Study On Preparation And Purification Process Of D-phenylglycine Methyl Ester Hydrochloride

D-phenylglycine methyl ester hydrochloride,a type of white crystalline powder and important pharmaceutical intermediate,is an essential active side chain for the production of cephalexin,cefaclor,and other ?-lactam antibiotics.In this paper,the synthesis and crystallization purification technique of D-phenylglycine methyl ester hydrochloride is systematically studied.The study on the synthesis of D-phenylglycine methyl ester hydrochloride.A preliminary synthetic route of D-phenylglycine methyl ester hydrochloride was designed,and sulfoxide chloride method was determined experimentally as a preferred synthetic route.In the experiment,the synthesis technique conditions such as the sequence of adding reagents,the ratio of reagents,the reaction temperature,the reflux time,and the adding rate of sulfoxide chloride were investigated and optimized.After the completion of the reaction,the vacuum azeotropic distillation and cooling crystallization with the temperature controlling should be done to the mother liquor.Finally through the post-processing,we can get the crystal product of D-phenylglycine methyl ester hydrochloride.The purity of the product detected by using HPLC is more than 98.5%,with the yield more than 96%.The study on the thermodynamics of D-phenylglycine methyl ester hydrochloride crystallization.The solubility and supersolubility of D-phenylglycine methyl ester hydrochloride in six pure solvents(water,methanol,ethanol,acetone,ethyl acetate,and toluene)as well as in two kinds of binary mixed solvents with different compositions(methanol-ethyl acetate and methanol-toluene)were measured under the conditions of atmospheric pressure and the temperature range of 283.15K~333.15 K by using Laser Dynamics Method.Then the Apelblat equation,CNIBS/Redlich-Kister equation,and NRTL equation were used to correlate the data of solubility,and it showed a satisfactory result.Finally,thermodynamic properties in the dissolution process were analyzed systematically,and changes of the free energy of standard molar enthalpy,standard molar entropy and standard Gibbs of D-phenylglycine methyl ester hydrochloride in the dissolution process in different solvents were calculated.The study on thermodynamics of crystallization of D-phenylglycine methyl ester hydrochloride provides a theoretical reference and data base for the development of its crystallization technique.The crystallization kinetics of D-phenylglycine methyl ester hydrochloride was studied by batch dynamic methods.Samples of different times were measured under different processing conditions.Then the CSD was analyzed by laser granulometer.Crystallization dynamic models of D-phenylglycine methyl ester hydrochloride were established based on the mass balance equation and population balance equation.After transformation of moments on the experimental data,the mathematical models for crystal growth rate and secondary nucleation rate were obtained,and the operating parameters which affected the crystallographic progress were analyzed.The study on the crystallization technique of D-phenylglycine methyl ester hydrochloride.The crystallization technique of D-phenylglycine methyl ester hydrochloride was studied on the basis of crystallization thermodynamics and dynamics.The influence of crystallization method and process conditions on the quality and yield of product was studied.A new crystallization and purification technique of D-phenylglycine methyl ester hydrochloride was developed.The crystals produced by this new technique is of high purity,high yield,and good color level(level 1),and their particle size increased and uniformed obviously.With stable quality of the product,low production cost as well as easy operation control,this technique has applied for China National invention patent.And the industrialization of the annual output of thousand tons has been realized.