Synthesis And Crystallization Of P-hydroxyphenylglycine Methyl Ester

D-p-hydroxyphenylglycine methyl ester（D-p-HPGM）is a side chain ester necessary for the synthesis ofβ-lactam antibiotics such as amoxicillin,and its crystal properties will directly affect the subsequent synthesis of raw materials.D-p-hydroxyphenylglycine（D-p-HPG）is the main raw materials for the synthesis of D-p-HPGM.With the aggravation of population aging,population expansion and environmental pollution,the demand for drugs such as amoxicillin is also increasing.The demand for drug dosage directly leads to the increasing demand for the production of intermediates of this series of drugs.With the personalized demand for the efficacy and quality of target drugs,the requirements for the shape（crystal form,particle size distribution,etc.）of this series of products are also increasing.At present,the synthesis mechanism of p-HPG has not been put forward clearly in the domestic literature,and the reaction time is long,the selectivity and yield are not very high in the synthesis process of p-HPG;The production process of D-p-HPGM generally has problems such as unstable product quality.In this paper,the synthesis and crystallization process of D-p-HPGM was systematically studied,including process analysis technology,on-line monitoring of p-HPG synthesis process and process optimization;D-p-HPGM synthesis,crystallization kinetics and crystallization process optimization.The synthesis process and reaction mechanism of p-HPG from sulfamic acid,glyoxylic acid and phenol were investigated.Real-time monitoring and analysis of p-HPG synthesis process were carried out by using online mid-infrared technology.The optimal process conditions were obtained as follows:reaction at 301±1 K for 9 h,rapid heating to 349±1 K for4 h,yield of 74.78%,purity of 98.64%.A reasonable reaction mechanism was proposed.There were two reaction paths in the reaction.Path I is the condensation product of glyoxylic acid and aminosulfonic acid,2-（sulfoimino）acetic acid（intermediate c）,was heated to desulfonate to produce iminoacetic acid（substance d）,and the product p-HPG was obtained by condensation of substance d with phenol;the yield of this path was very low.Path II is the intermediate c of condensation product of glyoxylic acid and sulfamic acid is condensed with phenol to obtain 2-（4-hydroxyphenyl）-2-（sulfamino）acetic acid（intermediate f）,and the product p-HPG is obtained after the sulfonation radical is removed by heating;the reaction yield of this path is high.In the process,we found that the condensation of glyoxylic acid and sulfamic acid is a thermodynamically controlled reaction,and the reaction rate is slow at low temperature.Using the on-line mid-infrared spectroscopy,we detected the key intermediates c and f to verify the rationality of the mechanism.The p-HPG process was synthesized from phenol,glyoxylic acid and aminosulfonic acid in one pot at low temperature and then at high temperature.Path II was the main reaction path,which could reduce the formation of by-products p-hydroxymandelic acid and o-hydroxymandelic acid,and obtain the best yield.The synthesis and crystallization process of D-p-HPGM was investigated by using a Focused Beam Reflectometer（FBRM）,and the reaction crystallization process was optimized.The optimum process conditions for the synthesis of D-p-HPGM are as follows:the amount of catalyst is D-p-HPGM:H₂SO₄=1:1（molar ratio）,esterification is carried out at 353±1 K,the system is dissolved and distilled at atmospheric pressure for 5h,and the yield can reach 98.71%.The effect of different p H and temperature on the nucleation process is obtained through the study of crystallization kinetics.The temperature increases,and the metastable zone narrows.Through the calculation of the nucleation energy parameters,it can be seen that high temperature and high supersaturation are conducive to nucleation,but secondary nucleation is also easy to occur,resulting in small size of the final product.In addition,FBRM was used to explore the reaction crystallization process.Through investigating the ammonia concentration,stirring speed,p H and other conditions,it was finally concluded that the temperature was 283±1K,the ammonia concentration was 15%,the stirring speed was 400 r/min,and the p H was7.4～7.6.The method of double-drop addition was the best process condition for D-p-HPGM reaction crystallization.The purity and yield of D-p-HPGM prepared by this method are qualified and the particle size distribution is uniform.