纤维素-[2,3-(4-取代苯基)-6-(3,5-二氯苯基)]氨基甲酸酯的合成及作为HPLC手性固定相的手性识别

合成了3种新的纤维素苯基氨基甲酸酯类衍生物:纤维素-[2,3-二苯基-6(3,5-二氯苯基)]氨基甲酸酯、纤维素-[2,3-二(4-甲基苯基)-6-(3,5-二氯苯基)]氨基甲酸酯及[2,3-二(4-氯苯基)-6-(3,5-二氯苯基)]氨基甲酸酯,并将其涂敷在氨丙基硅胶表面制备 HPLC 手性固定相.利用<'1>H N...     

多糖类氨基甲酸酯衍生物的区域选择性合成及其手性识别

通过糖单元6-位羟基的保护和去保护,运用区域选择性方法合成了6种新型多糖类氨基甲酸酯衍生物,分别为纤维素/直链淀粉-[2,3-二(3,5-二甲基苯基)-6-环己基]氨基甲酸酯、[2,3-二(3,5-二氯苯基)-6-环己基]氨基甲酸酯及[2,3-二(4-氯苯基)-6-环己基]氨基甲酸酯,并将其涂敷在氨丙基硅胶的表面制备HPLC手性固定相.利用1H-NMR与FTIR光谱技术对所合成衍生物进行结构表征和分析,并应用HPLC法评价其对于9种手性化合物的手性识别能力.通过与以手性识别能力高而著称且含有单一取代基的纤维素/直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)等手性固定相的对比分析表明,所合成新型手性固定相对于某些对映体显示出更优的手性识别能力.由进一步分析表明,糖单元2-、3-和6-位取代基的性能对于纤维素和直链淀粉氨基甲酸酯类衍生物的手性识别能力均具有较大影响.     

16种手性化合物在不同自制手性固定相上的拆分比较

采用高效液相色谱法,在自制的纤维素-三(3,5-二甲基苯基氨基甲酸酯)(ATEO-OD)、纤维素-三(4-甲基苯基氨基甲酸酯)(ATEO-OG)和纤维素-三(4-甲基苯基甲酸酯)(ATEO-OJ)3种手性柱上对16种不同结构的手性化合物进行了拆分和比较.试验结果表明:16个手性样品在这3种手性固定相上分别获得了不同程度的拆分,A TEO-OD对所分析样品具有更好的手性识别能力,ATEO-OG和ATEO-OJ的手性识别能力相当.     

高效液相色谱的8种商品手性柱对52种手性化合物的拆分研究

用8种手性柱纤维素-三(3,5-二甲基苯基氨基甲酸酯)涂敷型固定相(Chiralcel OD)、纤维素-三(3,5-二甲基苯基氨基甲酸酯)键合型固定相(Chiralpak IB)、直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)涂敷型固定相(Chiralpak AD)、直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)键合型固定相(Chiralpak IA)、直链淀粉-三((S)-α-甲基苄基氨基甲酸酯)涂敷型固定相(Chiralpak AS)、Pirkle型固定相((S,S)-Whelk-O1)、弱阴离子交换剂固定相(Chiralpak QN-AX)和替考拉宁固定相(Chirobitotic T柱)对52种外消旋体化合物进行了拆分,并讨论拆分条件对一些手性柱分离情况的影响。结果表明,这8根手性柱对这些对映体具有良好的手性识别效果和互补性。它们对这些样品手性拆分实验结果比较可得出其手性识别能力为:Chirobitotic TODADIAASIB(S,S)-Whelk-O1Chiralpak QN-AX。     

淀粉及纤维素三(3-三氟甲基苯基氨基甲酸酯)手性固定相的制备及其性能评价

为了扩展多糖类手性固定相的种类,制备了基于淀粉及纤维素三(3-三氟甲基苯基氨基甲酸酯)的涂敷型手性固定相,以正己烷-异丙醇混合液为流动相,对8种手性化合物进行了高效液相色谱拆分。研究表明: 虽然与应用最广泛的分别以淀粉及纤维素三(3,5-二甲基苯基氨基甲酸酯)为手性选择因子的商品化手性柱Chiralpak AD和Chiralcel OD相比,所制备的手性固定相的手性分离能力较低,但纤维素三(3-三氟甲基苯基氨基甲酸酯)手性固定相显示出特异的手性识别能力,一些手性化合物在此固定相上得到了比在Chiracel OD上更好的分离;所制备的手性固定相的手性识别能力随流动相中异丙醇含量的降低而变好,当流动相中正己烷与异丙醇的体积比为95:5时所制备的手性固定相显示出相对较高的手性识别能力;总体来说,淀粉三(3-三氟甲基苯基氨基甲酸酯)手性固定相的手性识别能力稍强于纤维素三(3-三氟甲基苯基氨基甲酸酯)手性固定相,同时两种手性固定相的手性识别能力具有一定的互补性。     

双选择体的涂覆量对手性固定相分离特性的影响

研究了涂敷量对双选择体手性固定相分离特性的影响。分别将纤维素-三(3,5-二甲基苯基氨基甲酸酯)与纤维素-三(4-甲基苯甲酸酯),直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)与直链淀粉-三(4-甲基苯甲酸酯)进行共混,得到两种共混合物。以这两种共混合物为手性选择体,制备了涂覆量分别为17%及25%的四种手性固定相。评价了这些固定相的手性分离性能,结果表明:增加手性选择体的涂覆量,直链淀粉衍生物双选择体固定相的手性分离性能得到提高,而纤维素衍生物固定相的手性分离性能则稍有降低。较高涂覆量的纤维素衍生物固定相在含叔丁醇、异丁醇和正丁醇流动相中的保留因子依次减小,而其手性识别能力依次增强。     

键合型纤维素-苯基氨基甲酸酯手性固定相的制备及用于对映异构体拆分

采用化学键合法,利用4,4′-二苯基甲基二异氰酸酯作间隔臂,通过纤维素葡萄糖单元上2、3或6-位上的羟基将纤维素衍生物键合在氨丙基硅胶上,制备了键合型纤维素-苯基氨基甲酸酯手性固定相.同时,以微晶纤维素和苯基异氰酸酯为原料,合成了纤维素-三苯基氨基甲酸酯,并以未修饰的硅胶为载体,制备了涂敷型纤维素-三苯基氨基甲酸酯手性固定相.分别对键合型和涂敷型两类手性固定相进行了表征,并首次在纤维素-苯基氨基甲酸酯手性柱上拆分了安息香.     

高效液相色谱的4种商品手性柱对38种手性化合物的拆分研究

采用纤维素-三(3,5-二甲基苯基氨基甲酸酯)涂敷型手性固定相(Chiralcel OD柱)、直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)涂敷型手性固定相(Chiralpak AD柱)、直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)键合型手性固定相(Chiralpak IA柱)和Pirkle型的(S,S)-Whelk-01手性固定相对38种外消旋体化合物进行手性拆分。实验结果表明,4种固定相的手性识别能力为:OD>AD>IA>(S,S)-Whelk-01,OD固定相的手性识别率达到60%,并且它们之间的手性识别性能还具有一定的互补性。本研究对4种常用手性固定相的拆分能力进行了对比,为拆分手性化合物时有的放矢地选择手性固定相提供了参考。     

纤维素苯基氨基甲酸酯的均相合成及其手性拆分性能评价

认识多糖类手性拆分材料的结构性能关系对于构建新型高效手性固定相具有重要指导意义。该文中,以1-烯丙基-3-甲基咪唑氯离子液体为介质,合成了系列不同结构的纤维素苯基氨基甲酸酯,进而考察了取代度、取代基团种类和位置对产物手性拆分性能的影响。结果表明,随着取代度的增加,纤维素苯基氨基甲酸酯对于绝大部分手性分子的拆分效果提高;苯环上取代基团的种类和位置对纤维素苯基氨基甲酸酯手性拆分性能影响显著,弱吸电子基团氯基和给电子基团甲基在合适的位置能显著增强纤维素苯基氨基甲酸酯的手性拆分性能;纤维素3-甲基-4-氯苯基氨基甲酸酯、3,5-二氯苯基氨基甲酸酯和2-甲基-5-氯苯基氨基甲酸酯对一些手性分子的拆分效果优于纤维素3,5-二甲基苯基氨基甲酸酯。     

戊唑醇对映体在新型纤维素键合手性固定相上的拆分

利用4,4-二苯基甲基二异氰酸酯作为连接臂, 采用6-位选择键合法制备了键合型纤维素-(3,5-二甲基苯基氨基甲酸酯)固定相, 并将其应用于戊唑醇的手性分离, 还考察了异丙醇的浓度、不同的醇类改性剂、四氢呋喃以及三氯甲烷对戊唑醇在该固定相上的手性分离的影响.     

Phenylcarbamate derivatives of cellulose and amylose immobilized onto silica gel as chiral stationary phases for high-performance liquid chromatography

Three polysaccharide phenylcarbamate derivatives [cellulose 2,3-bis(3,5-dimethylphenylcarbamate)-6-(3,5-dimethylphenylcarbamate)/(2-methacryloyloxyethylcarbamate), cellulose 2,3-bis(3,5-dichlorophenylcarbamate)-6-(3,5-dichlorophenylcarbamate)/(2-methacryloyloxyethylcarbamate), and amylose 2,3-bis(3, 5-dimethylphenylcarbamate)-6-(3,5-dimethylphenylcarbamate)/(2-methacryloyloxyethylcarbamate)] with vinyl groups were prepared and coated onto silica gel to immobilize them via radical copolymerization with 2,3-dimethylbutadiene. The copolymerization efficiently proceeded, and the coated polysaccharide derivatives were mostly immobilized on the surface of the silica gel. The immobilized polysaccharide derivatives showed high chiral recognition abilities similar to those of the corresponding coated polysaccharide derivatives. They could be used with an eluent containing chloroform, which dissolved the polysaccharide derivatives. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4704–4710, 2004     

Experimental probing and modeling of key sorbent-solute interactions of norephedrine enantiomers with polysaccharide-based chiral stationary phases

The key interactions of a chiral solute, norephedrine or 2-amino-1-phenyl-1-propanol (PPA), with three commercially important polysaccharide-based chiral stationary phases, amylose Tris(3,5-dimethylphenylcarbamate) (ADMPC), amylose Tris((S)-alpha-methylbenzylcarbamate) (ASMBC) and cellulose Tris(3,5-dimethylphenylcarbamate) (CDMPC) are studied in detail using different experimental techniques and molecular simulations. The HPLC retention factors of the enantiomers of PPA in n-hexane/2-propanol (90/10, v/v) at 298 K vary significantly with these sorbents. The enantioselectivities of -PPA versus +PPA are 2.4, 1.0, and 0.8 (reversal in the elution order), respectively. The observed changes in the wavenumbers and the intensities of the amide bands of these polymers in the attenuated total reflection-infrared spectroscopy (ATR-IR) spectra upon absorption of each enantiomer are different. The IR wavenumbers, and the H-bonding interaction energies of the polymer side chains with each enantiomer (polymer-solute) in four different binding configurations are estimated and ranked using the density functional theory (the DFT/B3LYP/6-311+g(d,p) level of theory). X-ray diffraction (XRD) results show that the polymer crystallinity increases significantly upon absorption of each enantiomer. The helical pitches and the inter-rod packing for these polymers are inferred from the XRD results and incorporated into the molecular dynamics (MD) simulations. The elution orders predicted for the enantiomers of PPA using MD simulations of the polymer-PPA binary systems are consistent with the chromatography results. The enantioselectivity observed in ADMPC is hypothesized to be due to having three simultaneous interactions (two H-bond and one pi-pi) of the polymer with -PPA versus two interactions (one H-bond and one pi-pi) with +PPA.     

Comparison of separation performance of polysaccaride-based chiral stationary phases in enantioseparation of 1-(4-chlorobenzhydryl)piperazine benzamide derivatives by HPLC

Analytical high-performance liquid chromatographic enantioseparation of 1-(4-chlorobenzhydryl) piperazine benzamide derivatives was accomplished on different chiral stationary phases. The enantiomers of the compounds were resolved by normal-phase chromatography on silica-based amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD-H), cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD-H) and cellulose tris(4-methylbenzoate) (Chiralcel OJ) columns with mobile phases consisting of mixtures of n-hexane and ethanol in different proportions (90: 10, 80: 20). The mobile phase and the chiral stationary phase were varied to achieve the best resolution. The effect of the concentration of ethanol in the mobile phase was studied. The resolution obtained on the three columns was significant.     

Separation of the enantiomers of 4-aryl-7,7-dimethyl- and 1,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones by chiral HPLC

Summary Analytical HPLC methods using derivatized cellulose chiral stationary phases have been developed for separation of the enantiomers of 25 racemic 4-aryl-7,7-dimethyl- or 1,77-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones, condensed derivatives of dihydropyrimidines. The enantiomers of the compounds were resolved by normal-phase chromatography on silica-based cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD) and amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD) columns with mobile phases consisting of mixtures ofn-hexane and an alcohol (2-propanol, ethanol, or methanol) in different proportions. The mobile phase and the chiral stationary phase were varied to achieve the best resolution. The effect of the concentration of alcohol in the mobile phase was studied. The resolution obtained on the two columns was complementary.     

Development and validation of HPLC methods for enantioseparation of mirtazapine enantiomers at analytical and semipreparative scale using polysaccharide chiral stationary phases

Novel HPLC methods were developed for the analytical and semipreparative resolution of new antidepressant drug mirtazapine enantiomers. At analytical scale, the separation of the mirtazapine enantiomers was investigated using both cellulose and amylose tris(3,5-dimethylphenylcarbamate) (CDMPC and ADMPC) chiral stationary phases under normal-phases and polar organic modes. Good baseline enantioseparation was achieved using cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phases under both normal-phases and polar organic modes. Furthermore, the elution order of mirtazapine enantiomic pairs was found reversed by changing the stationary phase from the amylose-based ADMPC–CSPs to its cellulose-based counterpart, CDMPC–CSPs. The validation of the analytical methods including linearity, limit of detection (LOD), limit of quantification (LOQ), recovery and precision, together with the semipreparative resolution of mirtazapine racemate were carried out using cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phases and methanol as mobile phase without any basic additives under polar organic mode. At analytical scale, the elution times of both enantiomers were less than 6 min at normal temperature and 1.0 ml/min, with the separation factor () 1.99 and the resolution factor (Rs) 3.56. Then, the analytical methods were scaled up to semipreparative loading to obtain small quantities of both mirtazapine enantiomers. At semipreparative scale, about 16 mg/h enantiomers could be isolated and elution times of both enantiomers were less than 10 min at 2.0 ml/min. To increase the throughput, the technique of boxcar injections was used. One enantiomer ((−)-(R)-mirtazapine) was isolated with purity of >99.9% e.e. and >98.0% yield and another ((+)-(S)-mirtazapine) was isolated with purity of >97.0% e.e. and >99.0% yield. In addition, optical rotation and circular dichroism (CD) spectroscopy of both mirtazapine enantiomers isolated were also investigated.     

Separation and Recognition of the Enantiomers of trans Arylcyclopropanecarboxylic Acids and their Amide and Nitrile Derivatives on Polysaccharide Stationary Phases

Separation of the enantiomers of several trans arylcyclopropanecarboxylic acids and their amide and nitrile derivatives has been systematically studied on three polysaccharide HPLC stationary phases, amylose tris-(3,5-dimethylphenylcarbamate), cellulose tris-(3,5-dimethylphenylcarbamate), and cellulose tris-(4-methylbenzoate). Enantiomer recognition by the chiral stationary phases is discussed in terms of the type of functional group, electronic and steric effects of substituents on the analytes, the structure of the chiral stationary phase, and mobile phase composition.     

新型直链淀粉类手性固定相的制备与手性拆分性能

通过对糖单元2-位进行选择性酯化以及6-位保护与去保护,运用区域选择性方法合成了5种新型直链淀粉类衍生物,分别为直链淀粉-2-苯甲酸酯-3-(4-氯苯基氨基甲酸酯)-6-(3,5-二甲基苯基氨基甲酸酯)、直链淀粉-2-苯甲酸酯-3-(4-氯苯基氨基甲酸酯)-6-(3,5-二氯苯基氨基甲酸酯)、直链淀粉-2-苯甲酸酯-3,6-二(4-氯苯基氨基甲酸酯)、直链淀粉-2-(4-氯苯甲酸酯)-3,6-二(3,5-二氯苯基氨基甲酸酯)和直链淀粉-2-(4-氯苯甲酸酯)-3,6-二(环己基氨基甲酸酯),并将其涂覆在氨丙基硅胶表面制备了HPLC手性固定相。利用核磁共振-氢谱(¹H-NMR)和傅里叶变换红外光谱(FT-IR)技术对所合成衍生物的结构进行了表征和分析,并用HPLC法评价所合成衍生物的手性识别能力。与具有单一取代基直链淀粉类手性固定相的对比分析表明,所合成的新型直链淀粉类手性固定相对于某些对映体具有更为优异的拆分结果。进一步分析表明,2-、3-和6-位取代基的性能和引入位置对直链淀粉衍生物的手性识别能力均有较大的影响。     

一种手性中间体在键合型和涂覆型纤维素手性固定相上的拆分

制备了涂覆型和键合型纤维素-(3, 5-二甲基苯基氨基甲酸酯)固定相, 分别在制备的纤维素手性固定相上成功地拆分了一种手性中间体, 通过考察流动相中的改性剂(醇、四氢呋喃、三氯甲烷)对手性拆分的影响, 优化了手性中间体在两种手性固定相上的色谱分离条件, 并比较了手性中间体在涂覆和键合型纤维素手性固定相上的拆分. 结果表明, 涂覆型和键合型手性固定相对这种手性中间体均有较好的拆分效果, 在150 mm的色谱柱上, 这两种手性固定相对这种手性中间体的拆分能力相差不大, 但键合型固定相上可选择的流动相范围更广.     

Enantiomeric separation of precursors of rho-kinase inhibitors by HPLC on polysaccharide-based chiral stationary phases

Summary The separation of enantiomers of substituted cyclohexanecarboxamides, benzamides and chemical precursors of Rho-kinase inhibitors was achieved using derivatized polysaccharide-based chiral stationary phases. Separations were by normal phase HPLC with a mobile phase ofn-hexane-alcohol (methanol, ethanol or 2-propanol) in various proportions, and a silica-based cellulose tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H), tris-methylbenzoate (Chiralcel OJ), a silica-based amylose tris-(S)-1-phenylethylcarbamate (Chiralpak AS), or tris-3,5-dimethylphenylcarbamate (Chiralpak AD). The effects of cencentration of various aliphatic alcohols in the mobile phase were investigated. The effect of structural features on the discrimination between the enantiomers was examined. The isolation of milligram amounts of enantiomers of two derivatives was performed on an analytical column by multiple repetitive injections under overload conditions.