Experimental And Simulated Study On Chiral Extraction Of ?-receptor Blockers

The?-receptor blockers are important drugs for treating hypertension,angina pectoris,arrhythmia and so on.Currently,they are marketed mainly in the form of racemate.So it is of great significance to the enantiomeric separation research for?-receptor blockers.In this thesis,enantioselective extraction of a variety of?-receptor blocker enantiomers was performed with tartaric acid derivatives and boric acid?BA?as chiral extractant,and mechanism of reactive extraction was deeply studied.The extraction systems were further used in centrifugal fractional extraction process,and then simulation and optimization of the complicated process were performed.Mechanism of the reactive extraction of esmolol?ES?,atenolol?AT?and bisoprolol?BS?by tartrate-boric acid was studied.An interfacial reaction mechanism concerning formation of an ternary complex complexes among tartrate,BA and protonated?-receptor blockers enantiomers was proposed.Based on the reactive extraction mechanism,chemical equilibrium equations,phase equilibrium equations and mass conservation equations,the mathematical model of liquid-liquid extraction equilibrium was established.Combined with the single-stage extraction model and the law of mass conservation,the mathematical model of centrifugal fractional extraction was established.The mathematical model can be used to simulate the influence of concentration,pH,volume flow ratio,feed position and the number of stage on the extraction process,and it also can be used to optimize the extraction process.In experimental part,the centrifugal fractional extraction for enantiomers of ES,AT and BS was studied.Firstly,the single-stage extraction experiments were carried out to construct the extraction system for ES,AT and BS enantiomers through investigating type of the organic solvent,type of tartaric acid derivatives and temperature on the influence of the extraction performance.It is found that the S-isomer is preferentially identified by L-tartrate while R-isomer is preferentially identified by D-tartrate.Then the thermodynamic constants like P₀?K_TR?K_TS?K_BRR and K_BSS of ES,AT and BS were obtained by the regression analysis of single-stage extraction experimental data.After that,the effects of pH value,tartrate concentration,BA concentration and enantiomers concentration on the extraction performance were investigated,and comparison between experimental data and model prediction indicates that the model can predict the extraction process well.Based on the validated model,centrifugal fractional extraction separation processes of symmetric separation and asymmetric separation were simulated and optimized.Under optimized conditions of symmetry separation,the ee_eq for ES,AT and BS can reach up to0.98 with the number of stages of 32,28 and 30,respectively.Under optimized conditions of asymmetry separation,the ee for S-ES,S-AT and S-BS can reach up to 0.98 with 10 stages of extraction.Finally,under the optimized conditions,the 10 stages centrifugal fractional extraction process was constructed,and the relative errors between the experimental results and the simulated values were less than 7.5%.The above study shows that the required number of stage is greatly reduced with high ee of S-isomer by asymmetric separation.