylamino)-3-methyl-butanoic acid was synthesized by the chlorination in the benzene ring. Also a favoritereaction condition was obtained after we studied the influence of ratio of reactant and temperature on the nucleophilic substitution reaction. Thus, the yield of the product reached 55%.In the second route, isopropanol as raw material and Concentrated sulphuric acid as catalyst, 2-bromopropane was obtained. Then ethyl 3-methyl-2-oxobutanoate was prepared via Grignard reaction. Besides, we studied the influence of the reaction temperature, ratio of reactant and the sequence of droping, and a favorite reaction conditionwas obtained with the yield of the product reaching 86.9% and purity 89.1%.Imine was obtained through the addition reaction of ethyl 3-methyl-2-oxobutanoate with 4-(trifluorornethyl)benzenamine. Then Sodium borohydride as the reductant, dichloromethane as the solvent and Copper chloride as the catalyst, ethyl 2-(4-(triflu-oromethyl)phenylamino)-3-methylbutanoate was obtained. After we studied the influenc- e of the ratio of reactant and the amount of the reductant and catalyst, a favorite reaction condition was obtained with the yield of the product reaching 81% and purity 60%.2-(2-chloro-4-(trifluoromethyl)phenylamino)-3-methylbutanoic acid was prepared through hydrolysis with ethyl 2-(4-(trifluoromethyl)phenylamino)-3-methylbuta-noate. ThenNCS as the chlorination reagent, 2-(2-chloro-4-(trifluor- omethyl)phenylam-ino)-3-met-hylbutanoic acid was synthesized by the chlorination. After we studied the influence of the amount of the caustic potash at hydrolysation reaction and the ratio of reactantat chlorination reaction. A favorite reaction condition was obtained with the yield of the product reaching 87% and purity 91%.