Research On Synthesis,Process Optimization And Crystal Of Ethyl 3-Bromo-1-(3-Chloro-2-Pyridinyl)-1H-Pyrazole-5-Carboxylic Acid

With the increasing awareness of environmental protection and agricultural demand,the development and application of highly efficient and pollution-free green pesticides has become a hot spot in current research.Chlorantraniliprole not only meets the above requirements for pesticides due to it is characterized by high efficiency,broad-spectrum,low toxicity,and is more friendly to the environment and humans and animals;But also chlorantraniliprole is a unique killing mechanism insecticides can activate ryanodine receptors in insects and cause the sustained release of Ca²⁺in cells.The study of the mechanism of action plays a guiding role for relevant researchers to further develop new pesticides.Chlorantraniliprole occupies a very important position in the pesticide market and has very broad application prospects.Ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid is an important intermediate in the synthesis of chlorobenzoamide.Therefore,it is necessary to improve the existing problems in the synthesis process,such as many steps,low yield and large consumption of raw materials.In addition,some intermediates of ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid can form single crystal in the synthesis,and the physical and chemical properties of related crystals can be studied,which can be used to regulate the solubility and stability of related compounds from the aspect of crystallography.Therefore,the research contents of this paper are as follows:1.Optimize the synthesis process of ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid.The synthesis route and process optimization of ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid were discussed.After determining the synthesis route,the synthesis of each intermediate was optimized from the aspects of saving raw materials,increasing yield and obtaining the optimal molar ratio.Meanwhile,the optimized synthesis process was obtained.The optimized five-step synthesis process can be summarized as the preparation of ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid from 2,3-dichloropyridine by hydrazine,cyclization,bromine,oxidation and hydrolysis.Each reaction process corresponding to the product of 3-chloro-2-hydrazinylpyridine,ethyl 2-（3-Chloro-2-pyridinyl）-5-oxo-3-pyrazolidinecarboxylate,ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-4,5-dihydro-1H-pyrazole-5-carboxylate,ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylate,ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid.In the improved four-step synthesis process,the reaction of cyclization and bromine is carried out in one-pot method.The specific synthesis process is as follows:（1）In the preparation of 3-chloro-2-hydrazinylpyridine,through the way of collection and reprocessing of hydrazine hydrate,effectively reduce the inventory of hydrazine hydrate,the yield of 97.78%could be obtained with the molar ratio of 2,3–dichloropyridine to hydrazine hydrate is 1:3.5,which improved much compared with the traditional the molar ratio of 2,3–dichloropyridine to hydrazine hydrate is 1:8.It could be matched with the concept of green chemistry,and the utilization rate of raw materials could be greatly improved.（2）In the cycination and bromine reactions,the method of one-step synthesis（one-pot method）was explored in order to effectively improve the synthesis efficiency.In the traditional synthesis process,the yield of cycination and bromine is 49.2%and95.9%,respectively.By improving the one-step synthesis method（one-pot method）,the total yield of two-step reaches 63.6%,which not only reduces the reaction steps and time,but also greatly increases the reaction yield.（3）The oxidation and hydrolysis reactions were further optimized to explore the best synthesis process.The total yield of ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid was 58.4%.2.Optimize the synthesis process of chlorobenzamideThe target product chlorantraniliprole was synthesized from 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid and 3-methyl-2-amino-5-chloro-benzoylmethylamine.The yield of 95.1%was obtained by investigating relate influence factors such as the effects of feed ratio,kinds of acid binding agents,solvents and optimizing the reaction conditions.3.The crystallographic properties of the intermediate in the synthesis process of chlorantraniliprole were studiedFour intermediates in the synthesis of ethyl 3-bromo-1-（3-chloro-2-pyridinyl）-1H-pyrazole-5-carboxylic acid were studied.The single crystal was obtained by solvent evaporation and the best solvent was selected.The crystallographic properties such as crystal shape and spatial structure were analyzed by X-ray diffraction method,the physical and chemical characteristics of crystal such as thermal stability were analyzed by thermal analysis method,and the spatial forces of crystal were analyzed by surface analysis of Hirshfeld.Therefore,it could be concluded that the physical and chemical properties of crystal.