Study Of The Triphenylcarbamate Cellulose Chiral Stationary Phases And The Chiral Chromatography Resolution Of Omeprazole

The productuin of individual enantiomers has become more and more important as the increased knowledge of the different medicine effect of enantiomers. There are several approaches to obtain enantiomerically pure chemicals. They are asymmetric synthesis, chemical derivation, crystallization, biotransformation, inclusion, membrane separation and chiral chromatography. The chiral chromatography is more attractive and has been developed rapidly in recent years. However, researcch was concentrated on the chiral analysis and chiral recognition mechanism, and the study on the preparative separation is not excessive. This work choose the chiral antiulcer drugs-omeprazole as the object to study the common technique of chiral chromatographic separation. After comparing the chiral resolution methods of omeprazole, we intend to separate the enantiomers of omeprazole by the triphenylcarbamate cellulose(TPCC) coated chiral stationary phase (CSP) chromatography.The project is divided into two parts: the preparation of TPCC coated chiral columns and chromatographic separation of omeprazole.In first part, A salt with compsition of NaChKNO3: LiCl-H2O(4:l:l) was mixed with micropore silica gel, and the weight ratio of salts to silica gel is 30:100. Then the mixture was torrefied at 650℃ for 2h to give macropore silica gel. The pore size of macropore silica gel obtained is in the range of 150 to 400nm and its specific surface is 10.8605m2/g.3-aminopropyl silica(APS) gel was prepared by the reaction of macropore silica gel with 3-aminopropyltriethoxyl silane in the dry tolulene with refulx for 24h.Triphenylcarbamate cellulose(TPCC) was prepared by the reaction of cellulose with an excess of isocyanates in dry pyridine at 100℃. Elemental analyses and IR spectra showed that hydroxy groups of cellulose were almost completely converted into the carbamate moieties after reaction of 24h. The TPCC was dissolved in organic solvent, and the coating support(macropore silica gel or APS) was suspended in the solution of TPCC, then the TPCC was coated on the surface of the support by evaporation of the solvent in a rotary evaporator. Then the CSPs were suspended in 2-propanol and, using slurry-packing technique, packed in chromatography columns with mixture of ethanol and hexane as displacing medium at a pressure of 28~30MPa.The theoretical plate numbers of such column was about 2300 at 0.5ml/min of flow rate of mobile phase.In the second part, the enantiomers of omeprazole were separated. (l)Using the TPCC coated chiral stationary, the separation of enantiomers omeprazole by ethanol/hexane is much better than that by 2-propanol/hexane proposed by Erlandsson. The two enantiomers was baseline separated under ethanol/hexane=40/60(V/V) at 0.4ml/min flow rate. The effects of composition, flow rate of mobile phase and column temperature on the resolution was investigated. As- the flow rate and the ethanol concentration of mobile phase increase, the resolution decreases. The column temperature has little effect on the resolution(Rs), although the capacity(k') and . separation factor( a ) decrease with the increase of column temperature. The elution order of enantiomers of omeprazole was determined that the (S)-omeprazole was eluted firstly. The reference has reported that the CSP based on silica gel can not separated the enantiomers of omeprazole, but our experiment results showed that such CSP can separated the enantiomers of omeprazqle nearly to baseline although the resolution is a little poorer than that on CSP based on APS. (2)The effect of coating solvent and the weight ratio of TPCC to support on resolution was studied. It was found that tetrahydrofuran is much better than acetone as coating solvent. The capacity increases as the weight ratio of TPCC to coating support increases, but the resolution decreases dramatically. The appropriate ratio is 1:4. (3)The chromatography separation process of omeprazole was studied. The effect of the composition and flow rate of mobile phase on the throughput and energy of solvent evap...