手性药物萃取拆分及分子印迹整体柱的制备研究
|
摘要
本文采用萃取、双水相萃取、分子印迹整体柱技术分别对扁桃酸(Mandelic acid,MA)、苯丙氨酸(Phenylalanine,Phe)和萘普生外消旋体的手性拆分进行了研究。
(1)研究了MA对映体在含二(2-乙基己基)磷酸(D2EHPA)与酒石酸衍生物对映单体复合手性选择剂的正辛醇和水两相系统萃取分配行为及其热力学性质,考察了酒石酸衍生物对映单体的种类、初始浓度,D2EHPA的初始浓度,MA的初始浓度,萃取温度对分配系数、分离因子的影响。实验表明:复合手性选择剂能提高分配系数和分离因子;D2EHPA与D-酒石酸衍生物对映单体的复合手性选择剂与L-MA对映体比与D-MA对映体能形成更稳定的非对映体复合物;且D2EHPA与二对甲基苯甲酰酒石酸对映单体(DTTA)的复合手性选择剂的手性选择性大于D2EHPA与二苯甲酰酒石酸对映单体(DBTA)的复合手性选择剂;同时,MA的初始浓度、萃取温度对分配系数和分离因子的影响也比较大,对萃取过程热力学分析表明该萃取过程为焓控过程。
(2)研究了MA对映体在含β-环糊精(β-cyclodextrin,β-CD)手性选择剂的聚乙二醇/硫酸铵(PEG/(NH_4)_2SO_4)双水相体系萃取分配行为,考察了pH、PEG和(NH_4)_2SO_4的质量分数、β-CD的浓度、MA的浓度与萃取温度等因素对拆分效果的影响,结果表明:当温度为30℃、pH=1.0、PEG2000质量分数为30%,(NH_4)_2SO_4质量分数为20%,β-CD的浓度为0.008 mol/L,MA的浓度为0.05 mol/L时,分离因子(α)达到2.46。双水相手性萃取具有很强的手性分离能力,对外消旋体化合物的制备性分离具有重要的意义。
(3)将组合拆分技术应用于Phe外消旋体的双水相萃取分离,主要研究了Phe对映体在双水相体系中的萃取分配行为,考察了不同手性选择剂、组合手性选择剂的摩尔浓度比、组合手性选择剂的总浓度、下相中pH值及缓冲液的种类和浓度等因素对Phe分配行为的影响,结果表明:组合手性选择剂的总浓度为0.01 mol/L(其中,β-CD与羟丙基β-环糊精(HP-β-cyclodextrin,HP-β-CD)的摩尔浓度比为2:3),Na_2HPO_4-H_3PO_4为缓冲溶液,pH值为5.5时,分离因子(α)达到1.53。
(4)以L-(-)-萘普生为模板分子、丙烯酰胺(Acrylamide,AM)为功能单体、二甲基丙烯酸乙二醇酯(Ethylene glycol dimethacrylate,EGDMA)作为交联剂、甲苯和十二醇混合溶液为致孔剂、偶氮二异丁睛(azobisisobutyronitrile,AIBN)为引发剂,采用原位分子印迹技术,合成了萘普生分子印迹整体柱。主要从模板-单体比例、交联剂比例、致孔剂中甲苯含量三方面对合成条件进行了优化,结果表明:模板-单体比例以1:4最佳,交联剂含量以占本身和单体总量的85%为最佳,致孔剂中甲苯的最佳含量为20%(体积比),其中,聚合温度和聚合时间分别为55℃和16 h;考察了萘普生外消旋体在制得的印迹整体柱上的拆分效果,研究发现,通过调整流动相中醋酸含量及流动相的流速和分离温度可以优化分离效果,实现L-(-)-萘普生与其对映体的手性拆分。当温度为60℃,以乙腈-醋酸(99.9:0.1,v/v)作流动相,流速0.6 mL/min,30 min内可完成萘普生外消旋体的手性拆分,分离因子达2.13。
Enantioseparation of MA,Phe,naproxen were investigated using co-extraction,aqueous two-phase extraction,molecular imprinting technique.
(1) The distribution behavior of MA enantiomers was examined in a two-phase aqueous-organic solvent mixture containing D2EHPA and tartaric acid derivatives as co-extractants.The influence of tartaric acid derivative's species and its initial concentration,the initial concentration of D2EHPA,D,L-MA and extractive equilibrium temperature on the distribution ratio and enantioselectivity were studied.The results showed that both the distribution ratio and enantioselectivity were greatly improved by using D2EHPA and tartaric acid derivatives as co-extractants in comparison with that using tartaric acid derivatives individually;the co-extractants of D2EHPA and D-tartaric acid derivatives formed more stable diastereomeric complexs with L-MA than with D-MA;the enantioselectivity of D2EHPA and DTTA co-extractants were better than D2EHPA and DBTA co-extractants;The influence of the intial concentration of D,L-MA and the extractive equilibrium temperature on the distribution ratio and enantioselectivity were insignificant.The thermodynamic studies on enantiomer separation of MA by chiral extraction indicated that the enantiomeric separation is an enthalpy-controlled process.
(2) The distribution behavior of MA enantiomers was investigated in aqueous two-phase systems composing of polyethylene glycol and ammonium sulfate containingβ-cyclodextrin as chiral selector.The influences of the pH,the mass fraction of polyethylene glycol and ammonium sulfate,the polymerization degree of polyethylene glycol,the initial concentration ofβ-cyclodextrin,MA enantiomers and extractive temperature on the distribution behavior were studied,respectively.The results showed thatβ-cyclodextrin is inclined to recognize L-enantiomer; under the optimized conditions,the enantioselectivity reaches 2.46. Aqueous two-phase chiral extraction is of strong chiral separation ability, plays a great role in preparative separation of racemic compounds and is important for the development of aqueous two phase extraction technique.
(3) The distribution behavior of Phe enantiomers was investigated in aqueous two-phase systems composing of polyethylene glycol and ammonium sulfate containing combinatproal chiral selector:β-CD and HP-β-CD in order to establish the optima chiral extraction conditions in this experiment.The influences of the molar concentration ratios of combinatorial chiral selectors,the total molar concentration of combinatorial chiral selectors,pH values,buffer type and its concentraction were investigated.The results showed that the enantioselectivity reaches 1.53 under the optima chiral extraction conditions.
(4) An naproxen molecularly imprinted monolithic column was prepared by in situ polymerization using AM as a functional monomer, EGDMA as a cross-linking agent,toluene and dodecanol as porogenic solvents,and AIBN as an initiator.The synthesis condition was optimized. The results showed the best ratio of template to functional monomer was 1:4,the crosslinker content in monomer mixture was 85%and the toluene content in porogen was 20%.Some chromatographic conditions such as the acetic acid concentration in mobile phase,the flow rate and temperature were characterized.The separation factor reached 2.13 under conditions of the temperature of 60℃,the flow rate of 0.6mL/min and the volume ratio of 99.9:0.1 between acetonitrile and acetic acid in mobile phase.
(1)研究了MA对映体在含二(2-乙基己基)磷酸(D2EHPA)与酒石酸衍生物对映单体复合手性选择剂的正辛醇和水两相系统萃取分配行为及其热力学性质,考察了酒石酸衍生物对映单体的种类、初始浓度,D2EHPA的初始浓度,MA的初始浓度,萃取温度对分配系数、分离因子的影响。实验表明:复合手性选择剂能提高分配系数和分离因子;D2EHPA与D-酒石酸衍生物对映单体的复合手性选择剂与L-MA对映体比与D-MA对映体能形成更稳定的非对映体复合物;且D2EHPA与二对甲基苯甲酰酒石酸对映单体(DTTA)的复合手性选择剂的手性选择性大于D2EHPA与二苯甲酰酒石酸对映单体(DBTA)的复合手性选择剂;同时,MA的初始浓度、萃取温度对分配系数和分离因子的影响也比较大,对萃取过程热力学分析表明该萃取过程为焓控过程。
(2)研究了MA对映体在含β-环糊精(β-cyclodextrin,β-CD)手性选择剂的聚乙二醇/硫酸铵(PEG/(NH_4)_2SO_4)双水相体系萃取分配行为,考察了pH、PEG和(NH_4)_2SO_4的质量分数、β-CD的浓度、MA的浓度与萃取温度等因素对拆分效果的影响,结果表明:当温度为30℃、pH=1.0、PEG2000质量分数为30%,(NH_4)_2SO_4质量分数为20%,β-CD的浓度为0.008 mol/L,MA的浓度为0.05 mol/L时,分离因子(α)达到2.46。双水相手性萃取具有很强的手性分离能力,对外消旋体化合物的制备性分离具有重要的意义。
(3)将组合拆分技术应用于Phe外消旋体的双水相萃取分离,主要研究了Phe对映体在双水相体系中的萃取分配行为,考察了不同手性选择剂、组合手性选择剂的摩尔浓度比、组合手性选择剂的总浓度、下相中pH值及缓冲液的种类和浓度等因素对Phe分配行为的影响,结果表明:组合手性选择剂的总浓度为0.01 mol/L(其中,β-CD与羟丙基β-环糊精(HP-β-cyclodextrin,HP-β-CD)的摩尔浓度比为2:3),Na_2HPO_4-H_3PO_4为缓冲溶液,pH值为5.5时,分离因子(α)达到1.53。
(4)以L-(-)-萘普生为模板分子、丙烯酰胺(Acrylamide,AM)为功能单体、二甲基丙烯酸乙二醇酯(Ethylene glycol dimethacrylate,EGDMA)作为交联剂、甲苯和十二醇混合溶液为致孔剂、偶氮二异丁睛(azobisisobutyronitrile,AIBN)为引发剂,采用原位分子印迹技术,合成了萘普生分子印迹整体柱。主要从模板-单体比例、交联剂比例、致孔剂中甲苯含量三方面对合成条件进行了优化,结果表明:模板-单体比例以1:4最佳,交联剂含量以占本身和单体总量的85%为最佳,致孔剂中甲苯的最佳含量为20%(体积比),其中,聚合温度和聚合时间分别为55℃和16 h;考察了萘普生外消旋体在制得的印迹整体柱上的拆分效果,研究发现,通过调整流动相中醋酸含量及流动相的流速和分离温度可以优化分离效果,实现L-(-)-萘普生与其对映体的手性拆分。当温度为60℃,以乙腈-醋酸(99.9:0.1,v/v)作流动相,流速0.6 mL/min,30 min内可完成萘普生外消旋体的手性拆分,分离因子达2.13。
Enantioseparation of MA,Phe,naproxen were investigated using co-extraction,aqueous two-phase extraction,molecular imprinting technique.
(1) The distribution behavior of MA enantiomers was examined in a two-phase aqueous-organic solvent mixture containing D2EHPA and tartaric acid derivatives as co-extractants.The influence of tartaric acid derivative's species and its initial concentration,the initial concentration of D2EHPA,D,L-MA and extractive equilibrium temperature on the distribution ratio and enantioselectivity were studied.The results showed that both the distribution ratio and enantioselectivity were greatly improved by using D2EHPA and tartaric acid derivatives as co-extractants in comparison with that using tartaric acid derivatives individually;the co-extractants of D2EHPA and D-tartaric acid derivatives formed more stable diastereomeric complexs with L-MA than with D-MA;the enantioselectivity of D2EHPA and DTTA co-extractants were better than D2EHPA and DBTA co-extractants;The influence of the intial concentration of D,L-MA and the extractive equilibrium temperature on the distribution ratio and enantioselectivity were insignificant.The thermodynamic studies on enantiomer separation of MA by chiral extraction indicated that the enantiomeric separation is an enthalpy-controlled process.
(2) The distribution behavior of MA enantiomers was investigated in aqueous two-phase systems composing of polyethylene glycol and ammonium sulfate containingβ-cyclodextrin as chiral selector.The influences of the pH,the mass fraction of polyethylene glycol and ammonium sulfate,the polymerization degree of polyethylene glycol,the initial concentration ofβ-cyclodextrin,MA enantiomers and extractive temperature on the distribution behavior were studied,respectively.The results showed thatβ-cyclodextrin is inclined to recognize L-enantiomer; under the optimized conditions,the enantioselectivity reaches 2.46. Aqueous two-phase chiral extraction is of strong chiral separation ability, plays a great role in preparative separation of racemic compounds and is important for the development of aqueous two phase extraction technique.
(3) The distribution behavior of Phe enantiomers was investigated in aqueous two-phase systems composing of polyethylene glycol and ammonium sulfate containing combinatproal chiral selector:β-CD and HP-β-CD in order to establish the optima chiral extraction conditions in this experiment.The influences of the molar concentration ratios of combinatorial chiral selectors,the total molar concentration of combinatorial chiral selectors,pH values,buffer type and its concentraction were investigated.The results showed that the enantioselectivity reaches 1.53 under the optima chiral extraction conditions.
(4) An naproxen molecularly imprinted monolithic column was prepared by in situ polymerization using AM as a functional monomer, EGDMA as a cross-linking agent,toluene and dodecanol as porogenic solvents,and AIBN as an initiator.The synthesis condition was optimized. The results showed the best ratio of template to functional monomer was 1:4,the crosslinker content in monomer mixture was 85%and the toluene content in porogen was 20%.Some chromatographic conditions such as the acetic acid concentration in mobile phase,the flow rate and temperature were characterized.The separation factor reached 2.13 under conditions of the temperature of 60℃,the flow rate of 0.6mL/min and the volume ratio of 99.9:0.1 between acetonitrile and acetic acid in mobile phase.
引文
[1]叶秀林.立体化学.北京:北京大学出版社,1999
[2]张永敏.物理有机化学.上海:上海科学技术出版社,2001
[3]尤田耙.手性化合物的现代研究方法.合肥:中国科学技术大学出版社,1993
[4]马纪伟,闰东良.手性和手性药物.井冈山医专学报,2005,12(3):24-26
[5]顿彬,刘会臣.手性药物对映体在药效学和药代动力学的相互作用.中国临床药理学杂志,2005,22(1):66-69
[6]杜建红,夏叔泉.药物发展中的外消旋体和对映体.国外医药-合成药、生化药、制剂分册,1994,15(4):206-208
[7]李全,谢毓云.药物的光学异构体与药效.中国药物化学杂志,1996,6(2):151-154
[8]慈薇,柴逸峰,刘荔荔等.毛细管电泳非环糊精体系拆分手性药物的研究进展.药学学报,2002,37(1):75-80
[9]Anon.FDA's Policy Statement for the Development of New Stereoisomeric Drugs,U.S.Food and Drug Administration Guidance,Washington,DC,1992.
[10]张骁,束梅英.手性药物研发进展.中国制药信息,2007,23(12):7-9
[11]黄蓓,杨立荣,吴坚平.手性拆分技术的工业应用.化工进展,2002,21(36):375-380
[12]王德才,陆伟等.酒石酸噻吗洛尔的合成及其降眼压作用的初步研究.中国医药杂志,1994,4(4):289-294
[13]Kaupp G.Resolution of rocemate by piotillation with inclusion compounds.Angew Chem Int Ed,1994,33:728-729
[14]邓金根.手性亚砜类化合物的包结拆分.化学研究与应用,1999,11(5):465-466
[15]Vries T,Wynberg H,Echte E,et al.The family approach to the resolution of racemates.Angew Chem Int Ed,1998,37,2349-2355
[16]Gihani E,Moharem T,Jonathan M J W.Dynamic kinetic resolution.Curr Opin Chem Biol,1999,3(1):11-15
[17]Allen J V,Williams J M J.Dynamic kinetic resolution with enzyme and palladium combinations.Tetrahed Lett,1996,37:1859-1862
[18]Jeffrey H,Spelberg L,Tang L,et al.Enzymatic dynamic kinetic resolution of epihalohydrins.Tetrahedron:Asymmetry,2004,(15):1095-1102
[19]Joly S,Nair M S.Studies on the enzymatic kinetic resolution of β-hydroxy ketones.J Mol Catal B-Enzym,2003,22:151-160
[20]王道宾,何炳林.用固定化氨基酰化酶拆分D,L-对氯苯丙氨酸.化学通报,1994.1:50-52
[21]徐诗伟,徐清.酶法拆分腈类制备光学活性2-芳基丙酸.微生物学通报,1995,22(3):184-187
[22]周志国,张红雁,于兆文,等.高效液相色谱法对外消旋药物的拆分.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 Chromatogr B,1996,687:303-336
[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 Chromatogr A,2001,906:443-458
[25]Kondo T,Imaoka T,Kawasaki T,et al.Fluorescence derivatization reagent for resolution of carboxylic acid enantiomers by hige-performance liquid chromatography.J Chromatogr,1999,645:75
[26]金东日,马奎蓉,张小勇,等.手性荧光衍生化反相高效液相色谱法分离肾上腺素对映体.色谱,2002,20(4):304-308
[27]洪建文,胡昌勤,盛龙生.喹诺酮类药物色谱手性分析的进展.药物分析杂志,2003,23(2):155-159
[28]杨丽,江树人,廖勇等.流动相添加剂法与手性固定相法对己唑醇光学异构体的拆分.农药学学报,2004,16(2):90-92
[29]吴永江,方昕.β-环糊精流动相添加剂法拆分特非那丁对映体.分析化学,2003,31(3):332-335
[30]夏小庆,方骏.使用手性冠醚及手性柱的HPLC和HPLC法拆分伯胺类药物对映体的对比研究.分析科学学报,2002,18(6):481-483
[31]Bhatti MM,Foster RT.Stereospecific high-performance liquid chromatographic assay of metoprolol.J Chromatogr,1992,579(2):361
[32]白冬梅,赵学明,胡宗定.高效液相色谱手性流动相添加剂分离乳酸对映体.分析化学,2001,29(4):413-415
[33]叶晓霞,俞雄.HPLC万古霉素手性柱和手性流动相添加剂法分离酮洛芬. 药学学报,2003,38(3):211-214
[34]Armstrong DW,Tang YB,Chen SS,et al.Macrocylic antiobiotics as a new class of selectors for liquid chromatography.Anal Chem,1994,66(9):1473-1478
[35]尤启东,林国强.手性药物:研究与应用.北京,化学工业出版社,2003,7
[36]王志欣,云自厚.脲衍生物型手性固定相拆分去甲黄碱药物对映体.色谱,1998,16(3):265-267
[37]张艳辉,云自厚.酰胺型手性固定相反相拆分药物对映体布洛芬.分析化学,1999,27(3):309-411
[38]汪海林,邹汉法,吕美玲,等.人血清白蛋白柱上药物的手性拆分.分析化学,1998,26(1):68-72
[39]刘学良,王俊德.高效液相色谱法直接拆分非甾体解热镇痛药物对映体.分析化学,2001,29(9):993-996
[40]邵保海,徐秀珠,吕建德,等.纤维素衍生物手性固定相用于高效液相色谱对映体分离.分析化学,2003,31(2):239-244
[41]李凌云,钱宝英,高如瑜,等.万古霉素手性固定相分离几种药物对映体.分析测试学报,2003,22(6):83-85
[42]侯经国,何天稀,毛学峰,等.红霉素作为手性选择剂对手性药物的毛细管电泳拆分.分析测试学报,2003,22(1):1-4
[43]侯经国,刘慧玲,何天稀,等.卡那霉素作为手性选择剂的毛细管电泳手性药物分离研究.分析测试技术与仪器,2002,8(1):19-22
[44]Schurig V.Chiral separations using gas chromatography.Trends Anal Chem,2002,21(9-10):647-661.
[45]Schurig V.Separation of enantiomers by gas chromatography.J Chromatogr A,2001,906(1-2):275-299
[46]Bicchi C,D'Amato A,Rubiolo P.Cyclodextrin derivatives as chiral selectors for direct gas chromatographic separation of enantionmers in the essential oil,aroma and flavour fields.J Chromatogr A,1999,843(1-2):99-121
[47]朱全红,马果东,邓芹英.薄层色谱用苯基异氰酸酯衍生化的β-环糊精键合固定相的制备及应用.分析化学,2000,28(3):349-352
[48]徐莉,何建峰,刘岚.薄层色谱用纤维素苯甲酸酯类手性固定相的制备及色谱性能.分析测试学报,2003,22(2):1-4
[49]Bhushan R,Vineeta P.Resolution of(±)-ibuprofen using 1-arginine -impregnated thin-layer chromatography.J Chromatogr A,1996,721(2):369-372
[50]Petersson P,Markides KE.Chiral separation performed by supercritical fluid chromatography.J Chromatogr A,1994,666:381-394
[51]Fauali S.An Introduction to Chiral Analysis by Capillary Electrophoresis.USA:Bio-Rad,1995
[52]陈义.毛细管电泳技术及应用.北京:化学工业出版社,2000,103-118
[53]Chankvetadze B,Blaschke G.Enantioseparation in capillary electromigration techniques-recent developments and furture trends.J Chromatogr A,2001,906:309-363
[54]谢锐,褚良银,曲剑波.手性拆分膜的研究与应用新进展.现代化工,2004,24(4):15-18
[55]Gabelman A,Hwang S-T.Hollow fiber membrane contactors.J Membrane Sci,1999,159:61-106
[56]Hadik Peter,Szabo Lujza-P,Nagy Endre.D,L-lactic acid and D,L-alanine enantioseparation by membrane ptocess.Desalination,2002,148(1-3):193-198
[57]Keurentjes JTF,Nabuurs LJWM,Vegter EA.Liquid membrane technology for the separation of racemic mixtures.J Membrane Sci,1996,113(2):351-360
[58]Pickering P J.Chaudhuri J B.Enantioselective extraction of(d)-phenylalanine from racemic(d/l)-phenylalanine using chiral emulsion liquid membranes.J Membrane Sci,1997,127(2):115-130
[59]Dzygiel P,Wieczorek P.Extraction of amino acids with emulsion liquid membranes using industrial surfactants and lecithin as stabilizers.J Membrane Sci,2000,172(2):223-232
[60]Krieg Henning M,Lotter Jeanette,Keizer Klaas,et al.Enrichment of chlorthlidone enantiomers by an aqueous bulk liquid membrane containing β-cyclodextrin[J].J Membrane Sci,2000,167(1):33-45
[61]Coelhoso I M,Cardoso M M,Viegas R M C,et al.Transport mechanisms and modelling in liquid membrane contactors.Separ Purif Technol,2000,19(3):183-197
[62]周丹,刘佳佳,唐课文.手性酯类萃取剂萃取拆分α-环己基扁桃酸外消旋体.分析测试学报,2006,25(6):49-52
[63]Tan B,Liu Y S,Qi X,et al.Enantioselective extraction of D,L-tryptophan by a new chiral selector:Complex formation with di(2-ethylhexyl) phosphoric caid and O,O'-dibenzoyl-(2R,3R)-tartaric acid.Separation Purification Technology,2006,49:186-191
[64]Tan B,Liu Y S,Wang J D.Enantioselective of amino acids by co-extractants with di(2-ethylhexyl) phosphoric caid and tartaric acid derivatives[J].Tetrahedron: asymmetry,2006,17:883-891
[65]Tang K W,Chen Y Y,Huang K L,et al.Enantioselective resolution of chiral aromatic acids by biphasic recognition chiral extraction.Tetrahedron:asymmetry,2007,18:2399-2408
[66]李俊,蔡水洪,朱中南,等.手性化合物的萃取拆分研究.化学世界,2001,5:233-236
[67]Vladimir P,Martin E.Lipophilic tartaric acid esters as enantioselective ionophores.Angew Chem Int Ed,1989,28:1147-1152
[68]唐课文,周春山.疏水性 L-酒石酸酯萃取分离氧氟沙星对映体.化工学报,2003,54(12):1729-1732
[69]唐课文,周春山.疏水性 L-酒石酸酯立体选择性萃取分离氯噻酮对映体.分析化学,2004,32(1):63-66
[70]Toshifumi T,Rikizo H,Takenori T.Enantioselective solvent extraction of neutral DL-Amino acids in two-phase systems containing N-n-alkyl-L-proline derivative and Copper(Ⅱ)ion.Anal Chem,1984,56:1152-1155
[71]唐课文,陈国斌,周春山.手性配体立体选择性萃取分离扁桃酸对映体.无机化学学报,2004,20(3):339-344
[72]Bauza R,Rios A,Valcarecel M.Supercritical fluid extraction with in situ chiral derivatization for the enantiospecific determination of ibuprofen in urine samples.Aanlytica Chimica Acta,2001,450:1-11
[73]Persson J,Lena N,Hans A,et al.Purification of recombinant proteins using thermoesparating aqucous two-phase system and polymer recycling.J Chem Technol Biotechnol,1999,74(3):238-243
[74]Wang X L,Yang B L,Zhang Z T,et al.Application of new separations technique in herb medicine.Chemical Industry and Engineering Progress(china),2002,21(2):131-135
[75]Sellergren B,Ekberg B.Preparative chiral separation in an aqueous two-phase system by a few counter-current extractions.J Chromatogr,1988,450:277-280
[76]Schweit L,Andersson L I,Nilsson S.Capillary electrochromatography with predetermined selectivity obtained through molecular imprinting.Anal Chem,1997,69(3):1179-1183
[77]Kempe M,Mosbach K.Direct resolution of naproxen on a non-convalently molecularly imprinted chiral stationary phase.J Chromatogr A,1994,664:276-279
[78]Matsui J,Kato T,Takeuchi M,et al.Molecular recognition in continuous polymer rods prepared by a molecular imprinting technique.Anal Chem,1993,65(17):2223-2224
[79]Huang Xiaodong,Zou Hanfa,Chen Xiaoming,et al.Molecularly imprinted monolithic stationary phases for liquid chromatographic separation of enantiomers and diastereomers.J Chromatogr A,2003,984:273-282
[80]Huang Xiaodong,Zou Hanfa,Luo Quanzhou,et al.Rapid liquid chromatographic separation of distereomers and enantiomers using superporous molecularly imprinted monolith,MIP2002 second International workshop on molecularly imprinted polymers,La Grande Motte,France,Sept,2002,96
[81]Suedee R,Songkram C,Petmoreekul A,et al.Direct enantioseparation of adrenergic drugs via thin-layer chromatography using molecularly imprinted polymers.J of Pharmaceutical and Biomedical Analysis,1999,19:519-527
[82]Hadik Peter,Szabo Lujza-p,Nagy Endre.D,L-lactic acid and D,L-alanine enantioseparation by membrane process.Desalination,2002,148:193-198
[83]宁凤容,黄可龙,焦飞鹏,瞿龙.手性配体立体选择性萃取拆分对映体动力学研究.化学通报,2006,(5):365-367
[84]XU Xiao-ping,LI Zhong-qin,CHEN Jie-bo.Study on partition of D(-)-mandelic acid in aqueous two-phase systems.Journal of Fuzhou University(Natural Science),2004,32(5):623-626
[85]沈同等.生物化学.北京:高等教育出版社(上).1990
[86]周力.阿斯巴甜的生产与应用.食品科学.1997,(7):18-21
[87]Folkers K,Rosell S,Xu JC,et al.,Antagonists of substance p from emphasis on position 11.Acta Chem Scand B.1983,37(7):623-627
[88]赵平,吴海君,高丽红等.外消旋体苯丙氨酸的配位萃取拆分.华东理工大学学报.2002,28(3):228-231
[89]黄量,戴立信,杜灿屏,等.手性药物的化学与生物学,北京:化学工业出版社,2002:137-145
[90]邓金根,迟永祥,朱槿等.化学拆分的新方法研究.合成化学,1999,7(4):340-345
[91]黄可龙,胡卫国,焦飞鹏,等.组合手性萃取拆分克伦特罗外消旋体,分析科学学报,2007,23(3):283-286
[92]Sellergem B.Molecularly imprinted polymers:man-made mimics of antiobodies and their application in analytical chemistry.Amsterdam:Elsevier Science,2001,113-117
[93] Komiyama M, Takeuchi T, Mukawa T, et al. Molecular imprinting from fundamentals to applications. Weinheim: WILEY-VCH Verlag GmbH& Co. KgaA, 2003,1-8
[94] Turiel E, Martin-Esteban A. Molecularly imprinted polymers: towards highly selective stationary phases in liquid chromatography and capillary electrophoresis. Anal Bioanal Chem, 2004, 378 (8): 1876-1886
[95] Sellergren B, Shea K J. Origin of peak asymmetry and the effect of temperature on solute retention in enantiomer separations on imprinted chiral stationary phases. J Chromatogr A, 1995, 690 (1): 29-39
[2]张永敏.物理有机化学.上海:上海科学技术出版社,2001
[3]尤田耙.手性化合物的现代研究方法.合肥:中国科学技术大学出版社,1993
[4]马纪伟,闰东良.手性和手性药物.井冈山医专学报,2005,12(3):24-26
[5]顿彬,刘会臣.手性药物对映体在药效学和药代动力学的相互作用.中国临床药理学杂志,2005,22(1):66-69
[6]杜建红,夏叔泉.药物发展中的外消旋体和对映体.国外医药-合成药、生化药、制剂分册,1994,15(4):206-208
[7]李全,谢毓云.药物的光学异构体与药效.中国药物化学杂志,1996,6(2):151-154
[8]慈薇,柴逸峰,刘荔荔等.毛细管电泳非环糊精体系拆分手性药物的研究进展.药学学报,2002,37(1):75-80
[9]Anon.FDA's Policy Statement for the Development of New Stereoisomeric Drugs,U.S.Food and Drug Administration Guidance,Washington,DC,1992.
[10]张骁,束梅英.手性药物研发进展.中国制药信息,2007,23(12):7-9
[11]黄蓓,杨立荣,吴坚平.手性拆分技术的工业应用.化工进展,2002,21(36):375-380
[12]王德才,陆伟等.酒石酸噻吗洛尔的合成及其降眼压作用的初步研究.中国医药杂志,1994,4(4):289-294
[13]Kaupp G.Resolution of rocemate by piotillation with inclusion compounds.Angew Chem Int Ed,1994,33:728-729
[14]邓金根.手性亚砜类化合物的包结拆分.化学研究与应用,1999,11(5):465-466
[15]Vries T,Wynberg H,Echte E,et al.The family approach to the resolution of racemates.Angew Chem Int Ed,1998,37,2349-2355
[16]Gihani E,Moharem T,Jonathan M J W.Dynamic kinetic resolution.Curr Opin Chem Biol,1999,3(1):11-15
[17]Allen J V,Williams J M J.Dynamic kinetic resolution with enzyme and palladium combinations.Tetrahed Lett,1996,37:1859-1862
[18]Jeffrey H,Spelberg L,Tang L,et al.Enzymatic dynamic kinetic resolution of epihalohydrins.Tetrahedron:Asymmetry,2004,(15):1095-1102
[19]Joly S,Nair M S.Studies on the enzymatic kinetic resolution of β-hydroxy ketones.J Mol Catal B-Enzym,2003,22:151-160
[20]王道宾,何炳林.用固定化氨基酰化酶拆分D,L-对氯苯丙氨酸.化学通报,1994.1:50-52
[21]徐诗伟,徐清.酶法拆分腈类制备光学活性2-芳基丙酸.微生物学通报,1995,22(3):184-187
[22]周志国,张红雁,于兆文,等.高效液相色谱法对外消旋药物的拆分.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 Chromatogr B,1996,687:303-336
[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 Chromatogr A,2001,906:443-458
[25]Kondo T,Imaoka T,Kawasaki T,et al.Fluorescence derivatization reagent for resolution of carboxylic acid enantiomers by hige-performance liquid chromatography.J Chromatogr,1999,645:75
[26]金东日,马奎蓉,张小勇,等.手性荧光衍生化反相高效液相色谱法分离肾上腺素对映体.色谱,2002,20(4):304-308
[27]洪建文,胡昌勤,盛龙生.喹诺酮类药物色谱手性分析的进展.药物分析杂志,2003,23(2):155-159
[28]杨丽,江树人,廖勇等.流动相添加剂法与手性固定相法对己唑醇光学异构体的拆分.农药学学报,2004,16(2):90-92
[29]吴永江,方昕.β-环糊精流动相添加剂法拆分特非那丁对映体.分析化学,2003,31(3):332-335
[30]夏小庆,方骏.使用手性冠醚及手性柱的HPLC和HPLC法拆分伯胺类药物对映体的对比研究.分析科学学报,2002,18(6):481-483
[31]Bhatti MM,Foster RT.Stereospecific high-performance liquid chromatographic assay of metoprolol.J Chromatogr,1992,579(2):361
[32]白冬梅,赵学明,胡宗定.高效液相色谱手性流动相添加剂分离乳酸对映体.分析化学,2001,29(4):413-415
[33]叶晓霞,俞雄.HPLC万古霉素手性柱和手性流动相添加剂法分离酮洛芬. 药学学报,2003,38(3):211-214
[34]Armstrong DW,Tang YB,Chen SS,et al.Macrocylic antiobiotics as a new class of selectors for liquid chromatography.Anal Chem,1994,66(9):1473-1478
[35]尤启东,林国强.手性药物:研究与应用.北京,化学工业出版社,2003,7
[36]王志欣,云自厚.脲衍生物型手性固定相拆分去甲黄碱药物对映体.色谱,1998,16(3):265-267
[37]张艳辉,云自厚.酰胺型手性固定相反相拆分药物对映体布洛芬.分析化学,1999,27(3):309-411
[38]汪海林,邹汉法,吕美玲,等.人血清白蛋白柱上药物的手性拆分.分析化学,1998,26(1):68-72
[39]刘学良,王俊德.高效液相色谱法直接拆分非甾体解热镇痛药物对映体.分析化学,2001,29(9):993-996
[40]邵保海,徐秀珠,吕建德,等.纤维素衍生物手性固定相用于高效液相色谱对映体分离.分析化学,2003,31(2):239-244
[41]李凌云,钱宝英,高如瑜,等.万古霉素手性固定相分离几种药物对映体.分析测试学报,2003,22(6):83-85
[42]侯经国,何天稀,毛学峰,等.红霉素作为手性选择剂对手性药物的毛细管电泳拆分.分析测试学报,2003,22(1):1-4
[43]侯经国,刘慧玲,何天稀,等.卡那霉素作为手性选择剂的毛细管电泳手性药物分离研究.分析测试技术与仪器,2002,8(1):19-22
[44]Schurig V.Chiral separations using gas chromatography.Trends Anal Chem,2002,21(9-10):647-661.
[45]Schurig V.Separation of enantiomers by gas chromatography.J Chromatogr A,2001,906(1-2):275-299
[46]Bicchi C,D'Amato A,Rubiolo P.Cyclodextrin derivatives as chiral selectors for direct gas chromatographic separation of enantionmers in the essential oil,aroma and flavour fields.J Chromatogr A,1999,843(1-2):99-121
[47]朱全红,马果东,邓芹英.薄层色谱用苯基异氰酸酯衍生化的β-环糊精键合固定相的制备及应用.分析化学,2000,28(3):349-352
[48]徐莉,何建峰,刘岚.薄层色谱用纤维素苯甲酸酯类手性固定相的制备及色谱性能.分析测试学报,2003,22(2):1-4
[49]Bhushan R,Vineeta P.Resolution of(±)-ibuprofen using 1-arginine -impregnated thin-layer chromatography.J Chromatogr A,1996,721(2):369-372
[50]Petersson P,Markides KE.Chiral separation performed by supercritical fluid chromatography.J Chromatogr A,1994,666:381-394
[51]Fauali S.An Introduction to Chiral Analysis by Capillary Electrophoresis.USA:Bio-Rad,1995
[52]陈义.毛细管电泳技术及应用.北京:化学工业出版社,2000,103-118
[53]Chankvetadze B,Blaschke G.Enantioseparation in capillary electromigration techniques-recent developments and furture trends.J Chromatogr A,2001,906:309-363
[54]谢锐,褚良银,曲剑波.手性拆分膜的研究与应用新进展.现代化工,2004,24(4):15-18
[55]Gabelman A,Hwang S-T.Hollow fiber membrane contactors.J Membrane Sci,1999,159:61-106
[56]Hadik Peter,Szabo Lujza-P,Nagy Endre.D,L-lactic acid and D,L-alanine enantioseparation by membrane ptocess.Desalination,2002,148(1-3):193-198
[57]Keurentjes JTF,Nabuurs LJWM,Vegter EA.Liquid membrane technology for the separation of racemic mixtures.J Membrane Sci,1996,113(2):351-360
[58]Pickering P J.Chaudhuri J B.Enantioselective extraction of(d)-phenylalanine from racemic(d/l)-phenylalanine using chiral emulsion liquid membranes.J Membrane Sci,1997,127(2):115-130
[59]Dzygiel P,Wieczorek P.Extraction of amino acids with emulsion liquid membranes using industrial surfactants and lecithin as stabilizers.J Membrane Sci,2000,172(2):223-232
[60]Krieg Henning M,Lotter Jeanette,Keizer Klaas,et al.Enrichment of chlorthlidone enantiomers by an aqueous bulk liquid membrane containing β-cyclodextrin[J].J Membrane Sci,2000,167(1):33-45
[61]Coelhoso I M,Cardoso M M,Viegas R M C,et al.Transport mechanisms and modelling in liquid membrane contactors.Separ Purif Technol,2000,19(3):183-197
[62]周丹,刘佳佳,唐课文.手性酯类萃取剂萃取拆分α-环己基扁桃酸外消旋体.分析测试学报,2006,25(6):49-52
[63]Tan B,Liu Y S,Qi X,et al.Enantioselective extraction of D,L-tryptophan by a new chiral selector:Complex formation with di(2-ethylhexyl) phosphoric caid and O,O'-dibenzoyl-(2R,3R)-tartaric acid.Separation Purification Technology,2006,49:186-191
[64]Tan B,Liu Y S,Wang J D.Enantioselective of amino acids by co-extractants with di(2-ethylhexyl) phosphoric caid and tartaric acid derivatives[J].Tetrahedron: asymmetry,2006,17:883-891
[65]Tang K W,Chen Y Y,Huang K L,et al.Enantioselective resolution of chiral aromatic acids by biphasic recognition chiral extraction.Tetrahedron:asymmetry,2007,18:2399-2408
[66]李俊,蔡水洪,朱中南,等.手性化合物的萃取拆分研究.化学世界,2001,5:233-236
[67]Vladimir P,Martin E.Lipophilic tartaric acid esters as enantioselective ionophores.Angew Chem Int Ed,1989,28:1147-1152
[68]唐课文,周春山.疏水性 L-酒石酸酯萃取分离氧氟沙星对映体.化工学报,2003,54(12):1729-1732
[69]唐课文,周春山.疏水性 L-酒石酸酯立体选择性萃取分离氯噻酮对映体.分析化学,2004,32(1):63-66
[70]Toshifumi T,Rikizo H,Takenori T.Enantioselective solvent extraction of neutral DL-Amino acids in two-phase systems containing N-n-alkyl-L-proline derivative and Copper(Ⅱ)ion.Anal Chem,1984,56:1152-1155
[71]唐课文,陈国斌,周春山.手性配体立体选择性萃取分离扁桃酸对映体.无机化学学报,2004,20(3):339-344
[72]Bauza R,Rios A,Valcarecel M.Supercritical fluid extraction with in situ chiral derivatization for the enantiospecific determination of ibuprofen in urine samples.Aanlytica Chimica Acta,2001,450:1-11
[73]Persson J,Lena N,Hans A,et al.Purification of recombinant proteins using thermoesparating aqucous two-phase system and polymer recycling.J Chem Technol Biotechnol,1999,74(3):238-243
[74]Wang X L,Yang B L,Zhang Z T,et al.Application of new separations technique in herb medicine.Chemical Industry and Engineering Progress(china),2002,21(2):131-135
[75]Sellergren B,Ekberg B.Preparative chiral separation in an aqueous two-phase system by a few counter-current extractions.J Chromatogr,1988,450:277-280
[76]Schweit L,Andersson L I,Nilsson S.Capillary electrochromatography with predetermined selectivity obtained through molecular imprinting.Anal Chem,1997,69(3):1179-1183
[77]Kempe M,Mosbach K.Direct resolution of naproxen on a non-convalently molecularly imprinted chiral stationary phase.J Chromatogr A,1994,664:276-279
[78]Matsui J,Kato T,Takeuchi M,et al.Molecular recognition in continuous polymer rods prepared by a molecular imprinting technique.Anal Chem,1993,65(17):2223-2224
[79]Huang Xiaodong,Zou Hanfa,Chen Xiaoming,et al.Molecularly imprinted monolithic stationary phases for liquid chromatographic separation of enantiomers and diastereomers.J Chromatogr A,2003,984:273-282
[80]Huang Xiaodong,Zou Hanfa,Luo Quanzhou,et al.Rapid liquid chromatographic separation of distereomers and enantiomers using superporous molecularly imprinted monolith,MIP2002 second International workshop on molecularly imprinted polymers,La Grande Motte,France,Sept,2002,96
[81]Suedee R,Songkram C,Petmoreekul A,et al.Direct enantioseparation of adrenergic drugs via thin-layer chromatography using molecularly imprinted polymers.J of Pharmaceutical and Biomedical Analysis,1999,19:519-527
[82]Hadik Peter,Szabo Lujza-p,Nagy Endre.D,L-lactic acid and D,L-alanine enantioseparation by membrane process.Desalination,2002,148:193-198
[83]宁凤容,黄可龙,焦飞鹏,瞿龙.手性配体立体选择性萃取拆分对映体动力学研究.化学通报,2006,(5):365-367
[84]XU Xiao-ping,LI Zhong-qin,CHEN Jie-bo.Study on partition of D(-)-mandelic acid in aqueous two-phase systems.Journal of Fuzhou University(Natural Science),2004,32(5):623-626
[85]沈同等.生物化学.北京:高等教育出版社(上).1990
[86]周力.阿斯巴甜的生产与应用.食品科学.1997,(7):18-21
[87]Folkers K,Rosell S,Xu JC,et al.,Antagonists of substance p from emphasis on position 11.Acta Chem Scand B.1983,37(7):623-627
[88]赵平,吴海君,高丽红等.外消旋体苯丙氨酸的配位萃取拆分.华东理工大学学报.2002,28(3):228-231
[89]黄量,戴立信,杜灿屏,等.手性药物的化学与生物学,北京:化学工业出版社,2002:137-145
[90]邓金根,迟永祥,朱槿等.化学拆分的新方法研究.合成化学,1999,7(4):340-345
[91]黄可龙,胡卫国,焦飞鹏,等.组合手性萃取拆分克伦特罗外消旋体,分析科学学报,2007,23(3):283-286
[92]Sellergem B.Molecularly imprinted polymers:man-made mimics of antiobodies and their application in analytical chemistry.Amsterdam:Elsevier Science,2001,113-117
[93] Komiyama M, Takeuchi T, Mukawa T, et al. Molecular imprinting from fundamentals to applications. Weinheim: WILEY-VCH Verlag GmbH& Co. KgaA, 2003,1-8
[94] Turiel E, Martin-Esteban A. Molecularly imprinted polymers: towards highly selective stationary phases in liquid chromatography and capillary electrophoresis. Anal Bioanal Chem, 2004, 378 (8): 1876-1886
[95] Sellergren B, Shea K J. Origin of peak asymmetry and the effect of temperature on solute retention in enantiomer separations on imprinted chiral stationary phases. J Chromatogr A, 1995, 690 (1): 29-39