Study On Synthesis Of Loxoprofen Soidum

As a excellent nonsteroidal anti-inflammatory drug,Loxoprofen Sodium has extensive clinical application at home and abroad.Its synthetic routes are generally divided into two types:one route is 2-(4′-（halomethyl）phenylpropanoic acid（or its ester）as the key intermediate,the other is 2-benzylcyclopentanone as the starting material.At present,the first synthetic route is mainly used in industry.However,in the production process,there are many problems such as serious pollution,low yield,and low crystallization rate,and so on.In this thesis,a novel technology was proposed on the basis of the study in detail on esterification,condensation,decarboxylation,salt formation and recrystallization with2-(4′-（halomethyl）phenylpropanoic acid used as raw material,and the yield of Loxoprofen Sodium increased to 81.5%,which not only partly solved various problems existing in routes,but also reduced production costs.（1）Esterification:Thethermodynamicsoftheesterificationreactionof2-(4′-（bromomethyl）phenylpropanoic acid and methanol was studied by Joback,Benson and ABWY group contribution methods.The results show that water has little effect on the esterification,and the theoretical yield based on 2-(4′-（halomethyl）phenylpropanoic acid can reach to 99.9%.The S₂O₈^2-/TiO₂-Al₂O₃-SiO₂ solid superacid was prepared by the coprecipitation-impregnation method.The characterization results of FT-IR、XRD、BET and NH₃-TPD show that there is bridged double coordination between S₂O₈^2-and the support oxides;the phase structure of TiO₂ is anatase;the average pore size and specific surface area are 8.3 nm and 113.92 m²/g,respectively,there are both weak acid sites and super acid sites on its surface.The yield of methyl 2-(4′-（bromomethyl）phenylpropanoic can reach to 73%with S₂O₈^2-/TiO₂-Al₂O₃-SiO₂ used as the catalyst,which is higher than that of concentrated sulfuric acid and p-toluenesulfonic acid under the same conditions.It is also found that the esterification has obvious solvent cage effect without the use of catalyst and the yield of the esterification increases with the decrease of the polarity of the solvent.When cyclohexane is used as the solvent,the yield is up to 99.2%.Under the condition of excessive methanol,the effect of the solvent cage effect on the activation energy and frequency factor of the reaction was studied.The results show that the smaller the polarity of the solvent is,the lower the activation energy and the lower frequency factor are.On the contrary,the greater the polarity of the solvents is,the larger the activation energy and the frequency factor are.When the methylation reaction of benzoic acid,2-phenylpropionic acid and p-bromopropionic acid were used as the probe reaction,it is found that the solvent cage effect is not only related to the interaction between molecules,but also related to the structure and properties of the material.（2）Condensation:The reaction conditions including base,solvent,phase transfer catalyst,molar ratio of reactans,reaction time and reaction temperature in the condensation reaction were discussed in the thesis.When using potassium carbonate as a catalyst,acetone as a solvent,A as a phase transfer catalyst and the amount of the phase transfer catalyst of 0.625%（based on the mass of raw materials）under the conditions of the reaction temperature of 35℃,the molar ratio of methyl 2-oxocyclopentane-1-carboxylate to methyl 2-(4′-（bromomethyl）phenylpropanoate of 1.15:1,and addition time of 2 h,the yield of the main product can be up to 93.3%.Orthogonal experimental shows that the order of influence on the reaction is as follows:addition time﹥reaction temperature﹥molar ratio of raw materials.（3）Decarboxylation,salt formation and recrystallization:In the mixture of hydrochloric acid and acetic acid with a volume ratio of 2.5:1,when the decarboxylation temperature is 70℃with the decarboxylation time of 6 h,the yield of the main product can reach to 92.7%.In the isopropyl ether-ethanol system with a volume ratio of 8:1,the yield of Loxoprofen Sodium can reach to 96.9%.The product is slightly yellowish powder,with the purity of product of 99.70%,the amount of maximum single impurity of 0.07%,and the amount of total impurity of 0.17%,and its infrared absorption spectrum is consistent with the standard spectrum.