多巴对映体的几种手性拆分方法
|
摘要
单一对映体手性药物的制备是当前国际药物研究最热门的课题之一。高效液相色谱法是应用最广泛、适用范围最宽的手性拆分技术,其中,手性流动相添加剂法拆分手性药物,由于拆分前无需衍生,操作起来更加简便,且成本较低,是进行对映体拆分及光学纯度检测的非常准确、简便的方法。手性液-液萃取法的分离体系有一定的规律可以遵循,有比较成熟的理论指导,适用范围比较宽,规模易于放大,是实现单一对映体药物的工业化制备的重要途径。中空纤维膜分离技术是近年发展起来的一种高效分离技术,克服了传统液液萃取的缺点,大大提高了分离的效率和立体选择性,受到众多研究者的重视,在日常生产生活中得到越来越广泛的应用。
本论文主要工作是采用高效液相色谱手性流动相添加剂法对多巴对映体进行定量分析;研究了手性液液萃取分离多巴对映体的最佳条件;将手性液液萃取与中空纤维膜相结合,对多巴对映体的制备性分离进行初步的研究。主要内容如下:
采用β-环糊精手性流动相添加剂法拆分多巴对映体。研究手性选择剂种类及浓度、有机改性剂种类及含量、缓冲盐种类、pH值、流速等对分离的影响,并对分离条件进行优化:流动相为甲醇/水=20/80(v/v,其中水中含β-环糊精浓度为5mmol/L),流速0.8mL/min,分离度为1.73。建立了多巴对映体的定量检测曲线。
以疏水性L-酒石酸正己酯为手性选择剂,研究了多巴对映体在水-有机溶剂两相中的萃取分配行为,建立了实验中优化的手性萃取条件:1,2-二氯乙烷为有机相溶剂,L-酒石酸正己酯浓度为0.25mmol/L,水相pH值控制在2.5,萃取温度为10℃,分离因子可达1.16。
以疏水性L-酒石酸正己酯为手性流动载体,采用中空纤维支撑液膜法萃取分离多巴对映体,考察膜相有机溶剂种类、手性流动载体浓度、料液相多巴外消旋体起始浓度、pH梯度对立体选择性分离的影响,建立优化的手性拆分条件。在多巴起始浓度为2mmol/L、L-酒石酸正己酯浓度为50mmol/L、料液相和接收相存在pH梯度时,多巴对映体能够被有效拆分,最大分离因子为1.42。
Preparative separation of chiral drugs has a great interesting potential. High performance liquid chromatography chiral mobile phase additives is the most widely used separation mothed because of its simple and low cost compared to derivative method or chiral stationary phase method. Chiral extraction is a very important method for the preparative separation of drugs enantiomers. It has some regularity and a larger application range. Hollow fiber membrane extraction is a very effective separation technology with great development. In the thesis, the dopa enantiomers were separated and determinated by method of chiral mobile phase additives; the optimal parameters of resolution of dopa by chiral extraction were investigated; combined with chiral extraction, the resolution of dopa enantiomers by hollow fiber supported liquid membrane extraction were further investigated. The main content and results can be summarized as following:
A method for chiral mobile phase additives enantiomeric resolution of racemic dopa has been established withβ-cyclodextrin as the chiral selector. The effects of type and concentration ofβ-cyclodextrin, sorts of organic solvents, buffer type and pH, velocity of mobile phase were investigated in detail, respectively. The appropriate conditions was: the mobile phase composed of methanol/water = 20/80 (v/v, in which containing 5mmol/Lβ-cyclodextrin), 0.8mL/min, the baseline separation could be obtained with resolution of 1.73. The quantitative ability of chiral mobile phase additives also be researched.
The distribution behavior of dopa enantiomers was examined in the aqueous and organic phase containing hydrophobic L-di-n-hexyl-L-tartaric ester as chiral selector, in order to establish the optima chiral extraction conditions in this experiment. The influence of organic solvent, concentration of chiral selector, pH in aqueous phase and extraction temperature on performances of chiral resolution were investigated. The results show that the separation factor is 1.16 under the optima conditions of pH2.5 in aqueous phase with 0.25mmol/L L-di-n-hexyl-L-tartaric ester.
Hollow fiber supported liquid membrane extraction containing hydrophobic L-di-n-hexyl-L-tartaric ester as chiral carrier was used for resolution of racemic dopa, the optima chiral separation conditions were established in this experiment. The effects of concentration of dopa, concentration of chiral carrier, pH in the strip phase, velocity of fluent on the extraction performance were investigated. The results show that the method of resolution of racemic dopa was effectively established under the optimal chiral separation conditions of 2mmol/Ldopa, 50mmol/L L-di-n-hexyl-L- tartaric ester, pH2.5 in the feed phase and pH7.5 in the strip phase. The separation factor is 1.42.
本论文主要工作是采用高效液相色谱手性流动相添加剂法对多巴对映体进行定量分析;研究了手性液液萃取分离多巴对映体的最佳条件;将手性液液萃取与中空纤维膜相结合,对多巴对映体的制备性分离进行初步的研究。主要内容如下:
采用β-环糊精手性流动相添加剂法拆分多巴对映体。研究手性选择剂种类及浓度、有机改性剂种类及含量、缓冲盐种类、pH值、流速等对分离的影响,并对分离条件进行优化:流动相为甲醇/水=20/80(v/v,其中水中含β-环糊精浓度为5mmol/L),流速0.8mL/min,分离度为1.73。建立了多巴对映体的定量检测曲线。
以疏水性L-酒石酸正己酯为手性选择剂,研究了多巴对映体在水-有机溶剂两相中的萃取分配行为,建立了实验中优化的手性萃取条件:1,2-二氯乙烷为有机相溶剂,L-酒石酸正己酯浓度为0.25mmol/L,水相pH值控制在2.5,萃取温度为10℃,分离因子可达1.16。
以疏水性L-酒石酸正己酯为手性流动载体,采用中空纤维支撑液膜法萃取分离多巴对映体,考察膜相有机溶剂种类、手性流动载体浓度、料液相多巴外消旋体起始浓度、pH梯度对立体选择性分离的影响,建立优化的手性拆分条件。在多巴起始浓度为2mmol/L、L-酒石酸正己酯浓度为50mmol/L、料液相和接收相存在pH梯度时,多巴对映体能够被有效拆分,最大分离因子为1.42。
Preparative separation of chiral drugs has a great interesting potential. High performance liquid chromatography chiral mobile phase additives is the most widely used separation mothed because of its simple and low cost compared to derivative method or chiral stationary phase method. Chiral extraction is a very important method for the preparative separation of drugs enantiomers. It has some regularity and a larger application range. Hollow fiber membrane extraction is a very effective separation technology with great development. In the thesis, the dopa enantiomers were separated and determinated by method of chiral mobile phase additives; the optimal parameters of resolution of dopa by chiral extraction were investigated; combined with chiral extraction, the resolution of dopa enantiomers by hollow fiber supported liquid membrane extraction were further investigated. The main content and results can be summarized as following:
A method for chiral mobile phase additives enantiomeric resolution of racemic dopa has been established withβ-cyclodextrin as the chiral selector. The effects of type and concentration ofβ-cyclodextrin, sorts of organic solvents, buffer type and pH, velocity of mobile phase were investigated in detail, respectively. The appropriate conditions was: the mobile phase composed of methanol/water = 20/80 (v/v, in which containing 5mmol/Lβ-cyclodextrin), 0.8mL/min, the baseline separation could be obtained with resolution of 1.73. The quantitative ability of chiral mobile phase additives also be researched.
The distribution behavior of dopa enantiomers was examined in the aqueous and organic phase containing hydrophobic L-di-n-hexyl-L-tartaric ester as chiral selector, in order to establish the optima chiral extraction conditions in this experiment. The influence of organic solvent, concentration of chiral selector, pH in aqueous phase and extraction temperature on performances of chiral resolution were investigated. The results show that the separation factor is 1.16 under the optima conditions of pH2.5 in aqueous phase with 0.25mmol/L L-di-n-hexyl-L-tartaric ester.
Hollow fiber supported liquid membrane extraction containing hydrophobic L-di-n-hexyl-L-tartaric ester as chiral carrier was used for resolution of racemic dopa, the optima chiral separation conditions were established in this experiment. The effects of concentration of dopa, concentration of chiral carrier, pH in the strip phase, velocity of fluent on the extraction performance were investigated. The results show that the method of resolution of racemic dopa was effectively established under the optimal chiral separation conditions of 2mmol/Ldopa, 50mmol/L L-di-n-hexyl-L- tartaric ester, pH2.5 in the feed phase and pH7.5 in the strip phase. The separation factor is 1.42.
引文
[1]尤启冬,林国强.手性药物-研究与应用[M].北京:化学工业出版社, 2004,149-177.
[2] Mitscher L A, Sharma P N, Chun-Daniel T W, et al. Chiral DNA gyrase inhibitors.2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluro-3-methyl-10(4-methyl-1- piperacinyl)-7-oxo-2, 3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6carboxylic acid (ofloxaci-n) [J]. J.Med.Chem., 1987,30(12):2283-2286.
[3] Knabe J. The enantioselectivity of drugs[J]. Arzneim-Forsch., 1989, 39(11):1379-1384.
[4] Middlefell V C, Price T L. 5-HT3 receptor agonism may be responsible for the emetic effect of zacopride in the ferret[J]. Br.J.Pharmacol., 1991,103:1011-1012.
[5] Blaschke G, Kraft H P, Fickentscher K, et al. Chromatographic racemic separation of thalidomide and teratogenic activity of its enantiomers[J]. Arzneim-Forsch., 1979, 29(10):1640-1642.
[6]尤田耙.手性化合物的现代研究方法[M].合肥:中国科学技术大学出版社,1993.
[7]黄蓓,杨立荣,吴坚平.手性拆分技术的工业应用[J].化工进展,2002,21(36):375-380.
[8]王德才,陆伟,周国林等.酒石酸噻吗洛尔的合成及其降眼压作用的初步研究[J].中国药物化学杂志,1994,4(4):289-291.
[9] Kaupp G. Resolution of Racemates by Distillation with Inclusion Compounds[J]. Angew.Chem. Int.Ed., 1994, 33:728-729.
[10] Tanaka K, Okada T, Toda F. Separation of the enantiomers of 2,2-dihydroxy-1,1-binaphthyl and10,10-dithydroxy-9,9-biphenanthryl by complextion with N-alhylcinchonidinium halides[J]. Angew.Chem.Int.Ed., 1993,32:1147-1148.
[11] Toda F, Tanaka K, Stein Z, et al. Optical resolution of binaphthyl and biphenanthnryl diols by inclusion crystallization with N-alhylcinchonidinium halides.Structural characterization of the resolved materials[J]. J.Org.Chem., 1994,59:5784-5751.
[12]邓金根,迟永祥,朱槿等.化学拆分的新方法研究[J].合成化学,1999,7(4):340-345.
[13] Vries T, Wynberg H, Echte E, et al. The family approach to the resolution of racemates[J]. AngewChem Int Ed, 1998, 37(17):2349-2354.
[14] Bevinakatti H S, Benerji A A. Practical chemoenzymatic synthesis of both enantiomers of propranolol[J]. J.Org.Chem., 1991,56(18):5372-5375.
[15] Gihani M T, Williams J M. Dynamic kinetic resolution[J]. Curr.Opin.Chem.Biol. 1999, 3(1): 11-15.
[16] Allenmark S. Chromatographic Enantioseparation:Methods and Applications[M].Chichester, West Sussex:Ellis Horwood,1988.
[17]何敏,赵书林,陈洁.青霉胺对映体的毛细管电泳手性分离及应用研究[J].分析化学,2006,34 (5):655-658.
[18] Heike H, Martin G S, Gerald G.Chiral separation of amino acids and glycyl dipeptides by chiral ligand-exchange capillary electrophoresis comparing Cu(II), Co(II), Ni(II) and Zn(II) complexes of three different sugar acids[J]. Journal of Chromatography A, 2008, 1204:210–218.
[19] Blanco M, Coello J, Iturriaga H, et al. Chiral and nonchiral determination of ketoprofen in pharmaceuticals by capillary zone electrophoresis[J].Journal of Chromatography A, 1998,799: 301-307.
[20] Williams K L, Sander L C. Enantiomer separations on chiral stationary phases in supercritical fluid chromatography[J]. J.Chromatogr. A, 1997, 785:149-158.
[21]于金刚,黄可龙,焦飞鹏,等.β-环糊精固载硅胶薄层色谱法拆分盐酸克伦特罗对映体[J].色谱,2005,23(4):431-433.
[22]周志强,张红雁,于兆文,等.高效液相色谱法对外消旋体药物的拆分[J].分析测试技术与仪器.1998,4(1):1-7.
[23] Bressolle F, Audran M, Pham T-N, et al. Cyclodextrins and enantiomeric separation of drugs by liquid chromatography and capillary electrophoresis:basic principles and new developments[J]. J Chromatogr B Biomed Appl., 1996, 687(2):303-336.
[24] Piras P, Roussel C, Pierrot-Sanders J. Reviewing mobile phases used on Chiralcel OD through an application of data mining tools to CHIRBASE database[J]. J Chromatogr A, 2001,906(1-2): 443-458.
[25] Marinko P, ?eljko D,Nikola B. Optimization of gas chromatographic method for the enantioseparation of arylpropionic non-steroidal anti-inflammatory drug methyl esters[J]. Journal of Pharmaceutical and Biomedical Analysis, 2005, 39(3-4):531–534.
[26] Schurig V. Separation of enantiomers by gas chromatography[J]. J. Chromatogr A, 2001, 906 (1-2):275-299.
[27]尹明明,史雪岩,边庆华,等.毛细管气相色谱手性固定相2,6-O-烯丙基-3-O-酰基-β-环糊精拆分环丙烷衍生物对映体[J].分析化学,2005,33(12):1747-1749.
[28]黄姣,陈小明,罗和安,等.一种β-环糊精衍生物作为手性固定相的研究[J].分析科学学报, 2005, 21(6):646-648.
[29]史雪岩,王敏,傅若农.环糊精衍生物气相色谱手性固定相研究进展[J].分析测试学报, 2001,20(6):75-79.
[30]周美杨,凌云,申刚义,等.新型噻吩杂环衍生化β-环糊精手性固定相合成及其气相色谱分离性能[J].高等学校化学学报,2008,29(3):493-497.
[31]赵艳芳,赵亮,明永飞,等.配体交换毛细管区带电泳拆分未衍生化氨基酸[J].分析化学,2006,34:S87-S90.
[32]赵艳芳,柳春晖,张红丽,等.手性配体交换毛细管电泳分离并拆分α-羟基酸对映体的研究[J].分析化学,2005,33(7):955-957.
[33] Schmid M G, Lecnik O, Sitte U, et al. Application of ligand-exchange capillary electrophorersis to the chiral separation of a-hydroxy acids and b-blockers[J]. Journal of Chromatography A, 2000, 875:307-314.
[34] Zheng Zhi-Xia, Lin Jin-Ming, Qu Feng. Chiral separation of underivatized and dansyl amino acids by ligand-exchange micellar electrokinetic capillary chromatography using a copper(II)–L- valine complex as selector[J]. Journal of Chromatography A, 2003, 1007:189–196.
[35]范瑞芳,史雪岩,傅若农,等.应用二元环糊精体系的毛细管区带电泳手性拆分.分析化学,2003,31(5):559-561.
[36]侯经国,何天稀,刘慧玲,等.红霉素作为毛细管区带电泳手性选择剂拆分两种联苯双酯类药物[J].色谱,2003,21(1):72-75.
[37] Nishi H, Terabe S. Micellar electrokinetic chromatography perspectives in drug analysis[J]. J Chromatogr A, 1996, 735:3-27.
[38] Dey J, Mohanty A, Roy S, et al. Cationic vesicles as chiral selector for enantioseparations of nonsteroidal antiinflammatory drugs by micellar electrokinetic chromatography[J]. Journal of Chromatography A, 2004, 1048(1):127-132.
[39] Cruzado I D, Vigh G. Chiral separation by capillary electrophoresis using cyclodextrin- containing gels[J].J Chromatogr,1992,608:421-425.
[40] Li S, Lloyd D K. Packed-capillary electrochromatographic separation of the enantiomers of neutral and anionic compounds usingβ-cyclodextrins as a chiral selector, effect of operating parameters and comparison with free-solution capillary electrophoresis[J]. J Chromatogr, 1994, 666: 321-335.
[41] Pesek J J, Matyska M T, Menezes S. Chiral separation by open tubular capillary electrokinetic chromatography[J]. J Chromatogr A, 1999, 853(1-2):151-158.
[42] Petersson P, Markides K E. Chiral separation performed by supercritical fluid chromatography[J]. J Chromatogr A, 1994, 666:381-394.
[43] Del Nozal M J,Toribio L,Bernal J L, et a1. Separation of albendazole sulfoxide enantiomers by chiral supercritical-fluid chromatography[J].J Biochem Biophys Methods,2002,54(1-3):339-345.
[44]朱全红,邓芹英,曾陇梅.手性药物的薄层色谱拆分[J].药物分析杂志, 2002,22( 2):155-158.
[45] Caldwell J. High-resolution thin-layer chromatography of gangliosides[J]. J Chromatogr A, 1996, 719:3-25.
[46]郝爱友,童林荟,张复生.β-环糊精为TLC流动相添加剂分离对映体[J].化学通报,1996,(4):16-18.
[47]曾苏.高效液相色谱手性试剂衍生化法及其应用[J].色谱,1994,12(6):406-410.
[48] Bi Hongyan, Weng Xuexiang, Qu Haiyun, et al. Strategy for Allosteric Analysis Based on Protein-Patterned Stationary Phase in Microfluidic Chip[J]. Journal of Proteome Research, 2005, 4(6):2154-2160.
[49]周志强,王鹏,江树人,等.涂敷型淀粉类液相色谱手性固定相对丙烯菊醇对映体的拆分[J].色谱,2003,21(1):44-45.
[50]陈小明,毛希琴,张曾子,等.键合型纤维素类手性固定相高效液相色谱法拆分对映异构体[J].化学学报,2002,60(1):93-97.
[51] Yuan zhi,He binglin. Preparation of polyvinylamine ligand exchange resin grafted with L-prolin[J]. Chinese science bulletin. 1991, 36(11):903-936.
[52]周爱玲,王秀玲,黄君眠,等.新型衍生化β-环糊精键合硅胶手性固定相的合成与性能研究[J].高等学校化学学报,2003,24(9):1610-1614.
[53]黄天宝,吴邦桂,龙远德,等.β-环糊精键合固定相的制备和评价[J].分析化学,1991,19(11): 1257-1260.
[54]丁国生,唐安娜,王俊德.替考拉宁键合手性固定相高效液相色谱法直接拆分泮托拉唑钠对映体[J].色谱,2006,24(1):46-48.
[55] Allenmark S, Bomgren B, Boren H. Direct liquid chromatographic separation of enantiomers on immobilized protein statioary phases[J]. J Chromatogr, 1983, 264:63-68.
[56] Kirkland K M, Neilson K L, McCombs D A. Comparison of a new ovomucoid and a second- generationα1-acid glycoprotein-based chiral column for the direct high-performance liquid chromatography resolution of drug enantiomers[J]. J Chromatogr, 1991, 545:43-58.
[57] Klemisch W,Von Odenberg A. HPLC separation of the enantiomers of an experimental antipsychotic drug (Cl-943) on Chiralcel OD and OJ columns[J]. J High Resolution Chromatography, 1992, 25:40.
[58]姚彤炜,曾苏,丁海青.环糊精类手性流动相添加剂及其在药物分析中的应用[J].色谱,1996,14(2): 106-110.
[59]李桂银,黄可龙,蒋玉仁,等.手性配体高效液相色谱法拆分扁桃酸对映体的热力学性质[J].应用化学,2008,25(1):9-12.
[60] Negawa M, Shoji F. Optical resolution by simulated moving-bed adsorption technology[J]. J.Chromatogr., 1992,590:113-117.
[61] Prelog V V, Stojanac ?, Kov evi K.über die Enantiomerentrennung durch Verteilungzwischen flüssigen Phasen. 3. Mitteilung. Selektivit?t der lipophilen Weins?ureester für chirale Ammonium-Salze verschiedener Konstitution und Konfiguration[J]. Helv.Chim.Acta.,1983,66 (7): 2279-2284.
[62]岑仲浙,蔡水洪.手性溶剂萃取麻黄碱差向异构体[J].化工学报,2000,51(3):418-420.
[63] Takeuchi T, Horikawa R, Tanimura T. Enantioselective solvent extraction of neutral DL-Amino acids in two-phase systems containing N-n-alkyl-L-proline derivative and copper(Ⅱ)ion[J]. Anal. Chem., 1984, 56(7):1152-1155.
[64]唐课文,周春山,蒋新宇.支持液膜双有机相萃取分离氧氟沙星外消旋体[J].中国科学,2002,32 (6) :491-496.
[65] Miyako E , Maruyama T , Kamiya N , et al . Enzyme-facilitated enantioselective transport of (S)–ibuprofen through a supported liquid membrane based on ionic liquids[J].Chemical Communications, 2003,23:2926 -2927.
[66] Keurentjes J T, Nabuurs L J, Vegter E A. Liquid Membrane Technology for the Separation of Racemic Mixtures[J].Journal of Membrane Science, 1996,113(2):351-360.
[67] Wieczorek P. Factors Influencing the Transport of Tryptophan Hydrochloride Through Supported Liquid Membranes Containing Macrocyclic Carriers[J]. Journal of Membrane Science, 1997, 127(1):87-92.
[68] Pickering P J, Chaudhuri J B. Enantioselective Extraction of (D)-Phenylalanine from Racemic (D/L)-Phenylalanine Using Chiral Emulsion Liquid Membranes[J]. Journal of Membrane Science, 1997, 127(2):115-130.
[69] Dzygiel P, Wieczorek P. Extraction of amino acids with emulsion liquid membranes using industrial surfactants and lecithin as stabilizers[J]. Journal of Membrane Science, 2000,172(1-2): 223-232.
[70] Pickering P J, Chaudhuri J B. Emulsion liquid membranes for chiral separations: Selective extraction of rac-phenylalanine enantiomers[J]. Chirality, 1997, 9(3):261-267.
[71]彭霞辉,黄可龙,于金刚.乳状液膜手性萃取分离氧氟沙星外消旋体[J].中南大学学报,2006, 37(3):527-531.
[72] Stella D, Calzado J A, Girelli A M, et al. Liquid membranes for chiral separations. Application of cinchonidine as a chiral carrier[J]. J Sep Sci, 2002, 25(4):229-238.
[73] Breccia P, Van G M, Perez-Fernandez R, et al. Guanidinium Receptors as Enantioselective Amino Acid Membrane Carriers[J].J Am Chem Soc, 2003,125(27): 8270-8284.
[74]黄可龙,胡卫国,焦飞鹏等.厚体液膜拆分克伦特罗外消旋体及其动力学研究[J].分析化学, 2007,35(4):479-483.
[75] Krieg H M, Lotter J , Keizer K, et al. Enrichment of chlorthalidone enantiomers by an aqueous bulk liquid membrane containing beta-cyclodextrin[J]. Journal of Membrane Science, 2000, 167(1): 33-45.
[76] Zhang Lijin, Song Meifang, Tian Qin, et al. Chiral separation of l,d-tyrosine and l,d-tryptophan by ct DNA[J]. Separation and Purification Technology, 2007, 55(3):388-391.
[77] Romero J, Zydney A. Chiral separations using ultrafiltration with a stereoselective binding agent[J]. Sep Sci Technol, 2001, 36(7):1575-1594.
[78] Lakshmi B B , Martin C R. Enantiosparation using apoenzymes immobilized in a porous polymeric membrane[J]. Nature, 1997, 388:758-760.
[79] Ito H, Nakamura M, Saito K. Comparison of l -tryptophan binding capacity of BSA captured by a polymer brush with that of BSA adsorbed onto a gel network[J]. J Chromatogr A, 2001, 925(1-2):41-47.
[80] Matsuoka Y, Kanda N, Lee Y M. Chiral separation of phenylalanine in ultrafiltration through DNA-immobilized chitosan membranes[J].Journal of Membrane Science,2006,280(1-2):116- 123.
[81]邴乃慈,许振良,王学军,等.左氧氟沙星分子印迹膜固相萃取选择性分离氧氟沙星[J].华东理工大学学报,2007,33(2):163-166.
[82] Yoshikawa M, Izumi J, Kitao T. Alternative molecular imprinting, a facile way to introduce chrial recgnition sites[J]. React.Funct Polym, 1999, 42 (1):93-102.
[83] Yoshikawa M, Ooi T, Izumi J. Novel membrane materials having EEE derivatives as a chiral recognition site[J]. EuroPolym J, 2001,37(2):335-342.
[84] Sarac S,Chankvetadze B,Blaschke G. Enantioseparation of 3,4-dihydroxyphenylalanine and 2-hydrazino-2-methyl-3-(3,4-dihydroxyphenyl)propanoic acid by capillary electrophoresis using cyclodextrins[J]. Journal of Chromatography A, 2000, 875:379-387.
[85] Maruszak W, Trojanowicz M, Margasinska M, et al. Application of carboxymethyl-β- cyclodextrin as a chiral selector in capillary electrophoresis for enantiomer separation of selected neurotransmitters[J]. Journal of Chromatography A, 2001,926 (2):327-336.
[86] Lou X W, Liu X L, Sheng Y F. et al. Direct enantiomeric separation of phenylalanine, DOPA and their intermediates by supercritical fluid chromatography[J]. Journal of Chromatography A, 1992, 605:103-107.
[87] Shen J S, Zhao S L. Enantiomeric separation of naphthalene-2,3-dicarboxaldehyde derivatized dl-3,4-dihydroxyphenylalanine and optical purity analysis of l-3,4-dihydroxyphenylalanine drug by cyclodextrin-modified micellar electrokinetic chromatography[J]. Journal of Chromatography A, 2004, 1059:209-214.
[88] Claudia B, Ulrike H. Enantioseparation of dopa and related compounds by cyclodextrin-modified microemulsion electrokinetic chromatography[J]. Journal of Chromatography A, 2008, 1204:191- 196.
[89] Wu Guang, Mario F. Hydrogen bonding as a possible interaction for the chiral separation of DL- dopa and DL-3-O-methyl-dopa in a chiral teicoplanin column[J]. Il Farmaco, 1999, 54:188-190.
[90]陈国斌,唐课文,陈铁花,等. L-酒石酸正己酯的合成[J].合成化学,2004,12:207-209.
[2] Mitscher L A, Sharma P N, Chun-Daniel T W, et al. Chiral DNA gyrase inhibitors.2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluro-3-methyl-10(4-methyl-1- piperacinyl)-7-oxo-2, 3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6carboxylic acid (ofloxaci-n) [J]. J.Med.Chem., 1987,30(12):2283-2286.
[3] Knabe J. The enantioselectivity of drugs[J]. Arzneim-Forsch., 1989, 39(11):1379-1384.
[4] Middlefell V C, Price T L. 5-HT3 receptor agonism may be responsible for the emetic effect of zacopride in the ferret[J]. Br.J.Pharmacol., 1991,103:1011-1012.
[5] Blaschke G, Kraft H P, Fickentscher K, et al. Chromatographic racemic separation of thalidomide and teratogenic activity of its enantiomers[J]. Arzneim-Forsch., 1979, 29(10):1640-1642.
[6]尤田耙.手性化合物的现代研究方法[M].合肥:中国科学技术大学出版社,1993.
[7]黄蓓,杨立荣,吴坚平.手性拆分技术的工业应用[J].化工进展,2002,21(36):375-380.
[8]王德才,陆伟,周国林等.酒石酸噻吗洛尔的合成及其降眼压作用的初步研究[J].中国药物化学杂志,1994,4(4):289-291.
[9] Kaupp G. Resolution of Racemates by Distillation with Inclusion Compounds[J]. Angew.Chem. Int.Ed., 1994, 33:728-729.
[10] Tanaka K, Okada T, Toda F. Separation of the enantiomers of 2,2-dihydroxy-1,1-binaphthyl and10,10-dithydroxy-9,9-biphenanthryl by complextion with N-alhylcinchonidinium halides[J]. Angew.Chem.Int.Ed., 1993,32:1147-1148.
[11] Toda F, Tanaka K, Stein Z, et al. Optical resolution of binaphthyl and biphenanthnryl diols by inclusion crystallization with N-alhylcinchonidinium halides.Structural characterization of the resolved materials[J]. J.Org.Chem., 1994,59:5784-5751.
[12]邓金根,迟永祥,朱槿等.化学拆分的新方法研究[J].合成化学,1999,7(4):340-345.
[13] Vries T, Wynberg H, Echte E, et al. The family approach to the resolution of racemates[J]. AngewChem Int Ed, 1998, 37(17):2349-2354.
[14] Bevinakatti H S, Benerji A A. Practical chemoenzymatic synthesis of both enantiomers of propranolol[J]. J.Org.Chem., 1991,56(18):5372-5375.
[15] Gihani M T, Williams J M. Dynamic kinetic resolution[J]. Curr.Opin.Chem.Biol. 1999, 3(1): 11-15.
[16] Allenmark S. Chromatographic Enantioseparation:Methods and Applications[M].Chichester, West Sussex:Ellis Horwood,1988.
[17]何敏,赵书林,陈洁.青霉胺对映体的毛细管电泳手性分离及应用研究[J].分析化学,2006,34 (5):655-658.
[18] Heike H, Martin G S, Gerald G.Chiral separation of amino acids and glycyl dipeptides by chiral ligand-exchange capillary electrophoresis comparing Cu(II), Co(II), Ni(II) and Zn(II) complexes of three different sugar acids[J]. Journal of Chromatography A, 2008, 1204:210–218.
[19] Blanco M, Coello J, Iturriaga H, et al. Chiral and nonchiral determination of ketoprofen in pharmaceuticals by capillary zone electrophoresis[J].Journal of Chromatography A, 1998,799: 301-307.
[20] Williams K L, Sander L C. Enantiomer separations on chiral stationary phases in supercritical fluid chromatography[J]. J.Chromatogr. A, 1997, 785:149-158.
[21]于金刚,黄可龙,焦飞鹏,等.β-环糊精固载硅胶薄层色谱法拆分盐酸克伦特罗对映体[J].色谱,2005,23(4):431-433.
[22]周志强,张红雁,于兆文,等.高效液相色谱法对外消旋体药物的拆分[J].分析测试技术与仪器.1998,4(1):1-7.
[23] Bressolle F, Audran M, Pham T-N, et al. Cyclodextrins and enantiomeric separation of drugs by liquid chromatography and capillary electrophoresis:basic principles and new developments[J]. J Chromatogr B Biomed Appl., 1996, 687(2):303-336.
[24] Piras P, Roussel C, Pierrot-Sanders J. Reviewing mobile phases used on Chiralcel OD through an application of data mining tools to CHIRBASE database[J]. J Chromatogr A, 2001,906(1-2): 443-458.
[25] Marinko P, ?eljko D,Nikola B. Optimization of gas chromatographic method for the enantioseparation of arylpropionic non-steroidal anti-inflammatory drug methyl esters[J]. Journal of Pharmaceutical and Biomedical Analysis, 2005, 39(3-4):531–534.
[26] Schurig V. Separation of enantiomers by gas chromatography[J]. J. Chromatogr A, 2001, 906 (1-2):275-299.
[27]尹明明,史雪岩,边庆华,等.毛细管气相色谱手性固定相2,6-O-烯丙基-3-O-酰基-β-环糊精拆分环丙烷衍生物对映体[J].分析化学,2005,33(12):1747-1749.
[28]黄姣,陈小明,罗和安,等.一种β-环糊精衍生物作为手性固定相的研究[J].分析科学学报, 2005, 21(6):646-648.
[29]史雪岩,王敏,傅若农.环糊精衍生物气相色谱手性固定相研究进展[J].分析测试学报, 2001,20(6):75-79.
[30]周美杨,凌云,申刚义,等.新型噻吩杂环衍生化β-环糊精手性固定相合成及其气相色谱分离性能[J].高等学校化学学报,2008,29(3):493-497.
[31]赵艳芳,赵亮,明永飞,等.配体交换毛细管区带电泳拆分未衍生化氨基酸[J].分析化学,2006,34:S87-S90.
[32]赵艳芳,柳春晖,张红丽,等.手性配体交换毛细管电泳分离并拆分α-羟基酸对映体的研究[J].分析化学,2005,33(7):955-957.
[33] Schmid M G, Lecnik O, Sitte U, et al. Application of ligand-exchange capillary electrophorersis to the chiral separation of a-hydroxy acids and b-blockers[J]. Journal of Chromatography A, 2000, 875:307-314.
[34] Zheng Zhi-Xia, Lin Jin-Ming, Qu Feng. Chiral separation of underivatized and dansyl amino acids by ligand-exchange micellar electrokinetic capillary chromatography using a copper(II)–L- valine complex as selector[J]. Journal of Chromatography A, 2003, 1007:189–196.
[35]范瑞芳,史雪岩,傅若农,等.应用二元环糊精体系的毛细管区带电泳手性拆分.分析化学,2003,31(5):559-561.
[36]侯经国,何天稀,刘慧玲,等.红霉素作为毛细管区带电泳手性选择剂拆分两种联苯双酯类药物[J].色谱,2003,21(1):72-75.
[37] Nishi H, Terabe S. Micellar electrokinetic chromatography perspectives in drug analysis[J]. J Chromatogr A, 1996, 735:3-27.
[38] Dey J, Mohanty A, Roy S, et al. Cationic vesicles as chiral selector for enantioseparations of nonsteroidal antiinflammatory drugs by micellar electrokinetic chromatography[J]. Journal of Chromatography A, 2004, 1048(1):127-132.
[39] Cruzado I D, Vigh G. Chiral separation by capillary electrophoresis using cyclodextrin- containing gels[J].J Chromatogr,1992,608:421-425.
[40] Li S, Lloyd D K. Packed-capillary electrochromatographic separation of the enantiomers of neutral and anionic compounds usingβ-cyclodextrins as a chiral selector, effect of operating parameters and comparison with free-solution capillary electrophoresis[J]. J Chromatogr, 1994, 666: 321-335.
[41] Pesek J J, Matyska M T, Menezes S. Chiral separation by open tubular capillary electrokinetic chromatography[J]. J Chromatogr A, 1999, 853(1-2):151-158.
[42] Petersson P, Markides K E. Chiral separation performed by supercritical fluid chromatography[J]. J Chromatogr A, 1994, 666:381-394.
[43] Del Nozal M J,Toribio L,Bernal J L, et a1. Separation of albendazole sulfoxide enantiomers by chiral supercritical-fluid chromatography[J].J Biochem Biophys Methods,2002,54(1-3):339-345.
[44]朱全红,邓芹英,曾陇梅.手性药物的薄层色谱拆分[J].药物分析杂志, 2002,22( 2):155-158.
[45] Caldwell J. High-resolution thin-layer chromatography of gangliosides[J]. J Chromatogr A, 1996, 719:3-25.
[46]郝爱友,童林荟,张复生.β-环糊精为TLC流动相添加剂分离对映体[J].化学通报,1996,(4):16-18.
[47]曾苏.高效液相色谱手性试剂衍生化法及其应用[J].色谱,1994,12(6):406-410.
[48] Bi Hongyan, Weng Xuexiang, Qu Haiyun, et al. Strategy for Allosteric Analysis Based on Protein-Patterned Stationary Phase in Microfluidic Chip[J]. Journal of Proteome Research, 2005, 4(6):2154-2160.
[49]周志强,王鹏,江树人,等.涂敷型淀粉类液相色谱手性固定相对丙烯菊醇对映体的拆分[J].色谱,2003,21(1):44-45.
[50]陈小明,毛希琴,张曾子,等.键合型纤维素类手性固定相高效液相色谱法拆分对映异构体[J].化学学报,2002,60(1):93-97.
[51] Yuan zhi,He binglin. Preparation of polyvinylamine ligand exchange resin grafted with L-prolin[J]. Chinese science bulletin. 1991, 36(11):903-936.
[52]周爱玲,王秀玲,黄君眠,等.新型衍生化β-环糊精键合硅胶手性固定相的合成与性能研究[J].高等学校化学学报,2003,24(9):1610-1614.
[53]黄天宝,吴邦桂,龙远德,等.β-环糊精键合固定相的制备和评价[J].分析化学,1991,19(11): 1257-1260.
[54]丁国生,唐安娜,王俊德.替考拉宁键合手性固定相高效液相色谱法直接拆分泮托拉唑钠对映体[J].色谱,2006,24(1):46-48.
[55] Allenmark S, Bomgren B, Boren H. Direct liquid chromatographic separation of enantiomers on immobilized protein statioary phases[J]. J Chromatogr, 1983, 264:63-68.
[56] Kirkland K M, Neilson K L, McCombs D A. Comparison of a new ovomucoid and a second- generationα1-acid glycoprotein-based chiral column for the direct high-performance liquid chromatography resolution of drug enantiomers[J]. J Chromatogr, 1991, 545:43-58.
[57] Klemisch W,Von Odenberg A. HPLC separation of the enantiomers of an experimental antipsychotic drug (Cl-943) on Chiralcel OD and OJ columns[J]. J High Resolution Chromatography, 1992, 25:40.
[58]姚彤炜,曾苏,丁海青.环糊精类手性流动相添加剂及其在药物分析中的应用[J].色谱,1996,14(2): 106-110.
[59]李桂银,黄可龙,蒋玉仁,等.手性配体高效液相色谱法拆分扁桃酸对映体的热力学性质[J].应用化学,2008,25(1):9-12.
[60] Negawa M, Shoji F. Optical resolution by simulated moving-bed adsorption technology[J]. J.Chromatogr., 1992,590:113-117.
[61] Prelog V V, Stojanac ?, Kov evi K.über die Enantiomerentrennung durch Verteilungzwischen flüssigen Phasen. 3. Mitteilung. Selektivit?t der lipophilen Weins?ureester für chirale Ammonium-Salze verschiedener Konstitution und Konfiguration[J]. Helv.Chim.Acta.,1983,66 (7): 2279-2284.
[62]岑仲浙,蔡水洪.手性溶剂萃取麻黄碱差向异构体[J].化工学报,2000,51(3):418-420.
[63] Takeuchi T, Horikawa R, Tanimura T. Enantioselective solvent extraction of neutral DL-Amino acids in two-phase systems containing N-n-alkyl-L-proline derivative and copper(Ⅱ)ion[J]. Anal. Chem., 1984, 56(7):1152-1155.
[64]唐课文,周春山,蒋新宇.支持液膜双有机相萃取分离氧氟沙星外消旋体[J].中国科学,2002,32 (6) :491-496.
[65] Miyako E , Maruyama T , Kamiya N , et al . Enzyme-facilitated enantioselective transport of (S)–ibuprofen through a supported liquid membrane based on ionic liquids[J].Chemical Communications, 2003,23:2926 -2927.
[66] Keurentjes J T, Nabuurs L J, Vegter E A. Liquid Membrane Technology for the Separation of Racemic Mixtures[J].Journal of Membrane Science, 1996,113(2):351-360.
[67] Wieczorek P. Factors Influencing the Transport of Tryptophan Hydrochloride Through Supported Liquid Membranes Containing Macrocyclic Carriers[J]. Journal of Membrane Science, 1997, 127(1):87-92.
[68] Pickering P J, Chaudhuri J B. Enantioselective Extraction of (D)-Phenylalanine from Racemic (D/L)-Phenylalanine Using Chiral Emulsion Liquid Membranes[J]. Journal of Membrane Science, 1997, 127(2):115-130.
[69] Dzygiel P, Wieczorek P. Extraction of amino acids with emulsion liquid membranes using industrial surfactants and lecithin as stabilizers[J]. Journal of Membrane Science, 2000,172(1-2): 223-232.
[70] Pickering P J, Chaudhuri J B. Emulsion liquid membranes for chiral separations: Selective extraction of rac-phenylalanine enantiomers[J]. Chirality, 1997, 9(3):261-267.
[71]彭霞辉,黄可龙,于金刚.乳状液膜手性萃取分离氧氟沙星外消旋体[J].中南大学学报,2006, 37(3):527-531.
[72] Stella D, Calzado J A, Girelli A M, et al. Liquid membranes for chiral separations. Application of cinchonidine as a chiral carrier[J]. J Sep Sci, 2002, 25(4):229-238.
[73] Breccia P, Van G M, Perez-Fernandez R, et al. Guanidinium Receptors as Enantioselective Amino Acid Membrane Carriers[J].J Am Chem Soc, 2003,125(27): 8270-8284.
[74]黄可龙,胡卫国,焦飞鹏等.厚体液膜拆分克伦特罗外消旋体及其动力学研究[J].分析化学, 2007,35(4):479-483.
[75] Krieg H M, Lotter J , Keizer K, et al. Enrichment of chlorthalidone enantiomers by an aqueous bulk liquid membrane containing beta-cyclodextrin[J]. Journal of Membrane Science, 2000, 167(1): 33-45.
[76] Zhang Lijin, Song Meifang, Tian Qin, et al. Chiral separation of l,d-tyrosine and l,d-tryptophan by ct DNA[J]. Separation and Purification Technology, 2007, 55(3):388-391.
[77] Romero J, Zydney A. Chiral separations using ultrafiltration with a stereoselective binding agent[J]. Sep Sci Technol, 2001, 36(7):1575-1594.
[78] Lakshmi B B , Martin C R. Enantiosparation using apoenzymes immobilized in a porous polymeric membrane[J]. Nature, 1997, 388:758-760.
[79] Ito H, Nakamura M, Saito K. Comparison of l -tryptophan binding capacity of BSA captured by a polymer brush with that of BSA adsorbed onto a gel network[J]. J Chromatogr A, 2001, 925(1-2):41-47.
[80] Matsuoka Y, Kanda N, Lee Y M. Chiral separation of phenylalanine in ultrafiltration through DNA-immobilized chitosan membranes[J].Journal of Membrane Science,2006,280(1-2):116- 123.
[81]邴乃慈,许振良,王学军,等.左氧氟沙星分子印迹膜固相萃取选择性分离氧氟沙星[J].华东理工大学学报,2007,33(2):163-166.
[82] Yoshikawa M, Izumi J, Kitao T. Alternative molecular imprinting, a facile way to introduce chrial recgnition sites[J]. React.Funct Polym, 1999, 42 (1):93-102.
[83] Yoshikawa M, Ooi T, Izumi J. Novel membrane materials having EEE derivatives as a chiral recognition site[J]. EuroPolym J, 2001,37(2):335-342.
[84] Sarac S,Chankvetadze B,Blaschke G. Enantioseparation of 3,4-dihydroxyphenylalanine and 2-hydrazino-2-methyl-3-(3,4-dihydroxyphenyl)propanoic acid by capillary electrophoresis using cyclodextrins[J]. Journal of Chromatography A, 2000, 875:379-387.
[85] Maruszak W, Trojanowicz M, Margasinska M, et al. Application of carboxymethyl-β- cyclodextrin as a chiral selector in capillary electrophoresis for enantiomer separation of selected neurotransmitters[J]. Journal of Chromatography A, 2001,926 (2):327-336.
[86] Lou X W, Liu X L, Sheng Y F. et al. Direct enantiomeric separation of phenylalanine, DOPA and their intermediates by supercritical fluid chromatography[J]. Journal of Chromatography A, 1992, 605:103-107.
[87] Shen J S, Zhao S L. Enantiomeric separation of naphthalene-2,3-dicarboxaldehyde derivatized dl-3,4-dihydroxyphenylalanine and optical purity analysis of l-3,4-dihydroxyphenylalanine drug by cyclodextrin-modified micellar electrokinetic chromatography[J]. Journal of Chromatography A, 2004, 1059:209-214.
[88] Claudia B, Ulrike H. Enantioseparation of dopa and related compounds by cyclodextrin-modified microemulsion electrokinetic chromatography[J]. Journal of Chromatography A, 2008, 1204:191- 196.
[89] Wu Guang, Mario F. Hydrogen bonding as a possible interaction for the chiral separation of DL- dopa and DL-3-O-methyl-dopa in a chiral teicoplanin column[J]. Il Farmaco, 1999, 54:188-190.
[90]陈国斌,唐课文,陈铁花,等. L-酒石酸正己酯的合成[J].合成化学,2004,12:207-209.