Study On Synthesis Process Of Spirotetramat And Bioactivity Structure Relationship Of Its Derivatives

This paper reviewed the application and development of the spiro compound in the area of pharmaceutical, agrochemical and materials; further elaborated the spiro insecticide of spirotetramat physicochemical properties, toxicity, safety, market conditions, degradation products, synthetic methods and routes; moreover, combined with the process of new pesticide discovery, a brief overview of quantitative structure-activity relationship was described.Spirotetramat developed by Bayer Company is a spiro insecticide containing a new structure, the unique mechanism of action and efficient bioactivity, which has caused widespread concern. On the basis of a literature review,4-methoxyphenol was used as raw material via catalytic hydrogenation reduction, Jones oxidation, Bucherer-Bergs reaction, alkaline hydrolysis and esterification to obtain1-amino-4-methoxycyclohexanecarboxylic acid, and then via amidation reaction with2,5-dimethyl phenylethyl chloride, Dieckmann condesation to form a ring, and finally to get the target compound Spiroteramat by the reaction with ethyl chloroformate. Total yield of the process was20.2%, and the purity of Spiroteramat was97%. All the intermediates and products was confirmed by1H NMR, MS detection. This process had the advantage of readily available raw materials, simple operation and the value of industrial production.In order to find and screen insecticidal lead compounds in line with requirements of the development of new pesticides, commercialized pesticide Spiroteramat was modified by structural transformation and optimize design to syntheses three series of compounds Ⅰ, Ⅱ,Ⅲ, which contained a total of26compounds and25compounds were not reported. All compounds were characterized by1H NMR, MS, and elemental analysis. All the target compounds were measured for its bioactivity in the help of Hunan Bioassay Center Department. The inhibition activity against Aphis fabae showed:some compounds showed good insecticidal activity at test concentration of100mg/L and the inhibition rate reached above90%, close to Spirotetramat, such as compounds Ⅰ-1,Ⅰ-2, Ⅰ-6,Ⅰ-7,Ⅰ-8,Ⅰ-12,Ⅰ-14,Ⅰ-15,Ⅰ-16, Ⅲ-2,Ⅲ-3. While at test concentration of10mg/L, compounds Ⅰ-6, Ⅲ-2, Ⅲ-3showed the high inhibition activity above87%. The inhibition activity against Tetranychus cinnabarinus showed:The inhibition rate of compounds Ⅰ-6,Ⅰ-11,Ⅰ-14reached above 75%at test concentration of100mg/L while compounds Ⅰ-2,Ⅰ-7,Ⅰ-8,Ⅰ-11,Ⅰ-12,Ⅰ-14,Ⅲ-2,Ⅲ-3showed higher bioactivity than Spirotetramat of26%inhibition rate at test concentration of10mg/L. The inhibition activity against Nilaparvata legen showed:the series Ⅰ and Ⅲ derivatives exhibited good bioactivity at test concentration of100mg/L and the inhibition rate of compounds Ⅰ-1,Ⅰ-3,Ⅰ-8, Ⅰ-12, Ⅲ-2,Ⅲ-3reached100%. However, all compounds displayed lower bioactivity or no bioactivity at test concentration of10mg/L.To further study the quantitative relationship of biological activity and structure,17kinds parameters of4-hydroxy-1-azaspiro[4.5]dec-3-ene-2,8-dione derivatives including physical chemistry and quantum chemistry descriptors were calculated using density functional theory method at B3LYP/6-31G (d) level.21compounds were used to establish a QSAR formula based on the Hansch model using multiple linear regression analysis. Four models were obtained and the R value for each model was greater than0.8with statistical significance, indicating that the models had good predictive ability. The models showed how to improve the bioactivity of4-hydroxy-1-azaspiro[4.5]dec-3-ene-2,8-dione derivatives compounds, considering the parameters such as:HOMO, LUMO, Q(N), Q(O), clogP, MR, Vw, DM and ET. The modes also gave a prediction on how to improve the bioactivity:increase the HOMO energy of the molecule, reduce the amount of charge in the Q(N) and Q(O), reduce the hydrophobicity values, meanwhile the molar refractive index and volume parameters need to be considered.