Preparation And Study On The Resolution Of Some Chiral Drugs With The Derivative Of Dehydroabietic Acid

Dehydroabietic acid,is an optically pure chiral chemical compound from disproportionated rosin,which is a potential chiral resolution agent.By the diastereomeric crystallization method,the resolution effect of 12,14-dinitrodehy-droabietic acid,dehydroabietylamine and 12,14-dinitrodehydroabietylamine as chiral resolving agent on several chiral drugs was researched in this experiment.The main contents of the research are as follows:（1）Dehydroabietic acid was prepared through recrystallization,and its structure was verified.By modification of dehydroabietic acid,we synthesized a kind of chiral resolving agent,12,14-dinitrodehydroabietic acid,through nitration method.And its structure was determined by TLC,NMR,HR-ESI-MS.The parameters:the reaction time,amount of mixed acid,and temperature of the synthesis process of 12,14-dinitrodehydroabietic acid by nitration method,were optimized employing single factor experiment.Dehydroabieticamine was prepared through p-toluene sulfonic acid.Using dehydroabieticamine as the raw material synthesise 12,14-dinitrodehydroabietyl amine,a kind of chiral resolving agent,and some methods were used to analysis and determine thier structure.（2）Using 12,14-dinitrodehydroabietic acid as a kind of chiral resolving agent,the chiral drugs propranolol,bupivacaine and voriconazole enantiomer were separated by diastereomeric crystallization method.The results showed that 12,14-dinitrodehydroabietic acid could not separate voriconazole,but could separate propranolol and bupivacaine enantiomer.Using 12,14-dinitrodehydroabietic acid as a kind of chiral resolving agent,we researched the effect of solvent type,the mole ratio,reaction temperature,the liquid-solid ratio and crystallization temperature on the yield and purity of R-propranoloL The results showed that isopropyl alcohol as solvent,12,14-dinitrodehydroabietic acid（R,S）-propranolol molar ratio of 1.00,reaction temperature of 60℃,crystallization temperature of 5℃,liquid-solid ratio of 25 mL·g^-1.Under the conditions above the yield of R-propranolol was about 83.3%,and the purity was about 64.1%.Then we verified the results by repeated experiments,we found the yield of R-propranolol was about 82.707%,and the purity was about 63.0%.（3）By diastereomeric crystallization method,we researched the separation of bupivacaine enantiomer.According to Box-Benhnken experiment design principles of response surface methodology,four factors and three levels of experiments were used to investigate the influences of the mole ratio,the reaction temperature,liquid-solid ratio and the crystallization temperature on the resolution effects of bupivacaine enantiomer.We researched the optimum reaction condition was mole ratio of 1.37,liquid-solid ratio of 18.12 mL.g^-1,reaction temperature of 63.36℃ and crystallization temerature of 3.67℃.We had done three times experiments under the condition above mentioned,we found the average purity of S-bupivacaine was 70.6%,and compared with the predicted values,the relative deviation of 1.3%;the average yield of S-bupivacaine of 64.4%,and compared with the predicted values,the relative deviation was 4.7%.The results showed that this model could be used to predict separation results for bupivacaine.（4）Establishing high performance liquid chromatography（HPLC）analysis methed for valsartan and methyl-valsartan enantiomer,we can separate valsartan and its enantiomer.Then we used dehydroabietylamine and 12,14-dinitrodehydroabietylamine as resolving agent,visa diastereomeric crystallization method to separate valsartan and methyl-valsartan enantiomer.We found that dehydroabietylamine and 12,14-dinitrodehydroabietylamine cound not separate valsartan and methyl-valsartan enantiomer in a conventional manner.