Evaluation of sulfated maltodextrin as a novel anionic chiral selector for the enantioseparation of basic chiral drugs by capillary electrophoresis

Introducing a new class of chiral selectors is an interesting work and this issue is still one of the hot topics in separation science and chirality. In this study, for the first time, sulfated maltodextrin (MD) was synthesized as a new anionic chiral selector and then it was successfully applied for the enantioseparation of five basic drugs (amlodipine, hydroxyzine, fluoxetine, tolterodine, and tramadol) as model chiral compounds using CE. This chiral selector has two recognition sites: a helical structure and a sulfated group which contribute to three corresponding driving forces; inclusion complexation, electrostatic interaction, and hydrogen binding. Under the optimized condition (buffer solution: 50 mM phosphate (pH 3.0) and 2% w/v sulfated MD; applied voltage: 18 kV; temperature: 20°C), baseline enantioseparation was observed for all mentioned chiral drugs. When instead of sulfated MD neutral MD was used under the same condition, no enantioseparation was observed which means the resolution power of sulfated MD is higher than neutral MD due to the electrostatic interaction between sulfated groups and protonated chiral drugs. Also, the countercurrent mobility of negatively charged MD (sulfated MD) allows more interactions between the chiral selector and chiral drugs and this in turn results in a successful resolution for the enantiomers. Furthermore, a higher concentration of neutral MD (approximately five times) is necessary to achieve the equivalent resolution compared with the negatively charged MD.     

Novel cinchona alkaloid O9-hydrazide derivatives as chiral anion-exchange-type selectors: Synthesis and chromatographic evaluation

Summary Six new quinine (QN) O₉-hydrazide derivatives with different substituents have been synthesized and immobilized on porous silica gel for HPLC. The chiral resolving power of these anion-exchange-type chiral stationary phases (CSPs) has been investigated and compared with that of four carbamate QN derivatives with analogous substitution. The unsubstituted QN-hydrazide derivative was usually the best chiral selector of the hydrazide series. Among the substituted hydrazide derivatives the introduction of a tritylcarbonyl or atert-butylcarbonyl group at the β position of the hydrazide function improved chiral recognition by the resulting CSPs. Although carbamate functionality seemed to favour the resolution of the enantiomers of many of the racemic compounds tested, the hydrazide series resulted in better separations of the enantiomers of the DNP derivatives of amino acids and of certain acidic drugs of therapeutic interest, such as the profens. The selectivity factors of these types of compounds on these QN-hydrazide derivatives are the best yet obtained on QN-derived chiral selectors.     

Syntheses of new C2-symmetric,optically active 1,2-diols bearing tertiary alkyl groups

New C₂-symmetric chiral 1,2-diols, 1,2-bis(1-adamantyl)-1,2-ethanediol and 3,3,6,6-tetramethyl-1,2-cyclohexanediol, were synthesized by the use of a new resolution method.     

Effect of the residual silanol group protection on the liquid chromatographic resolution of α‐amino acids and proton pump inhibitors on a ligand exchange chiral stationary phase

A new ligand exchange chiral stationary phase (new CSP) containing residual silanol group‐protecting n‐octyl groups on the silica surface was prepared by treating a ligand exchange CSP (original CSP) based on sodium N‐[(R)‐2‐hydroxy‐1‐phenylethyl]‐N‐undecylaminoacetate bonded to silica gel with excess n‐octyltriethoxysilane. The new and original CSPs containing an identical amount of chiral selector were applied to the resolution of α‐amino acids and proton pump inhibitors (PPIs) including omeprazole, pantoprazole, lansoprazole, and rabeprazole. The separation factors (α) and resolutions (R_S) were greater on the new CSP than on the original CSP except for the resolution of asparagine. The trends of the retention factors (k₁) for the resolution of α‐amino acids on the new and original CSPs with the variation of the organic modifier content in aqueous mobile phase were opposite to those for the resolution of PPIs. Removal of the nonenantioselective interactions between the residual silanol groups and the analytes and the improved lipophilicity of the new CSP were proposed to be responsible for the improved chiral recognition ability of the new CSP and the different retention behaviors of the enantiomers between the new and original CSPs.     

Combined use of l‐alanine tert butyl ester lactate and trimethyl‐β‐cyclodextrin for the enantiomeric separations of 2‐arylpropionic acids nonsteroidal anti‐inflammatory drugs

In this study, a new CE method, employing a binary system of trimethyl‐β‐CD (TM‐β‐CD) and a chiral amino acid ester‐based ionic liquid (AAIL), was developed for the chiral separation of seven 2‐arylpropionic acid nonsteroidal anti‐inflammatory drugs (NSAIDs). In particular, the enantioseparation of ibuprofen, ketoprofen, carprofen, indoprofen, flurbiprofen, naproxen, and fenoprofen was improved significantly by supporting the BGE with the chiral AAIL l ‐alanine tert butyl ester lactate (l ‐AlaC₄Lac). Parameters, such as concentrations of TM‐β‐CD and l ‐AlaC₄Lac, and buffer pH, were systematically examined in order to optimize the chiral separation of each NSAID. It was observed that the addition of the AAIL into the BGE improved both resolution and efficiency significantly. After optimization of separation conditions, baseline separation (R_s>1.5) of five of the analytes was achieved in less than 11 min, while the resolution of ibuprofen and flurbiprofen was approximately 1.2. The optimized enantioseparation conditions for all analytes involve a BGE of 5 mM sodium acetate/acetic acid (pH 5.0), an applied voltage of 30 kV, and a temperature of 20°C. In addition, the results obtained by computing the %‐RSD values of the EOF and the two enantiomer peaks, demonstrated excellent run‐to‐run, batch‐to‐batch, and day‐to‐day reproducibilities.     

Chiral Thin Films of Metal Oxide

In this paper, we describe for the first time the synthesis of new chiral nanosized metal oxide surfaces based on chiral self‐assembled monolayers (SAMs) coated with metal oxide (TiO₂) nanolayers. In this new type of nanosize chiral surface, the metal oxide nanolayers enable the protection of the chiral self‐assembled monolayers while preserving their enantioselective nature. The chiral nature of the SAM/TiO₂ films was characterized by variety of unique techniques, such as second‐harmonic generation circular dichroism (SHG‐CD), quartz crystal microbalance, and chiral adsorption measurements with circular dichroism spectroscopy. The chiral resolution abilities of the SAMs coated with metal oxide (TiO₂) nanolayers were investigated in the crystallization of a racemic mixture of threonine and glutamic acid. Our proposed methodology for the preparation of nanoscale chiral surfaces described in this article could open up opportunities in other fields of chemistry, such as chiral catalysis.     

几种苯甲酰胺类抗精神病药物的手性色谱拆分及其对映体含量的测定

采用直链淀粉-三(5-氯-2-甲基苯基氨基甲酸酯)手性固定相(CSP),以0.1%二乙胺正己烷和0.1%二乙胺乙醇为流动相梯度洗脱,以舒必利、阿米舒必利和莫沙必利为目标物,利用高效液相色谱法研究了这3种苯甲酰胺类药物的手性色谱分离行为。分别考察了流动相组成、添加剂及柱温对3种药物对映体分离的影响,从热力学和结构上探讨了色谱拆分的机理。结果表明: 在优化的色谱条件下,舒必利、阿米舒必利和莫沙必利对映体的分离度Rs＞1.5;计算了3种药物对映体的色谱保留因子k和分离因子α,以及与CSP相互作用的热力学函数,其相互作用大小依次为舒必利＞阿米舒必利＞莫沙必利。已将该方法成功地应用于上述3种药物片剂和血清中其对映体的测定,方法简便、准确、可靠。     

High-performance liquid chromatographic enantioseparation of drugs containing multiple chiral centers on polysaccharide-type chiral stationary phases

Enantioseparation of drugs with multiple chiral centers is challenging. This article describes resolution of some drugs with multiple chiral centers using polysaccharide-type chiral stationary phases. Also, the use of the column-switching technique is demonstrated to achieve the resolution of this type of compounds.     

Synthesis and application of clindamycin succinate as a novel chiral selector for capillary electrophoresis

A novel chiral selector, clindamycin succinate, was synthesized and first used as a chiral selector in capillary electrophoresis (CE). The chiral resolution ability of this kind of clindamycin derivation was studied by CE using some racemic drugs as model analytes. From the experimental results, it was found that both resolution and selectivity of the selector were dependent on the following parameters: concentration of chiral selectors, pH of the running buffer, temperature of the capillary column, applied voltage and organic modifier used. The results show that the chiral selector possesses high resolution toward some racemic drugs, including ofloxacin, chlorphenamine, tryptophan, propranolol, sotalol and metoprolol. Excellent chiral resolution of these tested drugs was achieved under the optimal conditions of 50 mM clindamycin succinate, 10% MeOH v/v, 50 mM Tris buffer, pH 4.0, at 22 kV and 20 °C within 25 min.     

Dependence of chiral separations on the amount of cyclodextrins as selectors, employing the partial filling technique in capillary zone electrophoresis

Summary The enantioselectivity, resolution factor and migration times for some local anaesthetic drugs were evaluated at different selector concentrations and plug lengths with different cyclodextrins as chiral selectors using the partial filling technique. The resolution remained constant when equal amounts of the chiral selector at a concentration below the optimal concentration were introduced in the capillary. However, the selectivity factor increased with increasing concentration of the chiral selector.     

中性配合物Cr(acac)3、mer-和fac-[Cr(bza)3]的光学拆分

本文用新方法合成了Cr(bza)₃,改进了其mer-、fac-异构体的分离方法;增大了Cr(acac)₃的化学拆分量(1.5g)。试制了DBT(二苯甲酰-d-酒石酸)吸附型手性固定相(CSP),并成功地用于色谱拆分标题配合物的对映体,mer-[Cr(bza)₃]的部分拆分是首次发现的,其他配合物的拆分结果均优于文献方法。根据mer-[Cr(bza)₃)拆分流出液前、后组分的CD光谱,指定了其对映体绝对构型     

Preparation of a new crown ether-based chiral stationary phase containing thioester linkage for the liquid chromatographic separation of enantiomers

A new chiral stationary phase (CSP) containing thioester linkages was prepared by bonding (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid to mercaptopropylsilica gel. The chiral recognition ability of the new CSP was found to be greater than that of the previously reported CSP containing amide linkages in the resolution of the various α-amino acids that were tested, except for that of Met, Ser and Thr. In the resolution of racemic amines and amino alcohols, the new CSP was always better than the one containing amide linkages in terms of the separation factors (α) and the resolutions (R_S). Given the identical elution orders on the two CSPs, it was concluded that the chiral recognition mechanism is not affected by the change of the linkage type. In addition, the new CSP was found to be quite stable under the acidic mobile phase conditions that were utilized, indicating that the thioester linkage is useful as a tethering group.     

Synthesis of noval chiral tridentate amino alcohols as chiral solvating agents under ball-milling conditions

A new family of chiral solvating agents based on chiral didentate amino alcohols and chloromethyl pyridine derivatives were synthesized by ball milling in solvent free condition. The new chiral tridentate amino alcohols were tested as chiral NMR solvating agents for the Ts-derivatives of amino acids, other several acids and pyrazole drugs. For the Ts-derivatives of amino acids studied herein, chiral tridentate amino alcohol 3a could be used for the assignment of the absolute configurations of their racemes through the chemical shift non-equivalences of their CH₃ (Ts) protons with certain confidence.     

Mechanistic Principles in Chiral Separations Using Liquid Chromatography and Capillary Electrophoresis

Due to the importance of chiral separations of drugs, pharmaceuticals, agrochemicals and xenobiotics by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE), it is important to have the knowledge of the enantiomeric recognition mechanisms so that scientists may design and module the new chiral selectors for rapid, inexpensive and reproducible chiral separations; specially at preparative scale. The mechanisms of the chiral separation by HPLC and CE using polysaccharides, cyclodextrins, macrocyclic glycopeptide antibiotics, Pirkle type, ligand exchangers, crown ethers and other several types of chiral selectors have been discussed. Various complex formation and different types of interactions responsible for chiral resolution have been presented in detail.     

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

建立了一种以天然易得的卡那霉素为手性添加剂，用毛细管区带电泳法快速分离市售对乙肝有良好治疗效果的药物联苯双脂衍生物的方法，拓宽了毛细管电泳中手性选择剂的范围，通过实验研究了卡那霉素、甲醇 含量PH值，磷酸盐缓冲体系和硼硝缓冲体系对手性分离的影响，以及三种有机溶剂（甲醇、乙晴、异丙醇）添加剂对手性分离的影响，结果表明，在含有3％卡那霉素，30mol/L，硼砂缓冲体系（PH＝8．0）添加30％异丙醇是最佳的分离条件。     

New chiral cobalt salen complexes containing Lewis acid BF3; a highly reactive and enantioselective catalyst for the hydrolytic kinetic resolution of epoxides

A new type of chiral cobalt salen complexes bearing BF₃ Lewis acid proved to be reactive and enantioselective in the hydrolytic resolution of terminal epoxides. The polymer type salen catalysts also showed a high enantioselectivity in the same reaction.     

Resolution of naftopidil and bufuralol enantiomers by high-performance liquid chromatography on cellulose tris-(3,5-dimethylphenyl carbamate) column

The liquid Chromatographic resolution of the racemic cardiovascular drugs naftopidil and bufuralol to their corresponding enantiomers was achieved on cellulose tris-(3,5-dimethylphenyl carbamate) chiral stationary phase known as Chiralcel OD. The chiral recognition mechanism(s) involved between the chiral stationary phase and these drugs, which include hydrogen bonding, intercalative interactions, and steric interactions, among other factors, were discussed.     

Methods of studies on quantitative structure–activity relationships for chiral compounds

Chiral compounds are very important in drug development, organic synthesis, materials science, toxicology, or environmental chemistry. Therefore, for creating new drugs, several methods have been suggested in recent years. In several laboratories in the world, some new methods for the derivations of the parameters were constructed and used for studies on quantitative structure–activity/property relationships of chiral molecules. The algorithms reviewed in this paper involve Zargeb group chiral indices, chiral molecular connectivity index, chiral topological charge index, chiral A_m index, chiral indices based on the matrixes, chiral indices based on chiral product, conformation‐independent chirality code, conformation‐dependent chirality code, quantitative two‐dimensional chirality degrees of benzenoids, and so on. Copyright © 2012 John Wiley & Sons, Ltd.     

化学拆分的新方法研究

主要介绍了近年来发展起来的两种化学拆分新方法,包括拆分和组合拆分;并简要论述了化学拆分中的手性识别现象,以及化学拆分方法在手性药物制备中的应用。     

苯丙胺类、氯胺酮、卡西酮类毒品手性分离的研究进展

对映异构体在自然界中普遍存在,在药物化学领域尤为突出。虽然手性药物的对映异构体之间具有相同的化学结构,但它们在药理、毒理、药代动力学、代谢等生物活性方面存在明显差异。苯丙胺类、氯胺酮、卡西酮类毒品也是如此,这3类毒品的手性分离研究在常见毒品中具有代表性。目前常用的手性分离色谱方法有气相色谱法(GC)、高效液相色谱法(HPLC)和毛细管电泳法(CE)。苯丙胺类、氯胺酮、卡西酮类毒品使用以上3种方法进行的手性分离研究具有一定共性:GC较多使用N-三氟乙酰-L-脯胺酰氯和(+)R-α-甲氧基α-三氟甲基苯乙酸两种典型的手性衍生化试剂,HPLC主要应用蛋白质类、多聚糖类和大环抗生素类3种手性固定相,CE中环糊精及其衍生物是最常用的手性选择剂。然而这3种手性分离方法存在各自的不足,GC存在手性衍生化引入杂质、反应温度高影响手性分离等问题,HPLC的应用范围比较有限,成本较高,CE没有明确的方法判断哪种物质是合适的手性选择剂。近年来,这3类毒品的手性分离研究在法医毒物学领域的应用有各自的特点,苯丙胺类毒品的手性分离研究多用于推断市场上毒品的原型及合成路线,氯胺酮的手性分离研究涉及多种生物检材,卡西酮类毒品侧重于手性分离方法的广泛适用性。该文主要遴选近10年国内外核心期刊的文献,对苯丙胺类、氯胺酮、卡西酮类毒品的手性异构体特点及色谱法的手性识别机理进行简单介绍,重点对已有研究的共性以及手性分离在法医毒物学中的应用等内容进行综述。基于以上研究,该文提出未来可以从以下3个方面进行深入研究:一是利用计算机技术建立分子模型深入探究手性识别机理;二是研发新型技术,对超临界流体法进行商用研究;三是将手性分离应用于司法实践、医药研发等实际工作领域。