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。     

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.     

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。     

壳聚糖苯甲酰化衍生物固定相的制备及其手性识别

为制备新型手性分离材料,用含不同取代基的苯甲酰氯修饰壳聚糖,合成了壳聚糖-二(4-甲基苯甲酸酯)-(4-甲基苯甲酰胺)、壳聚糖-二(苯甲酸酯)-(苯甲酰胺)、壳聚糖-二(3,5-二甲基苯甲酸酯)-(3,5-二甲基苯甲酰胺)和壳聚糖-二(4-氯苯甲酸酯)-(4-氯苯甲酰胺)4种新的衍生物,以N,N-二甲基甲酰胺为溶剂,将壳聚糖衍生物涂敷于大孔的3-氨丙基硅胶上,制得相应的手性固定相.测试了固定相的手性识别性能,结果表明这些固定相均有较好的对映体选择性.涂覆量为16%的固定相比涂覆量为20%的固定相有更好的手性分离性能,以壳聚糖-二(3,5-二甲基苯基甲酸酯)-(3,5-二甲基苯基甲酰胺)制备的固定相有最强的手性识别性能,以壳聚糖-二(4-甲基苯甲酸酯)-(4-甲基苯甲酰胺)制备的固定相对手性化合物有最大的分离度.     

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。     

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。     

高效液相色谱法手性分离二茂铁衍生物

建立了4个单手性和3个双手性(含有手性中心和面手性)的二茂铁衍生物在Chiralpak IC(纤维素-三(3,5-二氯苯基氨基甲酸酯))和Chiralpak IE3(直链淀粉-三(3,5-二氯苯基氨基甲酸酯))手性固定相上的高效液相色谱分离方法。4个单手性二茂铁衍生物中有3个可以在Chiralpak IE3固定相上实现基线分离,另外1个则在Chiralpak IC手性固定相上实现基线分离。3个双手性二茂铁衍生物可在Chiralpak IC手性固定相上实现基线分离。研究表明,这两种手性固定相对二茂铁衍生物具有较好的手性识别作用,并且具有互补作用。这一研究结果可为手性二茂铁化合物的分离提供借鉴和参考。     

2-N-邻苯二甲酰亚胺壳聚糖基手性固定相的制备及手性识别能力研究

为了开发具有高效手性识别能力的新型多糖类手性固定相,合成了5种糖单元2-位具有邻苯二甲酰亚胺,而3,6-位同时具有4种不同苯基氨基甲酸酯基团(2-氯、3-氯、4-氯和3,5二氯取代的苯基氨基甲酸酯)和一种无取代的苯基氨基甲酸酯基团的壳聚糖类衍生物,并将其涂覆在氨丙基硅胶表面制备成HPLC手性固定相.利用红外光谱和核磁氢谱对所合成的衍生物进行结构表征与分析,并应用HPLC法评价其对10种对映体的手性识别能力.研究结果表明:这些新型壳聚糖类手性固定相的手性识别能力受苯基氨基甲酸酯取代基中芳环上侧基的引入位置、数量和空间位阻的影响较大.同时色谱测试中所使用流动相的成分对该类手性固定相的识别能力也具有较大影响.进一步探讨了这些衍生物的氨基甲酸酯残基核磁氢谱中N—H质子的化学位移和红外光谱中N—H波数与手性识别能力之间的关系.     

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...     

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.     

Preparation and chromatographic evaluation of β-cyclodextrin derivative CSPs bearing substituted phenylcarbamate groups for HPLC

Five β-cyclodextrin (β-CD) derivatives bearing substituted phenylcarbamate/3-(triethoxysilyl)propylcarbamate groups at the 2-, 3-, and 6-positions of glucose unit and another five derivatives containing benzoate at the 2-position and substituted phenylcarbamate/3-(triethoxysilyl)propylcarbamate groups at the 3- and 6-positions were synthesized using the regioselective esterification method. The obtained β-CD derivatives were efficiently immobilized onto the silica gel through the intermolecular polycondensation of a small amount of the triethoxysilyl groups, which were used as the chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC). The chiral separation properties of these CSPs were evaluated under the normal-phase HPLC. The effects of solvent polarity and the side chain structures of β-CD derivatives on the chiral recognition ability of the immobilized CSPs were investigated. Among these β-CD derivative CSPs, 2,3,6-tris(3,5-dichlorophenylcarbamate)-β-CD CSP showed a relatively high chiral recognition ability for the studied racemates. The regioselective esterification at the 2-position of glucose unit in the β-CD decreased the chiral recognition ability at the same conditions. For some racemates, the β-CD derivative CSPs showed chiral recognition abilities comparable or better to some chemical bonded β-CD derivative CSPs and 3,5-dichloro- and 3,5-dimethylphenylcarbamates of cellulose and amylose CSPs.     

Preparation of Regioselectively Modified Amylose Derivatives and Their Applications in Chiral HPLC

Four regioselectively modified amylose derivatives with three different substituents at the 2-, 3-, and 6-positions were prepared and their enantioseparations in HPLC were examined. Investigations indicated that the nature as well as the arrangement of the substituents significantly influenced their enantioseparations and each derivative exhibited characteristic chiral recognition. Amylose 2-benzoyl-3-(3,5-dimethylphenylcarbamate or 3,5-dichlorophenylcarbamate)-6-((S)-1-phenylethylcarbamate) exhibited chiral resolving abilities comparable to the commercial available amylose tris(3,5-dimethylphenylcarbamate)-based column, Chiralpak AD and the racemic compounds shown in this study were most effectively resolved on these two derivatives. The influence of mobile phase on chiral resolution was also examined.     

Preparation of Regioselectively Modified Amylose Derivatives and Their Applications in Chiral HPLC

Four regioselectively modified amylose derivatives with three different substituents at the 2-, 3-, and 6-positions were prepared and their enantioseparations in HPLC were examined. Investigations indicated that the nature as well as the arrangement of the substituents significantly influenced their enantioseparations and each derivative exhibited characteristic chiral recognition. Amylose 2-benzoyl-3-(3,5-dimethylphenylcarbamate or 3,5-dichlorophenylcarbamate)-6-((S)-1-phenylethylcarbamate) exhibited chiral resolving abilities comparable to the commercial available amylose tris(3,5-dimethylphenylcarbamate)-based column, Chiralpak AD and the racemic compounds shown in this study were most effectively resolved on these two derivatives. The influence of mobile phase on chiral resolution was also examined.

     

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     

Enantioseparation of selected chiral sulfoxides using polysaccharide-type chiral stationary phases and polar organic, polar aqueous-organic and normal-phase eluents

HPLC enantioseparation of selected chiral sulfoxides was studied using cellulose and amylose phenylcarbamate derivatives as chiral stationary phases (CSPs). The contributions of various functional groups of a chiral analyte as well as the polysaccharide derivatives in the analyte retention and chiral recognition were evaluated. A very high enantioseparation factor exceeding 110 was observed in the enantioseparation of 2-(benzylsulfinyl)benzamide (BSBA) on cellulose tris(3,5-dichlorophenylcarbamate) (CDCPC) CSP by using 2-propanol as a mobile phase. The enantiomer elution order was opposite on cellulose and amylose phenylcarbamates. For the polysaccharide-type CSPs, pure alcohols such as methanol, ethanol and 2-propanol represent a valuable alternative to more common alcohol-hydrocarbon and reversed-phase eluents.     

Synthesis and chiral recognition of novel amylose derivatives containing regioselectively benzoate and phenylcarbamate groups

A new class of regioselectively substituted amylose derivatives bearing three different substituents at 2-, 3- and 6-positions, and two different substituents at 2-position and 3-, 6-positions were synthesized by a sequential process based on the esterification of 2-position of a glucose unit. Their chiral recognition abilities were evaluated as chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC). Each derivative had its own characteristic recognition ability depending on the arrangement of side chains at the three positions. Among the derivatives, amylose 2-(4-t-butylbenzoate) and amylose 2-(4-chlorobenzoate) series exhibited high chiral recognition. Some racemates can be efficiently separated on these derivatives as well as on the amylose tris-3,5-dimethylphenylcarbamate, which is commercially available as Chiralpak AD and one of the most powerful CSPs. The structures of the amylose derivatives were also investigated by circular dichroism spectroscopy.     

Reversed-phase chiral HPLC and LC/MS analysis with tris(chloromethylphenylcarbamate) derivatives of cellulose and amylose as chiral stationary phases

Three polysaccharide-derived chiral stationary phases (CSP) were evaluated for the resolution of more than 200 racemic compounds of pharmaceutical interest in the reversed-phase (RP) separation mode. The population of test probes was carefully evaluated in order to insure that it covers as completely as possible all structural diversity of chiral pharmaceuticals. RP showed the highest potential for successful chiral resolution in HPLC and LC/MS analysis when compared to normal phase and polar organic separation modes. Method development consisted of optimizing mobile phase eluting strength, nature of organic modifier, nature of additive and column temperature. The newer CSPs, cellulose tris(3-chloro-4-methylphenylcarbamate) and amylose tris(2-chloro-5-methylphenylcarbamate), were compared to the commonly used cellulose tris(3,5-dimethylphenylcarbamate) in regards to their ability to provide baseline resolution. Comparable success rates were observed for these three CSPs of quite complimentary chiral recognition ability. The same method development strategy was evaluated for LC/MS analysis. Diethylamine as additive had a negative effect on analyte response with positive ion mode electrospray (ESI⁺) MS(/MS) detection, even at very low concentration levels (e.g., 0.025%). Decreasing the organic modifier (acetonitrile or methanol) content in the mobile phase often improved enantioselectivity. The column temperature had only a limited effect on chiral resolution, and this effect was compound dependent. Ammonium hydrogencarbonate was the preferred buffer salt for chiral LC with ESI⁺ MS detection for the successful separation and detection of most basic pharmaceutical racemic compounds. Ammonium acetate is a viable alternative to ammonium hydrogencarbonate. Aqueous formic acid with acetonitrile or methanol can be successfully used in the separation of acidic and neutral racemates. Cellulose tris(3-chloro-4-methylphenylcarbamate) and amylose tris(2-chloro-5-methylphenylcarbamate) emerge as CSPs of wide applicability in either commonly used separation modes rivaling such well established CSPs as cellulose tris(3,5-dimethylphenylcarbamate). Screening protocols including these two new CSPs in the preferentially screened set of chiral columns have higher success rates in achieving baseline resolution in shorter screening time.