| Enantiomers of chiral drugshave obvious differences in pharmacological activities and toxicity,which directlyaffect clinical efficacy and usage safety of drug.At present most of the chiral drugs are being used in the racemic form, by contrast, the clinical usage of single enantiomer being obtained by chemical synthesis or enantiomer separation are only for a few drugs. Thereforefurther development and research of separation of chiral drugs have a significance for improve efficiency, decrease toxicity and control the quality of drug.In this paper, synthesis of several new chiral function monomers on the basis of Acyl-L-Tryptophan(AT).A wide usage of 4 classes of drugs, which could respectively used toanti-inflammatory, antipsychotic, sedative-hypnotic and antidiabetes, including flurbiprofen, loxoprofen, pranoprofen, ibuprofen, sulpiride, cisapride, oxazepam tablets, lorazepam, pioglitazone hydrochloride, rosiglitazoneto systematically study the chromatographic separation performance of new chiral function monomers in seperating the enantiomer of chiral drugs. Comprehensive the above experimental results, discussed the seperating mechanism of high performance liquid chromatography in order to study the new function monomer which have better separation efficiency especially in inversed phase chromatography.The main research contentsare as follow:(1) The coarse product of Acyl-L-Tryptophan(AT) as reactant was respectively prepared with L-benzene ammonia alcohol and(1S,2R)-2-amino-1, 2-diphenyl ethanol to synthesize(N-[1-(2-Hydroxy-1-phenyl-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-acrylamid,HPEIEA) and(N-[1-(2-Hydroxy-1,2-diphenyl-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-acrylamide,HDEIEA). Through purification, the production rate of twochiral function monomers(HPEIEA and HDEIEA) of tryptophan-based derivative were respectively 62.5% and 60.3%. Their purity was respectively 90.5% and 91.3% which was determined by high performance liquid chromatography.The ultraviolet spectroscopy, infrared spectroscopy and proton nuclear magnetic resonance spectroscopy were used to characterize the structure of new chiral function monomers.(2) HDEIEA was used as functional monomer of molecularly imprinted polymer of R-flurbiprofen which was selected from HPEIEA and HDEIEA by ultraviolet spectroscopy and nuclear magnetic resonance hydrogenspectroscopy. The usage of dimethyl sulfoxide(DMSO)-acetonitrile as solvent andpropyl trimethoxy trimethacrylate(TRIM) as cross-linking agent to get the optimal synthetic conditions: The molar ratio of R-flurbiprofen, HDEIEA and TRIM was 1:4:20, the pore-foaming agent was 9 m L DMSO-acetonitrile(1:2) and the initiator was 60 mg azobisisobutyronitrile and then the thermopolymerization of MIP was conducted at 60℃ for 24 h. The imprinting factor could reach 1.88 and the adsorption quantity was119.31μg/g. For further application of this MIP material, it has been ultilized as material forpreparing slow-release tablets of R-flurbiprofen. The results showed that its release rate of R- flurbiprofen was 15% slower than that of normal tablets, which fully demonstrated that the R-flurbiprofen MIP could act as a good material to control the release rate.(3) HPEIEA and HDEIEA were grafted on the surface of amino-bonded silica as new chiral stationary phase HPEIEA-CSP and HDIEA-CSP to study chromatographic resolution behavior of 10 kinds of chiral drugs and the results showed that HPEIEA-CSP had noseperation effect for these 10 kinds of chiral drugs whatever in normal or reverse phase chromatography mode, while HDEIEA-CSP had some seperation effect for ibuprofen in normal phase chromatography mode and forloxoprofen, pranoprofen, sulpiride, oxazepam, lorazepamand pioglitazone inreverse phase chromatography mode. Therefore, HDEIEA-CSP had better separation effect in normal-phase chromatography, especially for pranoprofen. Its R was reached 0.85 and could be used to chiral separation of pranoprofen containing with plasma.(4)Study chromatographic resolution behavior of 10 kinds of chiral drugs by HDEIEA-CSP. Through the analysis of experimental results and their structures, a conclusion could be drown that the chiral function monomers of the benzene ring closing to alcoholic hydroxyl group and the indole ring of L-tryptophan had better chiral separation behavior. The benzene ring closing to alcoholic hydroxyl group was formed strong π-alkaline groups and had space steric effect, which played a significant role in chiral separation effect. The indole ring of L-tryptophan played the main role in forming hydrogen bond and steric-hinerance effect. It was suggested that the separation effect was best when benzene ring closing to alcoholic hydroxyl group and indole ringsimultaneously existed due to the mutual promoted effect for separation. |
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