Exploration And Reseerch On The Resolution Of Chiral Drugs With Dehydroabietic Acid

Dehydroabietic acid,for short DHAA,was a main chemical ingredient from disproportionated rosin,which has been used for sterilization,treating ulcer and tumor.It has a wide range of applications in the preparation of chemical.By the diastereomeric salt formation method and chiral extraction method,the resolution effect of dehydroabietic acid and its esters on several chiral drug enantiomers had been explored and researched in this topic.The contents were as follows:1.DHAA was prepared with disproportionated rosin as raw material by amination method.The structure of DHAA was determined through UV,IR,melting point and optical rotation detection,and the purity of prepared DHAA was 99.5%by HPLC.The homemade DHAA reacted with thionyl chloride,and the product reacted with alcohol to synthesis dehydroabietic acid esters,including n-butyl dehydroabietitate,isobutyl dehydroabietitate,n-amyl dehydroabietitate,isoamyl dehydroabietitate,n-hexyl dehydroabietitate,n-octyl dehydroabietitate and n-dodecyl dehydroabietitate.The presence of ester group was verified by the IR detector,and the purities of obtained dehydroabietic acid esters were greater than 90%by HPLC.2.Using DHAA as resolving agent,the chrial drugs bupivacaine,voriconazole and propranolol were separated by chemical resolution method.The results showed that DHAA could not separate bupivacaine and voriconazole,but could split chiral drug propranolol.We researched the effects of the molar ratio of DHAA and propranolol,the liquid-solid ratio and crystallization temperature on the yield and purity of S-propranolol by single factor test.According to the center combination(Box-Benhnken)experimental design principles,three factors and three levels of response surface methodology were used to investigate the influences of the mole ratio,liquid-solid ratio and the crystallization temperature on the resolution effects of propranolol.The quadratic regression models were established for the yield and purity of S-propranolol to optimize the resolution process.When the molar ratio was 1.1,liquid-solid ratio was 16.2 mL-g'1,crystallization temperature was-5?,S-propranolol was obtained with the purity of 94.8%and the yield of 72.2%.3.Using DHAA as resolving agent,the chrial drugs bupivacaine,voriconazole,propranolol and ofloxacin were separated by liquid-liquid extraction method.The results showed that dehydroabietic acid esters could not separate voriconazole,but could split other chiral drugs.The process conditions of resolution by liquid-liquid extraction method,about propranolol,bupivacaine and ofloxacin were optimized by the single factor test.Experiment results showed the optimized conditions for propranolol were as follows:concentration of propranolol was 20 mmol-L'1,concentration of boric acid was 0.4 mol·L-1,n-butyl dehydroabietitate as the extraction separation agent was 0.5 mol·L-1,chloroform as solvent,extraction temperature was 5?.Under the conditions,the separation factor a was 1.25.The optimized process condition for resolution of bupivacaine was as follows:concentration of bupivacaine was 0.2 g·L-1,the concentration of boric acid was 0.05 mol·L-1,octyl dehydroabietitate as the extraction separation agent was 0.1 mol·L-1,extraction temperature was 25?.1,2-dichloroethane as solvent.At this point,a was 1.20.The resolution effect of ofloxacin is poorer with dehydroabietic acid esters as extraction separation agent.Maximum of a was 1.08.