Study On Synthesis Process Of Novel Chiral Insecticide Indoxacarb And Its Polymorphism

With the environmental protection consciousness increasing, excess use of highly toxic and residue pesticides has made the negative impact on agricultural production and ecological environment, which has caused worldwide concern. Many countries and certain international organizations have developed policies to prohibit or restrict the use of highly toxic and residue pesticides, and the world rush to invest, research and development of new green pesticides, especially chiral pesticides. Indoxacarb with new structure, the unique mechanism of action and efficient bioactivity, was discovered as a new highly active blocker of the sodium channel by Du Pont in1992and was launched into the market in2001, which has caused widespread at home and abroad. Currently, DuPont has applied for China, the U.S. and the world patents. Its compounds and intermediates patents are about to expire in2015. Because of its expired patents, good efficacy, and better market prospects, indoxacarb has great value for development.The development trend of pesticide, the researches of chiral drugs, and the physicochemical properties, toxicity, safety, market conditions, synthetic methods and routes were systematically reviewed. On the basis of the literatures review, we ultimately developed a relatively low production cost, easy to operate and environmentally friendly process route. That is,5-chloro-l-indanone was used as raw material via methoxycarbonylation, asymmetric oxidation, hydrazone generated reaction, condensation and cyclization, catalytic hydrogenation and acylation to obtain the target compound indoxacarb. And based on the mechanism of impurity in each step, the factors affecting selective reactions:reaction solvent, catalyst, temperature, moisture, etc. were studied to optimize the reaction in each step to determine the optimum conditions, making the target product indoxacarb six-step total yield of slightly higher than the literature with59.1%, the product purity of96%, enantiomeric excess value (ee) of48-54%, which is more suitable for industrial production.In recent years, the impact of drug polymorphism on the physical and chemical properties, bioavailability and preparations quality of drugs attracted more and more attention of pharmacy workers. Thus the study on drug polymorphism has become an important part of the research, development and quality control process of drugs. To date, there is no indoxacarb crystal form reported in the literature. In this paper, we prepared indoxacarb form A and amorphous form. Based on the measured data with IR spectra, TGA, DSC and powder XRD instruments, we make sure that form A and amorphous form are two new crystal form which had been no reported in any literature.In order to study the bioactive differences of different crystal forms, the suspension concentrate and emulsifiable concentrate of form A and amorphous form were prepared. And their biological activities against Plutella xyllostella, Chilo suppressalis were evaluated. The results of preliminary bioassay showed that the activity of the emulsifiable concentrate of the form A or amorphous form was much higher than their crossponding suspension concentrates, and the activities of amorphous forms were higher than the crystal amorphous form. This paper filled the gaps of indoxacarb polymorphs research and laid an important theoretical and practical basis of indoxacarb formulations selected, cost reduction and industrial development.