纤维素三苯甲酸酯手性固定相制备及分离的研究
摘要
随着人们对手性化合物研究和认识的不断深入，手性拆分技术在医药、医药中间体中的应用正逐步为全世界医药卫生界所重视。手性固定相拆分技术以其高拆分效率、低运行成本、无污染等优势，在众多手性拆分技术中，显示出强大的优势，正逐步得到广泛应用。
本文对应用前景广泛的纤维素三苯甲酸酯手性固定相合成及手性拆分技术展开研究，从纤维素三苯甲酸酯的合成、固定相的浸渍、应用高效液相色谱评价固定相三方面，完成了纤维素三苯甲酸酯手性固定相的制备及评价工作。
吸收前人合成工艺的经验及教训，通过改变合成催化剂，改善了反应条件，缓解了反应结焦问题；同时优化结晶工艺，提高了产品质量及总反应收率，得到了高质量的纤维素三苯甲酸酯纯品。应用元素分析、红外光谱分析对制备得到的纤维素三苯甲酸酯进行评价，结果优于文献报道，同时证明了优化结晶技术，有助于提高纤维素三苯甲酸酯的纯度。
通过比较多种浸渍的方法把制备得到的纤维素三苯甲酸酯涂敷于烷基化硅胶上，最终选用等体积浸渍法得到了涂覆均匀、颗粒无团聚的优质手性固定相；根据用途需要，采用φ5μm、φ40μm的担体，制备了可用于高效液相色谱、制备级色谱的手性固定相。同时，本文对比等体积浸渍与非等体积浸渍，测定了不同颗粒直径硅胶浸渍过程中粒径分布、孔径分布数据，并对其进行了详细的讨论，得出了等体积浸渍法优于非等体积浸渍法的结论。
应用高效液相色谱系统对涂敷有纤维素三苯甲酸酯的手性固定相进行了评价。本文采用脉冲进样法选择适当的流动相、流速及检测器得到一系列检测峰，经过讨论，证明制备的纤维素三苯甲酸酯手性固定相具有较高的的手性拆分效力；并应用Origin 7.0及Peak Fitting Module 7.0软件，采用Gauss峰型数学模型函数进行拟合，并对拟合结果进行比较。通过讨论，得出在较低进样量下，Gauss峰形函数可较好的拟合色谱峰，拟合相关系数大于99％；在高进样量下，色谱柱过载，色谱峰不对称性严重，应用Gauss峰形函数拟合有较大偏差。
本文应用先进的合成工艺、优化的结晶技术及等体积浸渍技术，制备了高纯度的纤维素三苯甲酸酯手性固定相，为进一步研究以纤维素三苯甲酸酯手性固定相进行色谱分析、色谱分离、模拟移动床分离手性化合物和工业应用提供了物质
基础。
With the development on the research of chiral chemical compound, application of chiral split technology on pharmacy and pharmic intermediate was taken into account progressively. Chiral stationary phase split technology has the advantages of high split efficient, low running cost and non-pollution, which makes it widely used among many chiral split technologies.
The prospective were studied on this thesis. The preparation and evaluation of cellulose tribenzoate were committed from the synthesis, steep of stationary phase and characterization of stationary phase by high performance liquid chromatography.
Through changing synthetical catalyzer and improving the reaction condition, the damage of burn in reaction was alleviated. Also, the crystal craft was optimized to improve the product quality and overall reaction yield，and got high qualified and pure cellulose tribenzoate. The prepared cellulose tribenzoate was evaluated by elemental analysis and IR spectrum analysis. It showed better results than those reported from literature and proved that the optimization of crystal craft contributed improving the purity of cellulose tribenzoate。
By comparison of cellulose tribenzoate coated alkylating silica gels via multiple method of steep, isometric steep method was ultimately chosen to get uniform-coated and high quality chiral stationary phase without particle agglomeration. φ5μm andφ40μm carrier were used to prepare the chiral stationary phase for high performance liquid chromatography and preparative chromatography under the necessity of application. Comparing the isometric steep and no-isometric steep，the distribution of particle diameter and distribution of pore diameter data during the steep of different particle diameter were measured and discussed in detail. The result showed that the method of isometric steep was better than the method no-isometric steep.
The cellulose tribenzoate coated chiral stationary phase was evaluated by system of high performance liquid chromatography. For the analysis of actual situation, appropriate mobile phase, flow rate and detector were chosen by impulse input method to get a series of chromatographic peaks in this thesis. By argumentation, the prepared cellulose tribenzoate have high chiral split ability. Origin 7.0 and Peak Fitting Module 7.0 software were used to fit the experimental data for math model based on the Gauss formula and these results were compared. From the discussion, it could be seen that the math model based on the Gauss formula can fit the chromatographic peaks well under the lower input volume and the fitted correlation coefficient was higher than 99%. Under higher input volume，however, the math model based on the Gauss formula had more fitting deviation, because the
chromatographic column was overloaded and chromatographic peak was severely asymmetry .
A advanced cellulose tribenzoate preparative method by advanced synthetic method, optimization of crystal craft and the method of isometric steep was reported in this thesis, which supported the base of chromatographic analysis, chromatographic separation, simulated moving bed to split chiral compound by cellulose tribenzoate as chiral stationary phase in lab and industry.
本文对应用前景广泛的纤维素三苯甲酸酯手性固定相合成及手性拆分技术展开研究，从纤维素三苯甲酸酯的合成、固定相的浸渍、应用高效液相色谱评价固定相三方面，完成了纤维素三苯甲酸酯手性固定相的制备及评价工作。
吸收前人合成工艺的经验及教训，通过改变合成催化剂，改善了反应条件，缓解了反应结焦问题；同时优化结晶工艺，提高了产品质量及总反应收率，得到了高质量的纤维素三苯甲酸酯纯品。应用元素分析、红外光谱分析对制备得到的纤维素三苯甲酸酯进行评价，结果优于文献报道，同时证明了优化结晶技术，有助于提高纤维素三苯甲酸酯的纯度。
通过比较多种浸渍的方法把制备得到的纤维素三苯甲酸酯涂敷于烷基化硅胶上，最终选用等体积浸渍法得到了涂覆均匀、颗粒无团聚的优质手性固定相；根据用途需要，采用φ5μm、φ40μm的担体，制备了可用于高效液相色谱、制备级色谱的手性固定相。同时，本文对比等体积浸渍与非等体积浸渍，测定了不同颗粒直径硅胶浸渍过程中粒径分布、孔径分布数据，并对其进行了详细的讨论，得出了等体积浸渍法优于非等体积浸渍法的结论。
应用高效液相色谱系统对涂敷有纤维素三苯甲酸酯的手性固定相进行了评价。本文采用脉冲进样法选择适当的流动相、流速及检测器得到一系列检测峰，经过讨论，证明制备的纤维素三苯甲酸酯手性固定相具有较高的的手性拆分效力；并应用Origin 7.0及Peak Fitting Module 7.0软件，采用Gauss峰型数学模型函数进行拟合，并对拟合结果进行比较。通过讨论，得出在较低进样量下，Gauss峰形函数可较好的拟合色谱峰，拟合相关系数大于99％；在高进样量下，色谱柱过载，色谱峰不对称性严重，应用Gauss峰形函数拟合有较大偏差。
本文应用先进的合成工艺、优化的结晶技术及等体积浸渍技术，制备了高纯度的纤维素三苯甲酸酯手性固定相，为进一步研究以纤维素三苯甲酸酯手性固定相进行色谱分析、色谱分离、模拟移动床分离手性化合物和工业应用提供了物质
基础。
With the development on the research of chiral chemical compound, application of chiral split technology on pharmacy and pharmic intermediate was taken into account progressively. Chiral stationary phase split technology has the advantages of high split efficient, low running cost and non-pollution, which makes it widely used among many chiral split technologies.
The prospective were studied on this thesis. The preparation and evaluation of cellulose tribenzoate were committed from the synthesis, steep of stationary phase and characterization of stationary phase by high performance liquid chromatography.
Through changing synthetical catalyzer and improving the reaction condition, the damage of burn in reaction was alleviated. Also, the crystal craft was optimized to improve the product quality and overall reaction yield，and got high qualified and pure cellulose tribenzoate. The prepared cellulose tribenzoate was evaluated by elemental analysis and IR spectrum analysis. It showed better results than those reported from literature and proved that the optimization of crystal craft contributed improving the purity of cellulose tribenzoate。
By comparison of cellulose tribenzoate coated alkylating silica gels via multiple method of steep, isometric steep method was ultimately chosen to get uniform-coated and high quality chiral stationary phase without particle agglomeration. φ5μm andφ40μm carrier were used to prepare the chiral stationary phase for high performance liquid chromatography and preparative chromatography under the necessity of application. Comparing the isometric steep and no-isometric steep，the distribution of particle diameter and distribution of pore diameter data during the steep of different particle diameter were measured and discussed in detail. The result showed that the method of isometric steep was better than the method no-isometric steep.
The cellulose tribenzoate coated chiral stationary phase was evaluated by system of high performance liquid chromatography. For the analysis of actual situation, appropriate mobile phase, flow rate and detector were chosen by impulse input method to get a series of chromatographic peaks in this thesis. By argumentation, the prepared cellulose tribenzoate have high chiral split ability. Origin 7.0 and Peak Fitting Module 7.0 software were used to fit the experimental data for math model based on the Gauss formula and these results were compared. From the discussion, it could be seen that the math model based on the Gauss formula can fit the chromatographic peaks well under the lower input volume and the fitted correlation coefficient was higher than 99%. Under higher input volume，however, the math model based on the Gauss formula had more fitting deviation, because the
chromatographic column was overloaded and chromatographic peak was severely asymmetry .
A advanced cellulose tribenzoate preparative method by advanced synthetic method, optimization of crystal craft and the method of isometric steep was reported in this thesis, which supported the base of chromatographic analysis, chromatographic separation, simulated moving bed to split chiral compound by cellulose tribenzoate as chiral stationary phase in lab and industry.
引文
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［2］ 王普善，手性药物－药品和精细化学品工业中的挑战与机会，精细与专用化学品，2002.1：3-6
［3］ 蒋约珥，手性技术市场展望，精细与专用化学品，2002.7：12-12
［4］ 黄蓓，手性拆分技术的工业应用，化工进展，2002（6）：375-380
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［8］ Karen W L，Enantiomer separations on chiral stationary phases in supercritical fluid chromatography ，Journal of Chromatography A,1997,785:149-158
［9］ 潘子江，色谱扰动－响应法测定C8芳烃的吸附和传递参数，化工学报，1988；6：745-751
［10］ Kempe M, Direct resolution of naproxen on a no-covalently molecularly imprinted chiral stationary phase, J. Chromatogr. A, 1994, 664:276-279
［11］ Rekoske J E, Chiral Separation, American Ins. Chem. Eng. Journal 2001,47(1):2-5
［12］ Krzysztof K, Application of the general rate model and the generalized Maxwell-Stefan equation to the study of the mass transfer kinetics of a pair of enantiomers, J. Chromatogr. A,2002.962:57-67
［13］ Negawa M, Optical resolution by simulated moving-bed adsorption technology, J. Chromatogr. A, 1992,590:113-117
［14］ Schulte M，Comparison of the specific productivity of different chiral stationary phases used for simulated moving-bed chromatography, J. Chromatogr. A, 1997,769:93-100
［15］ Francotte. Eric R, Applications of simulated moving-bed chromatography to the separation of the enantiomers of chiral drugs, J. Chromatogr. A, 1997,769 (2):101-107
［16］ Pais L S，Separation of 1,1′-bi-2-naphthol enantiomers by continuous chromatography in simulated moving bed，Chem. Eng. Sci., 1997,52(2):245-257
［17］ Lopez J L ,A multiphase/extractive enzyme membrane reactor for production of diltiazem chiral intermediate, Membr. Sci., 1997, 125:189-211
［18］ Aoki T, Enantioselective permeation of racemates through a solid (+)-poly{2-[dimethyl(10-pinanyl)silyl]norbornadiene} membrane, Polymer., 1997, 38 :235-238
［19］ Nakamura M, Chiral separation of dl-tryptophan using porous membranes containing multilayered bovine serum albumin crosslinked with glutaraldehyde, J. Chromatogr. A, 1998,822:53-58
［20］ Chankvetadze B, Chloromethylphenylcarbamate derivatives of cellulose as chiral atationary phase for high-performance liquid chromatography, J. Chromatogr. A,1994,670: 39-49
Chankvetadze B，Dimethyl-, dichloro- and chloromethylphenyl- carbamates of amylose
［21］ as chiral stationary phases for high-performance liquid chromatography ，J. Chromatogr. A, 1995, 694(1):101-109
［22］ Yashima E, 3,5-Dimethylphenylcarbamates of cellulose and amylose regioselectively bonded to silica gel as chiral stationary phases for high-performance liquid chromatography , J. Chromatogr. A,1994,677:11-19
［23］ 黄慕斌，以小孔硅胶为载体的纤维素三醋酸酯手性柱的制备及对映体的分离，色谱，1998，16（1）：47-49
［24］ Okamoto Y, Review:Resolution by high-performance liquild chromatography using polysaccharide carbamates and benzoates as chiral stationary phase,J. Chromatogr. A, 1994,666:403-419
［25］ 施介华，三(4-氯苯甲酸)纤维素酯的合成及其作为色谱固定相的性能研究，宁波高等专科学校学报，2001，13：23-25
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［2］ 王普善，手性药物－药品和精细化学品工业中的挑战与机会，精细与专用化学品，2002.1：3-6
［3］ 蒋约珥，手性技术市场展望，精细与专用化学品，2002.7：12-12
［4］ 黄蓓，手性拆分技术的工业应用，化工进展，2002（6）：375-380
［5］ Croen M B, Synthesis and resolution of some heterohelicenes，J. Org. Chem. , 1971, 36:2797-2809
［6］ Cai D, Simple and Efficient Resolution of 1,1′-Bi-2-naphthol, Tetrahedron Lett., 1995,36:7991-7994
［7］ Fulling G, Enymatic second-ordered asymmetric hydrolysis of ketorolac esters: in situ racemization, American Chemical Society, 1987,109:2845-2846
［8］ Karen W L，Enantiomer separations on chiral stationary phases in supercritical fluid chromatography ，Journal of Chromatography A,1997,785:149-158
［9］ 潘子江，色谱扰动－响应法测定C8芳烃的吸附和传递参数，化工学报，1988；6：745-751
［10］ Kempe M, Direct resolution of naproxen on a no-covalently molecularly imprinted chiral stationary phase, J. Chromatogr. A, 1994, 664:276-279
［11］ Rekoske J E, Chiral Separation, American Ins. Chem. Eng. Journal 2001,47(1):2-5
［12］ Krzysztof K, Application of the general rate model and the generalized Maxwell-Stefan equation to the study of the mass transfer kinetics of a pair of enantiomers, J. Chromatogr. A,2002.962:57-67
［13］ Negawa M, Optical resolution by simulated moving-bed adsorption technology, J. Chromatogr. A, 1992,590:113-117
［14］ Schulte M，Comparison of the specific productivity of different chiral stationary phases used for simulated moving-bed chromatography, J. Chromatogr. A, 1997,769:93-100
［15］ Francotte. Eric R, Applications of simulated moving-bed chromatography to the separation of the enantiomers of chiral drugs, J. Chromatogr. A, 1997,769 (2):101-107
［16］ Pais L S，Separation of 1,1′-bi-2-naphthol enantiomers by continuous chromatography in simulated moving bed，Chem. Eng. Sci., 1997,52(2):245-257
［17］ Lopez J L ,A multiphase/extractive enzyme membrane reactor for production of diltiazem chiral intermediate, Membr. Sci., 1997, 125:189-211
［18］ Aoki T, Enantioselective permeation of racemates through a solid (+)-poly{2-[dimethyl(10-pinanyl)silyl]norbornadiene} membrane, Polymer., 1997, 38 :235-238
［19］ Nakamura M, Chiral separation of dl-tryptophan using porous membranes containing multilayered bovine serum albumin crosslinked with glutaraldehyde, J. Chromatogr. A, 1998,822:53-58
［20］ Chankvetadze B, Chloromethylphenylcarbamate derivatives of cellulose as chiral atationary phase for high-performance liquid chromatography, J. Chromatogr. A,1994,670: 39-49
Chankvetadze B，Dimethyl-, dichloro- and chloromethylphenyl- carbamates of amylose
［21］ as chiral stationary phases for high-performance liquid chromatography ，J. Chromatogr. A, 1995, 694(1):101-109
［22］ Yashima E, 3,5-Dimethylphenylcarbamates of cellulose and amylose regioselectively bonded to silica gel as chiral stationary phases for high-performance liquid chromatography , J. Chromatogr. A,1994,677:11-19
［23］ 黄慕斌，以小孔硅胶为载体的纤维素三醋酸酯手性柱的制备及对映体的分离，色谱，1998，16（1）：47-49
［24］ Okamoto Y, Review:Resolution by high-performance liquild chromatography using polysaccharide carbamates and benzoates as chiral stationary phase,J. Chromatogr. A, 1994,666:403-419
［25］ 施介华，三(4-氯苯甲酸)纤维素酯的合成及其作为色谱固定相的性能研究，宁波高等专科学校学报，2001，13：23-25
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