多聚糖PC类衍生物CSPs的合成及手性分离能力的研究
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摘要
众所周知,光学纯对映体在生命体内的药理活性及毒性方面存在着较大的差异,因此拆分外消旋化合物,使之成为单一纯对映体的研究尤为重要。手性拆分法是获得光学纯化合物的主要手段,在生物医药学、农业化学和现代合成化学等领域均有重要意义。到目前为止,酶拆分法、结晶拆分法、化学拆分法、不对称转换拆分法、色谱拆分法等一些手性拆分方法已经成功应用于对映体的拆分及制备中,在这些手性体拆分的方法中,用固定相分离外消旋体的高效液相色谱法(HPLC-CSPs)是一种快速高效、有巨大发展潜力的拆分方法之一,在测试对映体的光学纯度及大规模拆分方面具有举足轻重的地位。在众多的手性固定相(CSPs)中,多糖(纤维素和直链淀粉)类衍生物CSPs使用最为广泛。
通常将多糖酯类或氨基甲酸酯类衍生物固定相,涂覆在作为支撑材料的氨丙基硅胶表面上,以正己烷/异丙醇(90/10,v/v)为流动相下,在高效液相色谱中对大多数外消旋化合物都表现出很好的手性分离能力。然而,涂覆型固定相易溶解或溶胀于很多良好的有机溶剂中,限制其实际应用范围。键合型多糖类手性固定相则克服了流动相受限问题,通过加入极性溶剂(如氯仿或四氢呋喃),调整流动相配比,可获得更好的拆分效果,使其在对映体制备及分析方面具有更大的灵活性。
本实验主要合成涂覆型和键合型多糖类手性分离固定相,并利用HPLC评价其手性拆分性能,本论文研究工作分为三部分：
首先,利用苯胺和三光气,合成苯基异氰酸酯,利用普通硅胶和3-氨丙基三乙氧基硅烷,制备氨丙基化多孔硅胶,通过1H核磁共振和红外光谱表征其结构。
然后,合成了纤维素-三(苯基氨基甲酸酯)(CSP-1)和直链淀粉-三(苯基氨基甲酸酯)(CSP-2)衍生物,制备HPLC用涂覆型手性固定相。在常规流动相正己烷/异丙醇(90/10,v/v)的条件下,考察两类色谱柱对7种典型的手性对映体的手性拆分能力。实验结果表明：这两类手性固定相对一些对映体都表现出很好的手性拆分性能,总体上来说,CSP-1和CSP-2在手性拆分性能方面相互补充,一些在CSP-1上不能拆分的对映体,在CSP-2上却得到很好的拆分,反之亦然。
最后,通过“一锅法”合成了含有不同硅氧烷基团(1%、2%、3%)含量的纤维素和直链淀粉苯基氨基甲酸酯衍生物,利用1H核磁共振和红外光谱表征衍生物结构,利用热失重测试键合效率；通过硅氧烷基团在酸性条件下的水解、缩合,可简单、高效地实现在氨丙基硅胶表面的化学键合,制得键合型HPLC用手性分离固定相,可以使用强极性有机溶剂作为流动相,通过调整流动相中含有氯仿(CDC13)或者四氢呋喃(THF)的成分和配比,不但克服了涂覆型手性色谱柱流动相选择溶剂受限的问题,还可极大地提高手性拆分性能。一些在涂覆型固定相中无法分离的对映体,得到了很好的拆分,扩大了流动相的选择范围,实现外消旋化合物的最佳手性拆分,并且延长了手性柱的使用寿命。
As is known to all, a pair of optically pure enantiomers may show great different pharmacological and toxicological activities, and therefore, the separation of enantiomers has been becoming increasingly important. Enantioseparation has been one of the important ways to obtain optical purity compounds, which plays an important role in modern synthetic chemistry, bio-medicine, and agricultural chemicals and so on. Numerous chiral separation methods have been successfully applied to enantiomeric resolution and preparation, such as biological separation, crystallization, chemical separation method, asymmetric conversion, chromatography and so on. Among these methods, the high-performance liquid chromatographic separation of enantiomers using chiral stationary phase (CSPs) is a direct-fast and great potential method, which is important for determining enantiomeric purities and preparing separation for a large scale. The polysaccharide such as cellulose and amylose derivatives are the most widely used in a great deal of CSPs.
The esters and carbamates of polysaccharide coated on aminopropyl silica gel have been greatly studied and widely applied for the high-performance liquid chromatography (HPLC) as CSPs. Most of them which exhibit broad applicability to a large number of chiral racemates can be used for a long time with a hexane-isopropanol (90/10, v/v) as the eluent. However, they usually have the shortcomings of poor properties of resisting solvent. The CSPs of immobilized polysaccharide derivatives on aminopropyl silica gel overcome the strict solvent limitation of eluents and have greater flexibility in enantiomeric resolution and preparation.
This paper mainly focus on the synthesis and resolution ability of polysaccharide-based coated-type and immobilized-type chiral separation stationary phase which include three parts as the following:
Firstly, we prepared the raw materials phenyl isocyanate and aminopropyl silica gel, which structures were characterized by 1H NMR and IR spectrum.
Secondly, cellulose and amylose tris(phenylcarbamate) derivatives were synthesized, respectively. 1H nuclear magnetic resonance (1H NMR) and infrared spectroscopy (IR) showed that most of the hydroxyl groups on glucose untis of the cellulose or amylose had been converted into carbamate groups. The chiral stationary phases (CSPs) were prepared by coating CSP-1 or CSP-2 on the aminopropyl silica gel. The chiral recognition abilities of obtained derivatives were evaluated by using 7 typical racemates and a hexane/isopropanol (90/10, v/v) mixture as the eluent. The experimental results show that some racemates were better resolved on the two CSPs. On the whole, CSP-1 and CSP-2 have different chiral resolution ability of some enantiomers. Although CSP-1 has better chiral recognition ability than CSP-2, some racemates which can not be resovled on CSP-1 were better resolved on CSP-2.
Finally, the phenycarbamates of cellulose and amylose bearing different amounts of 3-(triethoxysilyl)propyl residues (1%,2%,3%) were synthesized by a one-pot process and efficiently immobilized onto a silica gel through intermolecular polycondensation of the triethoxysilyl groups under acid condition. The structure of the synthesized polysaccharide derivatives was characterized by 1H NMR and IR. The obtained chiral packing materials (CPMs) were evaluated by HPLC. The immobilization efficiencies were calculated by TG. By using the eluents containing chloroform or tetrahydrofuran, which cannot be used with the conventional coated-type CPMs, most of the racemates could be better resolved on immobilized-type CSPs than coated-type CSPs. Many racemates, which can not be resolved on the coated-type CPMs, could be separated on immobilized-type CSPs.
通常将多糖酯类或氨基甲酸酯类衍生物固定相,涂覆在作为支撑材料的氨丙基硅胶表面上,以正己烷/异丙醇(90/10,v/v)为流动相下,在高效液相色谱中对大多数外消旋化合物都表现出很好的手性分离能力。然而,涂覆型固定相易溶解或溶胀于很多良好的有机溶剂中,限制其实际应用范围。键合型多糖类手性固定相则克服了流动相受限问题,通过加入极性溶剂(如氯仿或四氢呋喃),调整流动相配比,可获得更好的拆分效果,使其在对映体制备及分析方面具有更大的灵活性。
本实验主要合成涂覆型和键合型多糖类手性分离固定相,并利用HPLC评价其手性拆分性能,本论文研究工作分为三部分：
首先,利用苯胺和三光气,合成苯基异氰酸酯,利用普通硅胶和3-氨丙基三乙氧基硅烷,制备氨丙基化多孔硅胶,通过1H核磁共振和红外光谱表征其结构。
然后,合成了纤维素-三(苯基氨基甲酸酯)(CSP-1)和直链淀粉-三(苯基氨基甲酸酯)(CSP-2)衍生物,制备HPLC用涂覆型手性固定相。在常规流动相正己烷/异丙醇(90/10,v/v)的条件下,考察两类色谱柱对7种典型的手性对映体的手性拆分能力。实验结果表明：这两类手性固定相对一些对映体都表现出很好的手性拆分性能,总体上来说,CSP-1和CSP-2在手性拆分性能方面相互补充,一些在CSP-1上不能拆分的对映体,在CSP-2上却得到很好的拆分,反之亦然。
最后,通过“一锅法”合成了含有不同硅氧烷基团(1%、2%、3%)含量的纤维素和直链淀粉苯基氨基甲酸酯衍生物,利用1H核磁共振和红外光谱表征衍生物结构,利用热失重测试键合效率；通过硅氧烷基团在酸性条件下的水解、缩合,可简单、高效地实现在氨丙基硅胶表面的化学键合,制得键合型HPLC用手性分离固定相,可以使用强极性有机溶剂作为流动相,通过调整流动相中含有氯仿(CDC13)或者四氢呋喃(THF)的成分和配比,不但克服了涂覆型手性色谱柱流动相选择溶剂受限的问题,还可极大地提高手性拆分性能。一些在涂覆型固定相中无法分离的对映体,得到了很好的拆分,扩大了流动相的选择范围,实现外消旋化合物的最佳手性拆分,并且延长了手性柱的使用寿命。
As is known to all, a pair of optically pure enantiomers may show great different pharmacological and toxicological activities, and therefore, the separation of enantiomers has been becoming increasingly important. Enantioseparation has been one of the important ways to obtain optical purity compounds, which plays an important role in modern synthetic chemistry, bio-medicine, and agricultural chemicals and so on. Numerous chiral separation methods have been successfully applied to enantiomeric resolution and preparation, such as biological separation, crystallization, chemical separation method, asymmetric conversion, chromatography and so on. Among these methods, the high-performance liquid chromatographic separation of enantiomers using chiral stationary phase (CSPs) is a direct-fast and great potential method, which is important for determining enantiomeric purities and preparing separation for a large scale. The polysaccharide such as cellulose and amylose derivatives are the most widely used in a great deal of CSPs.
The esters and carbamates of polysaccharide coated on aminopropyl silica gel have been greatly studied and widely applied for the high-performance liquid chromatography (HPLC) as CSPs. Most of them which exhibit broad applicability to a large number of chiral racemates can be used for a long time with a hexane-isopropanol (90/10, v/v) as the eluent. However, they usually have the shortcomings of poor properties of resisting solvent. The CSPs of immobilized polysaccharide derivatives on aminopropyl silica gel overcome the strict solvent limitation of eluents and have greater flexibility in enantiomeric resolution and preparation.
This paper mainly focus on the synthesis and resolution ability of polysaccharide-based coated-type and immobilized-type chiral separation stationary phase which include three parts as the following:
Firstly, we prepared the raw materials phenyl isocyanate and aminopropyl silica gel, which structures were characterized by 1H NMR and IR spectrum.
Secondly, cellulose and amylose tris(phenylcarbamate) derivatives were synthesized, respectively. 1H nuclear magnetic resonance (1H NMR) and infrared spectroscopy (IR) showed that most of the hydroxyl groups on glucose untis of the cellulose or amylose had been converted into carbamate groups. The chiral stationary phases (CSPs) were prepared by coating CSP-1 or CSP-2 on the aminopropyl silica gel. The chiral recognition abilities of obtained derivatives were evaluated by using 7 typical racemates and a hexane/isopropanol (90/10, v/v) mixture as the eluent. The experimental results show that some racemates were better resolved on the two CSPs. On the whole, CSP-1 and CSP-2 have different chiral resolution ability of some enantiomers. Although CSP-1 has better chiral recognition ability than CSP-2, some racemates which can not be resovled on CSP-1 were better resolved on CSP-2.
Finally, the phenycarbamates of cellulose and amylose bearing different amounts of 3-(triethoxysilyl)propyl residues (1%,2%,3%) were synthesized by a one-pot process and efficiently immobilized onto a silica gel through intermolecular polycondensation of the triethoxysilyl groups under acid condition. The structure of the synthesized polysaccharide derivatives was characterized by 1H NMR and IR. The obtained chiral packing materials (CPMs) were evaluated by HPLC. The immobilization efficiencies were calculated by TG. By using the eluents containing chloroform or tetrahydrofuran, which cannot be used with the conventional coated-type CPMs, most of the racemates could be better resolved on immobilized-type CSPs than coated-type CSPs. Many racemates, which can not be resolved on the coated-type CPMs, could be separated on immobilized-type CSPs.
引文
[1]陈立仁.液相色谱手性分离[M].北京：科学出版社,2006.
[2]杜祖银.键合型高效液相色谱手性固定相的制备及其拆分性能研究[D].天津：天津理工大学,2005.
[3]潘春秀.高效液相色谱手性固定相分离药物对映体[D].浙江：浙江大学,2005.
[4]尤田耙.手性化合物现代研究方法[M].合肥：中国科技大学出版社,1993.
[5]Anastas P T, Warner J C. Green chemistry theory and practice[M]. New York:oxford university press,1998.
[6]危凤.纤维素三苯基氨基甲酸酯手性固定相的研制与奥美拉唑的手性色谱分离[D].杭州：浙江大学,2003.
[7]付春江,王军,余立新等.手性选择性阳离子交换膜的制备及其评价[J].高等化学工程学报,2007,21(4)：206-210.
[8]Crosby J. Synthesis of optically active compounds:a large scale perspective [J]. Tetrahedrom,1991,47(27):4789-4846.
[9]袁黎明.手性拆别材料[M].北京：科学出版社,2010.
[10]王明媚.手性药物的制备方法[J].医学导报,2004,25(4)：325-327.
[11]任国宾,詹予忠,郭士岭.手性拆分技术进展[J].河南化工,2002(1)：1-3.
[12]Maier N M, Franco P, Lindner W. Separation of enantiomers:needs, challenges, perspectives[J]. J. Chromatogr. A,2001,906:3.
[13]Yamada S, Hongo C, Ryuzo Y. Preparation of D-P-hydroxyphenylglycine optical resolution of DL-p-hydroxyphenylglycine with d-3-bromocamphor-8-sulfonic acid[J]. Agric. Biol. Chem,1979,43 (2):395-396.
[14]Shirai T, Tashiror R, Aoki S. Process for the preparation of optically active p-hydroxyphenylglycine[P]. US:4002006,1997-01-11.
[15]Degner D, Pander H J, Siegel H.4-Tert-butoxyphenylg-lycinonitrile and the preparation of D-(-) and L-(+)-4-hydroxyphenylglycine[P]. US:4350641,1982-09-21.
[16]车超,代星,毛淑芬等.手性仲丁胺的制备拆分和光学纯度的测定[J].有机化学,2002,3(4)：390.
[17]汪朝阳.手性技术[J].自然杂质,2002,24(4)：219-223.
[18]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(6)： 375-380.
[19]林国强,陈耀全,陈新滋等.手性合成——不对称反应及其应用[M].北京：科学出版社,2000：1.
[20]冯洪珍,孟昭力,王如斌.手性药物拆分的几种方法及研究进展[J].广东药学院学报,2003.19(1)：153-155.
[21]Henry J D, in:Alternative separation processes, Perry R H, Green D W, Maloney J O(Eds)[M]. Perry's Chemical Engineerings'Handbook, McGraw-Hill, New York:1984, 22-37.
[22]Nozal M J, Toribio L, Bernal J L, et al. Separation of albendazole sulfoxide enantiomers by chiral supereritieal-fluid ehro matography[J]. J Bioehem Biophys Methods,2002,54 (1—3):339.
[23]陈立仁.液相色谱手性分离[R].报告地：首届中国西部地区色谱学术交流会,2006.
[24]李兵.纤维素衍生物固定相的制备及其在色谱分离中的应用[D].杭州：浙江工业大学,2000.
[25]傅若农.色谱分析概论[M].北京：化学工业出版社,2000：188.
[26]达世禄,徐伟,董亚琼.手性高效液相色谱固定相[J].化学通报,1997,2：33-44.
[27]Hassan Y, Aboul E. High-performance liquid chromatographic enantioseparation of drugs containing multiple chiral centers on polysacharide-type chiral stationary phases [J]. J. Chromatogr. A.,2001,906:185-193.
[28]孟磊,袁黎明.纤维素及其衍生物作为高效液相色谱手性固定相的研究进展[J].化学试剂,2001,23(4)：220-223.
[29]Ye Y K, Slzingham R W, Wirth M J. Origin of enhanced chiral selectivity by acidic additives for a polysaccharide-based stationary phase[J]. J. Chromatogr. A.,2004,1057(1-2): 75-82.
[30]Wainer I W. Proposal for the classification of high-performance liquid chromatographic chiral stationary phase:how to choose the right column[J]. Trends Anal. Chem.,1987,6:125 —158.
[31]李发美,张丹丹,玄明浩.Pirkle型手性固定相的新发展与新应用[R].报告地：第十五次全国色谱学术报告会,2005年.
[32]Pirkle W H, Welch C J J. Chromatographic separation of the enantiomers of acylated amines on chiral stationary phases. Org. Chem.1984,49:138.
[33]Oi N, Nagase M, Sawada Y. High-performance liquid chromatographic separation of enantiomers on striazine derivatives of a tripeptide ester and a chiral amine bonded to silica gel. J. Chromatogr.,1984,292:427.
[34]刘育,尤长城,张衡益.超分子化学[M].天津：南开大学出版社,2001,166.
[35]李莉,字敏,任朝兴等.气相色谱手性固定相研究进展.化学进展,2007,19(2-3)：393.
[36]Armstrong D W. Ward T J. Pattabiraman N. et al. Separation of tamoxifen geometric isomers and metabolites by bonde-phase β-cyclodextrin chromatography. J. Chromatorgr., 1987,414:192.
[37]Armstrong D W, Ward T J. Armstrong, et al. Separation of drug stereoisomers by the formation of beta-cyclodextrin inclusion complexes. Science,1986,232:1132.
[38]Armstrong D W, Tang Y B, Chen S S, et al. Macrocyclic antibiotics as a new class of selectors for Liquid chromatography. Anal. Chem.,1994,66:1473.
[39]Beesley T E, Chirobiotic Handbook.3rd ed. Compton: Advanced Technologies Inc. 1999.
[40]Dent C E. A study of the behaviour of some sixty amino-acids and other ninhydrinreacting substances onphenolcollidine filter-paper chromatograms, with notes as to the occurrence of some of in biological fluids. Biochem. J.,1948,43:169-180.
[41]Kotake M, Sakan T, Senoh S. Studies on amino acid. Ⅳ. The synthesis of 3-hydroxykynurenine. J. Am. Chem. Soc.,1951,73:1832-1834.
[42]Dalgliesh C E. The synthesis of N-formyl-DL-Kynurenine, N a-acetyl-DL-kynurenine and related compounds, and observations on the synthesis of kynurenine. J. Chem. Soc.,1952, 137:3940-3942.
[43]Kusters E, Loux V, Schmid E. Enantiomeric eparation of chiral sulphoxides:Screening of cellulose-based sorbents with particular reference to cellulose tribenzoate[J]. J. Chromatogr. A.,1994,666:421-432.
[44]Hesse G, Hagel R. Eine vollstandige racemattrennung durch elutions-chromatographie an cellulose-tri-acetar. Chromatographia,1973,6:277.
[45]Hesse G, Hagel R. Chromatographic resolution of racemates. Liebigs Ann. Chem.,1976, 916.
[46]Blaschke G, Chromatographic resolution of chiral drugs on polyamides and cellulose triacetate J. Lip. Chromatogr.,1986,9:341.
[47]Shibata T, Okamoto Y, Ishii K. Chromatographic optical resolution on polysaccharides and their derivatives. J. Liq. Chromatogr.,1986,9:313.
[48]Francotte E. In:Aboul-Enein H Y, Wainer I W(Ed). The Impact of Stereo chemistry on Drug Development and Use. New York:Wiley,1997,23:633-683.
[49]Rimbock K H, Cuyegberg M A, Mannschreck A. Triacetylcellulose on silica compared with non-dilute triacetylcellulose I as a high-performance liquid chromatographic sorbent. Chromatographia,1986,21:223.
[50]Okamoto Y, Yashima E. Polysaccharide derivatives for chromatographic separation of enantiomers. Angew. Chem., Int. Ed.1998,37:1020.
[51]Ichida A, Shibata T, Okamoto I et al. Resolution of enantiomers by HPLC on cellulose derivatives. Chromatographia,1984,19:280.
[52]Shibata T, Okamoto I, Ishii K. Chromatographic optical resolution on polysaccharides and their derivatives. J. Lip. Chromatogr.,1986,9:313.
[53]Blaschke G. Chromatographic resolution of chiral drugs on polyamides and cellulose triacetate. J. Lip. Chromatogr.,1986,9(2-3):341.
[54]Okamoto Y, Aburatami R, Hatada K. Chromatographic chiral resolution:XIV. Cellulose tribenzoate derivatives as chiral stationary phases for high-performance liquid chromatography. J. Chromatogr. A.,1987,389:95.
[55]Wainer I W, Alembik M C. Resolution of enantiomeric amides on a cellulose-based chiral stationary phase:Steric and electronic effects. J. Chromatogr.,1986,358:85.
[56]Wainer I W, Alembik M C, Smith E. Resolution of enantiomeric amides on a cellulose tribenzoate chiral stationary phase:Mobie phase modifier effects on retention and stero-selectivity. J. Chromatogr.,1987,388:65.
[57]Wainer I W, Stiffin R M, Shibata T. Resolution of enantiomeric aromatics alcohols on a cellulose tribenzoate high-performance liquid chromatography chiral stationary phase:A proposed chiral recognition mechanism. J. Chromatogr.,1987,411:139.
[58]Corey E J, Letavie M A. Enantioselective total synthesis of gracilins B and C using catalytic asymmetric Dies-Alder methodology. J. Am. Chem. Soc.,1995,117:9616.
[59]Amadji M, Vadecarda J, Plaquevent J C, et al. First catalytic enantioselective proton abstraction using chiral alkoxides. J. Am. Chem. Soc.,1996,118:12483.
[60]Nakajima M, Sasaki Y, Shiro M, et al. A novel axially dissmmetric chiral ligand based on amine N-oxide:(R)-and (S)-3,3'-dimethyI-2,2-biquinoline N,N'-dioxide.Tetrahedro: Asymmetry,1997,8:341.
[61]Okamoto Y, Kaida Y. Resolution by high-performance liquid chromatography using polysaccharide carbamates and benzoates as chiral stationary phase. J. Chromatogr. A.,1994, 666:40331.
[62]Vogt U, Zugenmaier P. Presented at the European Science Foundation Workshop on Scientific Interaction in Polysaccharide Systems, Uppsala.1983,1.
[63]Okamoto Y, Kaida Y, Hayashida H. Tri(1-phenylethylcarbamate)s cellulose and amylose as useful chiral stationary phases for chromatographic optical resolution. Chem. Lett.,1990,909:912.
[64]Okamoto Y, Abuyatani R, Fukumoto T, et al. Useful chiral stationary phases for HPLC. Amylose tri(3,5-dimethylcarmate) and tri(3,5-dilorophenylcarbamate) support on silica gel. Chem. Lett.,1987,20:1857.
[65]Tang A W, Ikai T, Tsuji M, Okamoto Y. Immobilization and chiral recognition of 3,5-dimethylphenylcarbamates of cellulose and amylose bearing 4-(trimethoxysilyl)phenyl carbamate groups. Chirality,2010,22:165.
[66]Chankvetadze B, Yashima E, Okamoto Y. Dimethyl-, dichloro-and chloromethylphenyl carbamates of amylose as chiral stationary phases for high-performance liquid chromatography. J. Chromatogr. A,1995,694:101.
[67]Yashima E, Okamoto Y. Chiral discrimination on polysaccharides deriveatives. Bull. Chem. Jpn.,1995,68:3289.
[68]Levin S, Sterin M, Abu-Lafi S. Structural features affecting chiral resolution of cannabimimetic enantiomers by amylose 3,5-dimethylphenylcarbamate chiral stationary phase. Chirality,1995,7:140.
[69]William H W. Direct enantiomeric resolution of ibuprofen and flubiprofen by packed column SFC. Chirality,1994,6:216.
[70]Dindene J. In:Subramanian G(Ed). A practical Approach to Chiral Separation by Liquid Chramatography. New York:VCH,1994,115.
[71]马桂娟,龚波林,阎超.L-异亮氨酸聚合物手性配体交换固定相的制备及对DL-氨基酸的拆分[J].应用化学,2009(02)：125-129.
[72]邹汉法,张玉奎,卢佩章.高效液相色谱法[M].北京：科学出版社,2001.
[73]Sousa L R, Sopah Y. Host-guest complexation.12. Total optical resolution of amine and amino ester salts by chromatography[J]. J. Am. Chem. Soc,1978,100:4569.
[74]Shinbo T, Yamaguchi T, Yanagishita H, et al. Improved crown ether-based chiral stationary phase[J]. J.Chromalogr. A.,1992,625:101-108.
[75]邹公伟,郑琦,胡冠九,施耀曾.高效液相色谱中的纤维素衍生物手性固定相.分析化学,1995,23(4)：466-473.
[76]Okamoto Y, Aburatani R, Miura S. Chiral stationary phases for HPLC:cellulose tris(3,5-dimethylphenyl-carbamate) and tris(3,5-dichloro-phenylcarbamate) chemically bonded to silica gel. J. Lip. Chromatogr.,1987,10(8-9):1613-1628.
[77]Yashima E, Fukaya H, Okamoto Y.3,5-Dimethylphenylcarbamates of cellulose and amylose regioselectively bonded to silica gel as chiral phases for high-performance liquid chromatography. J. Chromatogr A.,1994,677:11-19.
[78]Chem X M, Liu Y Q, Qin F, et al. Synthesis of covalently bonded chiral stationary phases based on cellulose derivatives with a bifunctional reagent of 3-(triethoxysilyl)propyl isocyanate. J. Chromatogr. A.,2003,1010:185-194.
[79]Chem X M, Jin W H, Qin F, et al. Electrochromatographic separation of enantiomers on chemically bonded type of cellulose derivatives chiral stationary phases with a positively charged spacer. Electroporesis,2003,24:2559-2566.
[80]Ikai T, Yamamoto C, Kamigaitio M, et al. Efficient immobilization of cellulose phenylcarbamate bearing alkoxysilyl group onto silica gel by intermolecular polycondensation and its chiral recognition. Chem. Lett.2006,35:1250-1251.
[81]Ikai T, Yamamoto C, Kamigaitio M, et al. Immobilization of polysaccharide derivatives onto silica gel facile synthesis of chiral packing materials by means of intermolecular polycondensation of triethoxysilyl groups. J. Chromatogr. A.,2007,1157:151-158.
[82]Li J Q, Ikai T, Okamoto Y. Preparation and application of chiral stationary phase from 4-tert-butylphenylcarbamates of cellulose and amylose immobilized onto silica gel[J]. Journal of Separation Science,2009,32(17):2885-2891.
[83]王俊德,商振华,郁蕴璐.高效液相色谱法[M].北京：中国石化出版社,1992：107.
[84]侯经国,邓启良,邓晓蓉等.纤维素-三(3,5-二甲基苯基氨基甲酸酯)涂覆手性固定相的制备、表征及评价[J].色谱,2001,19(2)：154-156.
[85]韩莹,屠树滋.异氰酸酯的简单合成.化学试剂,2002,24(6),375.
[86]陈冠荣.化工百科全书[M].北京：化学工业出版社,1998.209-220.
[87]Apler H, Smith D J H. Process for the production of carbamate esters[P]. EP:O 173 457, 1986.
[88]邢凤兰,徐群,徐孙见.三光气代替光气合成系列化合物的研究和应用[J].精细与专用化学品,2006,14(21)：11-15.
[89]季宝,翟现明,许毅.三光气的反应机理和应用[J].2009,19(10)：136-137.
[90]崔小明.三光气的制备及应用[J].中国氯碱,1999(12)：29-30.
[91]王向辉,贺永宁,盘茂东等.三光气合成取代苯异氰酸酯[J].2008,37(9)：1019-1021.
[92]梁日忠,任强.4-氯苯基异氰酸酯的合成[J].河南化工,1998(4)：42.
[93]苏为科,李永曙,蔡鸿飞.异氰酸酯的化学合成方法[P].中国专利,02130077.1,2004-02-18.
[2]杜祖银.键合型高效液相色谱手性固定相的制备及其拆分性能研究[D].天津：天津理工大学,2005.
[3]潘春秀.高效液相色谱手性固定相分离药物对映体[D].浙江：浙江大学,2005.
[4]尤田耙.手性化合物现代研究方法[M].合肥：中国科技大学出版社,1993.
[5]Anastas P T, Warner J C. Green chemistry theory and practice[M]. New York:oxford university press,1998.
[6]危凤.纤维素三苯基氨基甲酸酯手性固定相的研制与奥美拉唑的手性色谱分离[D].杭州：浙江大学,2003.
[7]付春江,王军,余立新等.手性选择性阳离子交换膜的制备及其评价[J].高等化学工程学报,2007,21(4)：206-210.
[8]Crosby J. Synthesis of optically active compounds:a large scale perspective [J]. Tetrahedrom,1991,47(27):4789-4846.
[9]袁黎明.手性拆别材料[M].北京：科学出版社,2010.
[10]王明媚.手性药物的制备方法[J].医学导报,2004,25(4)：325-327.
[11]任国宾,詹予忠,郭士岭.手性拆分技术进展[J].河南化工,2002(1)：1-3.
[12]Maier N M, Franco P, Lindner W. Separation of enantiomers:needs, challenges, perspectives[J]. J. Chromatogr. A,2001,906:3.
[13]Yamada S, Hongo C, Ryuzo Y. Preparation of D-P-hydroxyphenylglycine optical resolution of DL-p-hydroxyphenylglycine with d-3-bromocamphor-8-sulfonic acid[J]. Agric. Biol. Chem,1979,43 (2):395-396.
[14]Shirai T, Tashiror R, Aoki S. Process for the preparation of optically active p-hydroxyphenylglycine[P]. US:4002006,1997-01-11.
[15]Degner D, Pander H J, Siegel H.4-Tert-butoxyphenylg-lycinonitrile and the preparation of D-(-) and L-(+)-4-hydroxyphenylglycine[P]. US:4350641,1982-09-21.
[16]车超,代星,毛淑芬等.手性仲丁胺的制备拆分和光学纯度的测定[J].有机化学,2002,3(4)：390.
[17]汪朝阳.手性技术[J].自然杂质,2002,24(4)：219-223.
[18]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(6)： 375-380.
[19]林国强,陈耀全,陈新滋等.手性合成——不对称反应及其应用[M].北京：科学出版社,2000：1.
[20]冯洪珍,孟昭力,王如斌.手性药物拆分的几种方法及研究进展[J].广东药学院学报,2003.19(1)：153-155.
[21]Henry J D, in:Alternative separation processes, Perry R H, Green D W, Maloney J O(Eds)[M]. Perry's Chemical Engineerings'Handbook, McGraw-Hill, New York:1984, 22-37.
[22]Nozal M J, Toribio L, Bernal J L, et al. Separation of albendazole sulfoxide enantiomers by chiral supereritieal-fluid ehro matography[J]. J Bioehem Biophys Methods,2002,54 (1—3):339.
[23]陈立仁.液相色谱手性分离[R].报告地：首届中国西部地区色谱学术交流会,2006.
[24]李兵.纤维素衍生物固定相的制备及其在色谱分离中的应用[D].杭州：浙江工业大学,2000.
[25]傅若农.色谱分析概论[M].北京：化学工业出版社,2000：188.
[26]达世禄,徐伟,董亚琼.手性高效液相色谱固定相[J].化学通报,1997,2：33-44.
[27]Hassan Y, Aboul E. High-performance liquid chromatographic enantioseparation of drugs containing multiple chiral centers on polysacharide-type chiral stationary phases [J]. J. Chromatogr. A.,2001,906:185-193.
[28]孟磊,袁黎明.纤维素及其衍生物作为高效液相色谱手性固定相的研究进展[J].化学试剂,2001,23(4)：220-223.
[29]Ye Y K, Slzingham R W, Wirth M J. Origin of enhanced chiral selectivity by acidic additives for a polysaccharide-based stationary phase[J]. J. Chromatogr. A.,2004,1057(1-2): 75-82.
[30]Wainer I W. Proposal for the classification of high-performance liquid chromatographic chiral stationary phase:how to choose the right column[J]. Trends Anal. Chem.,1987,6:125 —158.
[31]李发美,张丹丹,玄明浩.Pirkle型手性固定相的新发展与新应用[R].报告地：第十五次全国色谱学术报告会,2005年.
[32]Pirkle W H, Welch C J J. Chromatographic separation of the enantiomers of acylated amines on chiral stationary phases. Org. Chem.1984,49:138.
[33]Oi N, Nagase M, Sawada Y. High-performance liquid chromatographic separation of enantiomers on striazine derivatives of a tripeptide ester and a chiral amine bonded to silica gel. J. Chromatogr.,1984,292:427.
[34]刘育,尤长城,张衡益.超分子化学[M].天津：南开大学出版社,2001,166.
[35]李莉,字敏,任朝兴等.气相色谱手性固定相研究进展.化学进展,2007,19(2-3)：393.
[36]Armstrong D W. Ward T J. Pattabiraman N. et al. Separation of tamoxifen geometric isomers and metabolites by bonde-phase β-cyclodextrin chromatography. J. Chromatorgr., 1987,414:192.
[37]Armstrong D W, Ward T J. Armstrong, et al. Separation of drug stereoisomers by the formation of beta-cyclodextrin inclusion complexes. Science,1986,232:1132.
[38]Armstrong D W, Tang Y B, Chen S S, et al. Macrocyclic antibiotics as a new class of selectors for Liquid chromatography. Anal. Chem.,1994,66:1473.
[39]Beesley T E, Chirobiotic Handbook.3rd ed. Compton: Advanced Technologies Inc. 1999.
[40]Dent C E. A study of the behaviour of some sixty amino-acids and other ninhydrinreacting substances onphenolcollidine filter-paper chromatograms, with notes as to the occurrence of some of in biological fluids. Biochem. J.,1948,43:169-180.
[41]Kotake M, Sakan T, Senoh S. Studies on amino acid. Ⅳ. The synthesis of 3-hydroxykynurenine. J. Am. Chem. Soc.,1951,73:1832-1834.
[42]Dalgliesh C E. The synthesis of N-formyl-DL-Kynurenine, N a-acetyl-DL-kynurenine and related compounds, and observations on the synthesis of kynurenine. J. Chem. Soc.,1952, 137:3940-3942.
[43]Kusters E, Loux V, Schmid E. Enantiomeric eparation of chiral sulphoxides:Screening of cellulose-based sorbents with particular reference to cellulose tribenzoate[J]. J. Chromatogr. A.,1994,666:421-432.
[44]Hesse G, Hagel R. Eine vollstandige racemattrennung durch elutions-chromatographie an cellulose-tri-acetar. Chromatographia,1973,6:277.
[45]Hesse G, Hagel R. Chromatographic resolution of racemates. Liebigs Ann. Chem.,1976, 916.
[46]Blaschke G, Chromatographic resolution of chiral drugs on polyamides and cellulose triacetate J. Lip. Chromatogr.,1986,9:341.
[47]Shibata T, Okamoto Y, Ishii K. Chromatographic optical resolution on polysaccharides and their derivatives. J. Liq. Chromatogr.,1986,9:313.
[48]Francotte E. In:Aboul-Enein H Y, Wainer I W(Ed). The Impact of Stereo chemistry on Drug Development and Use. New York:Wiley,1997,23:633-683.
[49]Rimbock K H, Cuyegberg M A, Mannschreck A. Triacetylcellulose on silica compared with non-dilute triacetylcellulose I as a high-performance liquid chromatographic sorbent. Chromatographia,1986,21:223.
[50]Okamoto Y, Yashima E. Polysaccharide derivatives for chromatographic separation of enantiomers. Angew. Chem., Int. Ed.1998,37:1020.
[51]Ichida A, Shibata T, Okamoto I et al. Resolution of enantiomers by HPLC on cellulose derivatives. Chromatographia,1984,19:280.
[52]Shibata T, Okamoto I, Ishii K. Chromatographic optical resolution on polysaccharides and their derivatives. J. Lip. Chromatogr.,1986,9:313.
[53]Blaschke G. Chromatographic resolution of chiral drugs on polyamides and cellulose triacetate. J. Lip. Chromatogr.,1986,9(2-3):341.
[54]Okamoto Y, Aburatami R, Hatada K. Chromatographic chiral resolution:XIV. Cellulose tribenzoate derivatives as chiral stationary phases for high-performance liquid chromatography. J. Chromatogr. A.,1987,389:95.
[55]Wainer I W, Alembik M C. Resolution of enantiomeric amides on a cellulose-based chiral stationary phase:Steric and electronic effects. J. Chromatogr.,1986,358:85.
[56]Wainer I W, Alembik M C, Smith E. Resolution of enantiomeric amides on a cellulose tribenzoate chiral stationary phase:Mobie phase modifier effects on retention and stero-selectivity. J. Chromatogr.,1987,388:65.
[57]Wainer I W, Stiffin R M, Shibata T. Resolution of enantiomeric aromatics alcohols on a cellulose tribenzoate high-performance liquid chromatography chiral stationary phase:A proposed chiral recognition mechanism. J. Chromatogr.,1987,411:139.
[58]Corey E J, Letavie M A. Enantioselective total synthesis of gracilins B and C using catalytic asymmetric Dies-Alder methodology. J. Am. Chem. Soc.,1995,117:9616.
[59]Amadji M, Vadecarda J, Plaquevent J C, et al. First catalytic enantioselective proton abstraction using chiral alkoxides. J. Am. Chem. Soc.,1996,118:12483.
[60]Nakajima M, Sasaki Y, Shiro M, et al. A novel axially dissmmetric chiral ligand based on amine N-oxide:(R)-and (S)-3,3'-dimethyI-2,2-biquinoline N,N'-dioxide.Tetrahedro: Asymmetry,1997,8:341.
[61]Okamoto Y, Kaida Y. Resolution by high-performance liquid chromatography using polysaccharide carbamates and benzoates as chiral stationary phase. J. Chromatogr. A.,1994, 666:40331.
[62]Vogt U, Zugenmaier P. Presented at the European Science Foundation Workshop on Scientific Interaction in Polysaccharide Systems, Uppsala.1983,1.
[63]Okamoto Y, Kaida Y, Hayashida H. Tri(1-phenylethylcarbamate)s cellulose and amylose as useful chiral stationary phases for chromatographic optical resolution. Chem. Lett.,1990,909:912.
[64]Okamoto Y, Abuyatani R, Fukumoto T, et al. Useful chiral stationary phases for HPLC. Amylose tri(3,5-dimethylcarmate) and tri(3,5-dilorophenylcarbamate) support on silica gel. Chem. Lett.,1987,20:1857.
[65]Tang A W, Ikai T, Tsuji M, Okamoto Y. Immobilization and chiral recognition of 3,5-dimethylphenylcarbamates of cellulose and amylose bearing 4-(trimethoxysilyl)phenyl carbamate groups. Chirality,2010,22:165.
[66]Chankvetadze B, Yashima E, Okamoto Y. Dimethyl-, dichloro-and chloromethylphenyl carbamates of amylose as chiral stationary phases for high-performance liquid chromatography. J. Chromatogr. A,1995,694:101.
[67]Yashima E, Okamoto Y. Chiral discrimination on polysaccharides deriveatives. Bull. Chem. Jpn.,1995,68:3289.
[68]Levin S, Sterin M, Abu-Lafi S. Structural features affecting chiral resolution of cannabimimetic enantiomers by amylose 3,5-dimethylphenylcarbamate chiral stationary phase. Chirality,1995,7:140.
[69]William H W. Direct enantiomeric resolution of ibuprofen and flubiprofen by packed column SFC. Chirality,1994,6:216.
[70]Dindene J. In:Subramanian G(Ed). A practical Approach to Chiral Separation by Liquid Chramatography. New York:VCH,1994,115.
[71]马桂娟,龚波林,阎超.L-异亮氨酸聚合物手性配体交换固定相的制备及对DL-氨基酸的拆分[J].应用化学,2009(02)：125-129.
[72]邹汉法,张玉奎,卢佩章.高效液相色谱法[M].北京：科学出版社,2001.
[73]Sousa L R, Sopah Y. Host-guest complexation.12. Total optical resolution of amine and amino ester salts by chromatography[J]. J. Am. Chem. Soc,1978,100:4569.
[74]Shinbo T, Yamaguchi T, Yanagishita H, et al. Improved crown ether-based chiral stationary phase[J]. J.Chromalogr. A.,1992,625:101-108.
[75]邹公伟,郑琦,胡冠九,施耀曾.高效液相色谱中的纤维素衍生物手性固定相.分析化学,1995,23(4)：466-473.
[76]Okamoto Y, Aburatani R, Miura S. Chiral stationary phases for HPLC:cellulose tris(3,5-dimethylphenyl-carbamate) and tris(3,5-dichloro-phenylcarbamate) chemically bonded to silica gel. J. Lip. Chromatogr.,1987,10(8-9):1613-1628.
[77]Yashima E, Fukaya H, Okamoto Y.3,5-Dimethylphenylcarbamates of cellulose and amylose regioselectively bonded to silica gel as chiral phases for high-performance liquid chromatography. J. Chromatogr A.,1994,677:11-19.
[78]Chem X M, Liu Y Q, Qin F, et al. Synthesis of covalently bonded chiral stationary phases based on cellulose derivatives with a bifunctional reagent of 3-(triethoxysilyl)propyl isocyanate. J. Chromatogr. A.,2003,1010:185-194.
[79]Chem X M, Jin W H, Qin F, et al. Electrochromatographic separation of enantiomers on chemically bonded type of cellulose derivatives chiral stationary phases with a positively charged spacer. Electroporesis,2003,24:2559-2566.
[80]Ikai T, Yamamoto C, Kamigaitio M, et al. Efficient immobilization of cellulose phenylcarbamate bearing alkoxysilyl group onto silica gel by intermolecular polycondensation and its chiral recognition. Chem. Lett.2006,35:1250-1251.
[81]Ikai T, Yamamoto C, Kamigaitio M, et al. Immobilization of polysaccharide derivatives onto silica gel facile synthesis of chiral packing materials by means of intermolecular polycondensation of triethoxysilyl groups. J. Chromatogr. A.,2007,1157:151-158.
[82]Li J Q, Ikai T, Okamoto Y. Preparation and application of chiral stationary phase from 4-tert-butylphenylcarbamates of cellulose and amylose immobilized onto silica gel[J]. Journal of Separation Science,2009,32(17):2885-2891.
[83]王俊德,商振华,郁蕴璐.高效液相色谱法[M].北京：中国石化出版社,1992：107.
[84]侯经国,邓启良,邓晓蓉等.纤维素-三(3,5-二甲基苯基氨基甲酸酯)涂覆手性固定相的制备、表征及评价[J].色谱,2001,19(2)：154-156.
[85]韩莹,屠树滋.异氰酸酯的简单合成.化学试剂,2002,24(6),375.
[86]陈冠荣.化工百科全书[M].北京：化学工业出版社,1998.209-220.
[87]Apler H, Smith D J H. Process for the production of carbamate esters[P]. EP:O 173 457, 1986.
[88]邢凤兰,徐群,徐孙见.三光气代替光气合成系列化合物的研究和应用[J].精细与专用化学品,2006,14(21)：11-15.
[89]季宝,翟现明,许毅.三光气的反应机理和应用[J].2009,19(10)：136-137.
[90]崔小明.三光气的制备及应用[J].中国氯碱,1999(12)：29-30.
[91]王向辉,贺永宁,盘茂东等.三光气合成取代苯异氰酸酯[J].2008,37(9)：1019-1021.
[92]梁日忠,任强.4-氯苯基异氰酸酯的合成[J].河南化工,1998(4)：42.
[93]苏为科,李永曙,蔡鸿飞.异氰酸酯的化学合成方法[P].中国专利,02130077.1,2004-02-18.