Study On Crystallization Process Of Spirotetramet-Enol

Cis 3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro [4.5] decane-3-en-2-one is an important intermediate in the production of spirotetramat,also known as spirotetramat enol.At present,the product of spirotetramat enol has some shortcomings,such as uneven particle size distribution,incomplete crystal habit and low purity.Based on this background,this study developed a new crystallization process of spirotetramat enol and systematically studied its crystallization process.Obtain the crystal diffraction pattern of spirotetramat enol using powder XRD.Use molecular simulation software Materials Studio 8.0 to analyze X-ray diffraction data and further refine the XRD results to obtain crystal cell parameters.The structure of spirotetramat enol crystal was obtained through molecular construction,optimization,and module refinement.The solubility of spirotetramat enol in four binary mixed solvents(methanol + water,ethanol + water,acetonitrile + water,and n-propanol + water)was determined within T =(288.15–328.15)K under 101.1 k Pa by dynamic laser method.At the same time,the supersolubility were also determined in binary mixed solvents(methanol-water,ethanolwater,isopropanol-water,acetonitrile-water)with varied compisitions as a function of temperature and then the solubility data was correlated by applying Van’t Hoff model,λh model,Wilson model and NRTL model.Calculate the solvent effect using the KAT-LSER model.AIC analysis was used to find the best model which was then used to correlate the solubility data.Thermodynamics parameters containing enthalpy change,entropy change and Gibbs free energy change of spirochemical enol in binary mixed solvents were calculated,which provided basic data for kinetics and crystallization process.The metastable zone of spirotetramat enol in binary mixed solvents was measured by using laser dynamics method as function of temperature,and the relationship between the variation pattern of stable zone and induction period in different solvents and supersaturation ratio.Based on the classical homogeneous nucleation theory,the interfacial tension,radius of critical nucleusand and nucleation free energy were calculated.Meanwhile,the study on crystallization kinetics was carried out by utilizing intermittent dynamic method.The particle sizes of samples taken out at different time were measured by Mastersizer 3000 granulometer.Based on the population balance equations,the experimental data was processed by using the moments method.Then the nucleation rate and growth rate models were obtained according to nonlinear regression method,and the influences of various conditions for crystallization process were analyzed.A solvent crystallization process for spirotetramat enol was developed through systematic experiments.The optimal process conditions for the separation and purification of intermediate six during the solvent crystallization process were explored using a multiindex orthogonal experiment.The effects of five factors,including stirring rate,solvent addition rate,crystallization time,cooling rate,and p H,on product yield and particle size distribution were investigated,and the optimal crystallization process was calculated.Under the developed process conditions,a product with a median particle size distribution of 600μm and a span of 1.162 was obtained.