Synthesis Of Ethaboxam Analogues Containing5-aminothiazole Ring

So far,heterocyclic compounds have occupied an irreplaceable position in the history of drug development because of their high activity and variable structures.Among heterocyclic compounds,aminothiazoles and thiazolylamides as the branch of thiazole derivatives have played a dominant role in the development of drugs,and their studies in medical field also showed a diversified trend.2-aminothiazoles,as a aminothiazole derivative,due to its simple synthetic method and he diversity of biological activity,many of them had been put into the market as pesticides and pharmaceutical products.However,the study on the biological activity of 5-aminothiazoles have been limited as their special construction and difficult to be synthesized.Therefore,it is of great significance to study the synthesis methods and biological activity of 5-aminothiazole in the foundation of new pesticides.Ethaboxam which has the characters of low toxicity,no teratogenicity,safe for bees,no cross-resistance to metalaxyl and azoxystrobin and good bactericidal effect,is a moderate endogenous 2-aminothiazolamide fungicide for controlling oomycete diseases,However,the common disadvantage of the internal absorption fungicide is that the function is single,and it is easy to produce drug resistance.In order to find the new fungicide of green and low toxicity,twelve Ethaboxam analogue containing 5-aminothiazole ring nucleus novel compounds were designed and synthesized using ethaboxam as leading compound by making use of bioisosterism theory,the 2-aminothiazole ring nucleus replaced with5-aminothiazole ring nucleus,through the modification of the thiophene group fragment.The structures of all target compounds were confirmed by NMR.In this paper,four routes were designed and discussed to synthesize the target compounds,through exploring and optimizing the reaction conditions in each route,The synthesis route of the target compound was determined as follows: the intermediate 4-ethyl-5-aminothiazo-2-Carboxylic acid 6c was synthesized by the reaction of α-aminobutyronitrile(5a)with ethyl 2-ethyl thioalkyl-2-thioester-ethyl acetate(6b)using triethylamine as catalyst in one pot.the key intermediate4-ethyl-5-ethylaminothiazole-2-carboxylic acid(4e)was synthesized from the intermediate(6c)through the reactions of amino-ethylation and ester hydrolysis.The target compound Ethaboxam analogues were synthesized from the key intermediate 4e through the reactions of carboxylic acid chloroacylation and then condensation with intermediate 2-amino substituted nitrile(a),with total yield of 14.6%.The synthesis method has the characterization of simple operation,mild reaction conditions,simple post-treatment,high yield and high practicability.In this paper,the one-pot method for the synthesis of5-aminothiazolecarboxylic acid derivatives was developed and three compounds were synthesized by this method.Among them,two compounds were not reported in the literature.In addition,five5-aminothiazole amide compounds were synthesized,of which four compounds were not reported in the literature.The synthesis of the above intermediates has the advantages of high yield,convenient operation and environmental protection,so the synthesis method can provide reference for the research and development and production of downstream products.