Role of the charge in continuous beds in the chiral separation of hydroxy acids by ligand-exchange capillary electrochromatography

This paper deals with the chiral separation of hydroxy acids using diallyl-dimethylammonium chloride as a positive charge-providing agent in the continuous bed. The chiral continuous bed was prepared by in situ copolymerization of monomers, including an L-4-hydroxyproline derivative as a chiral selector. This phase was applied to the chiral separation of hydroxy monocarboxylic acids and hydroxy dicarboxylic acids, respectively. The influence of both the selector concentration and the charge-providing agent on retention and separation was investigated.     

Enantioseparation of hydroxy acids on easy-to-prepare continuous beds for capillary electrochromatography

This paper deals with the enantioseparation of hydroxy acids by ligand-exchange capillary electrochromatography. A chiral continuous bed was easily prepared by in situ polymerization of monomers, including an L-4-hydroxyproline derivative. This phase showed chiral recognition for several hydroxy acids, in addition to amino acids.     

New particle-loaded monoliths for chiral capillary electrochromatographic separation

Fritless particle-loaded monoliths for chiral capillary electrochromatographic (CEC) separation were prepared. Silica particles containing a chiral selector are suspended in a monomer solution, which is drawn into the capillary followed by in situ polymerization. Thereby the silica-based particles containing the chiral selector are embedded in a nonchiral continuous bed. This kind of chiral stationary phase is inexpensive, easy, and reproducible to prepare and circumvents the preparation of frits. As a model, teicoplanin aglycone as chiral selector bonded to 3 microm silica particles was used. The applicability of this approach is demonstrated by means of the chiral separation of aliphatic and aromatic amino acids and dipeptides. As a further application, the chiral selector ristocetin A bonded to 3 microm silica particles was used for the enantiomeric separation of chiral alpha-hydroxy acids. Since alpha-hydroxy acids migrate toward the anode, a cationic charge-providing agent was copolymerized with the matrix. This served to reverse the direction of the electroosmatic flow (EOF).     

双柱切换色谱制备系统设计和实现

在模拟移动床色谱和循环色谱分离手性样品原理的基础上,设计了双柱切换系统及控制软件。该系统具有固定相的利用率高和溶剂的消耗量小的特点。为了验证分离原理的可行性。用该系统对华法令进行了连续制备。     

原位聚合那格列奈分子印迹手性固定相的分子识别特性研究

以手性药物那格列奈为模板分子,采用原位聚合法制备了具有特定识别性能和手性拆分能力的分子印迹聚合物,并用作高效液相色谱固定相实现了那格列奈与其对映体的手性拆分．通过静态结合方法考察了该聚合物的选择结合能力,并讨论了手性分离过程中的热力学性质．结果表明,原位聚合法制备的棒状聚合物固定相对模板分子及其对映体有很好的手性拆分性能．     

Synthesis of 4-aryl-2-pyrrolidones and beta-aryl-gamma-amino-butyric acid (GABA) analogues by Heck arylation of 3-pyrrolines with arenediazonium tetrafluoroborates. Synthesis of (+/-)-rolipram on a multigram scale and chromatographic resolution by semipreparative chiral simulated moving bed chromatography

We report herein a new, practical, and economic synthesis of the phosphodiesterase inhibitor Rolipram on a multigram scale as well as the synthesis of new 4-aryl pyrrolidones and beta-aryl-gamma-amino butyric acids (GABA derivatives) employing an efficient Heck-Matsuda arylation of 3-pyrroline with aryldiazonium tetrafluoroborates. Racemic Rolipram was resolved into its enantiomers using chiral simulated moving bed chromatography having the low-cost microcrystalline cellulose triacetate as a chiral stationary phase.     

Poly(glycidyl methacrylate-divinylbenzene-triallylisocyanurate) continuous-bed protein chromatography

A novel continuous bed with high dynamic adsorption capacity for protein has been developed. It is a macroporous poly(glycidyl methacrylate-divinylbenzene-triallylisocyanurate) rod prepared by in situ copolymerization in a chromatographic tube. The bed matrix contained epoxy groups, so diethylaminohydroxypropyl groups were coupled to the matrix, leading to an anion-exchange continuous bed. The component, specific surface area, and the pore structure of the bed matrix were characterized by Fourier transform infrared spectroscopy, BET method and scanning and transmission electron microscopies, respectively. The flow properties, column efficiency and the dynamic adsorption behavior of the bed were studied. The results show that the continuous bed, a ternary copolymer of glycidyl methacrylate (GMA), divinylbenzene (DVB) and triallylisocyanurate (TAIC) with a specific surface area of 56.4 m2/g, consisted of a three-dimensional structure made up of continuous clusters of microspheres (300 nm) and interconnected irregular pores. The rate of mass transfer is enhanced by the convection of the mobile phase through the pores. The dynamic adsorption isotherm of the anion-exchange column for bovine serum albumin was expressed by the Langmuir equation with a dynamic capacity as high as 76.0 mg/g. Moreover, the separation of proteins, i.e. lysozyme, hemoglobin and bovine serum albumin, is little affected by mobile-phase velocity up to 902.5 cm/h; it was completed within 5 min at 902.5 cm/h.     

Enantiomer separation by capillary electrochromatography on a cyclodextrin-modified monolith

A chiral monolithic stationary phase was prepared by packing a capillary with bare porous silica and sintering the silica bed at high temperature. The resulting silica monolith was polymer-coated with Chirasil-Dex, a permethylated beta-cyclodextrin covalently linked via an octamethylene spacer to dimethylpolysiloxane. Subsequently, Chirasil-Dex was thermally immobilized on the silica support and a chiral monolith of very high stability (30 kV, more than 400 bar pressure) was obtained. The enantiomer separation of various chiral compounds by monolithic (rod) capillary electrochromatography (rod-CEC) was feasible. This method was compared with capillary liquid chromatography (LC) in a single-column mode using unified equipment. About two to three times higher efficiency was found in the rod-CEC mode as compared to rod-LC. The influence of pressure-driven flow support on efficiency, resolution, elution time and baseline stability was investigated. The amount and nature of organic modifier strongly influences efficiency and resolution.     

Self‐Supported Chiral Titanium Cluster (SCTC) as a Robust Catalyst for the Asymmetric Cyanation of Imines under Batch and Continuous Flow at Room Temperature

A robust heterogeneous self‐supported chiral titanium cluster (SCTC) catalyst and its application in the enantioselective imine‐cyanation/Strecker reaction is described under batch and continuous processes. One of the major hurdles in the asymmetric Strecker reaction is the lack of availability of efficient and reusable heterogeneous catalysts that work at room temperature. We exploited the readily hydrolyzable nature of titanium alkoxide to synthesize a self‐supported chiral titanium cluster (SCTC) catalyst by the controlled hydrolysis of a preformed chiral titanium‐alkoxide complex. The isolated SCTC catalysts were remarkably stable and showed up to 98 % enantioselectivity (ee) with complete conversion of the imine within 2 h for a wide variety of imines at room temperature. The heterogeneous catalysts were recyclable more than 10 times without any loss in activity or selectivity. The robustness, high performance, and recyclability of the catalyst enabled it to be used in a packed‐bed reactor to carry out the cyanation under continuous flow. Up to 97 % ee and quantitative conversion with a throughput of 45 mg h^?1 were achieved under optimized flow conditions at room temperature in the case of benzhydryl imine. Furthermore, a three‐component Strecker reaction was performed under continuous flow by using the corresponding aldehydes and amines instead of the preformed imines. A good product distribution was obtained for the formation of amino nitriles with ee values of up to 98 %. Synthetically useful ee values were also obtained for challenging α‐branched aliphatic aldehyde by using the three‐component continuous Strecker reaction.     

Increasing the scale of true moving bed electrophoretic separations using filtration to reduce solvent volumetric flows between sections II and III

Over the past decade the moving bed process has become a commonly used tool for the continuous separation of chiral compounds, and its recent application to electrophoretic separations allows the technique to be used as a model system for moving bed method improvements. Much of the recent research on moving bed separations has focused on improving the technique's efficiency and increasing the maximum attainable throughput. This paper presents a novel method for reducing or reversing the increases in tailing that stem from the addition of the feed stream in a moving bed process by adding a filtration unit which retains the products while removing fluid from the boundary between the sections above and below the feed stream. This filtration-enhanced moving bed process was applied to a true moving bed (TMB) electrophoresis separation in the Vortex Stabilized Electrophoresis Apparatus, and its effect on a homatropine enantiomer separation was studied. Experiments showed that there is a 2.4-fold increase in the homatropine processing rate when 0.5 ml/h of water is removed through a reverse osmosis filter at the boundary between the sections above and below the feed stream. In order to further understand the process, filtration-enhanced TMB (FE-TMB) was also analyzed using a linear model of the system which shows that the 99% purity operating region of the separation is greatly increased even with moderate permeate flowrates.     

Chemically L-prolinamide-modified monolithic silica column for enantiomeric separation of dansyl amino acids and hydroxy acids by capillary electrochromatography and mu-high performance liquid chromatography

A silica-based chiral monolithic column prepared by sol-gel process and chemical modification of chiral selector was used for enantioseparation of dansyl amino acids and hydroxy acids by capillary electrochromatography (CEC) and mu-high-performance liquid chromatography (mu-HPLC). L-Prolinamide was modified as a chiral selector. The chiral stationary phase (CSP), the chiral complex of Cu(II) with L-prolinamide, provides an anodic electroosmotic flow (EOF) in CEC. The EOF was found to be dependent on applied electric field strength, the pH, and the composition of mobile phases. Scanning electron micrograph showed that monolithic columns have the morphology of continuous skeleton and large through-pore. D-Enantiomers migrated before L-enantiomers except for dansyl-(Dns)-DL-Ser. The separation efficiencies of up to 17600 (D) and 13,200 plates m(-1) (L) were achieved for the separation of DL-indole-3-lactic acid.     

Suitability of teicoplanin-aglycone bonded stationary phase for simulated moving bed enantioseparation of racemic amino acids employing composition-constrained eluents

The suitability of a teicoplanin-aglycone based chiral stationary phase for the simulated moving bed (SMB) enantioseparation of amino acids under enzyme-compatible conditions was shown following a procedure that is based solely on model-based simulations and HPLC experiments. A set of eight amino acids could be separated employing aqueous solvent containing only 10% (v/v) methanol, five of them with baseline resolution. The impact of type and concentration of organic modifier and pH modifier and pH on the separation characteristics of racemic methionine was investigated. Invariant elution profiles of repetitive adsorption/desorption of large amounts of methionine representing SMB-like conditions suggest stable adsorption behavior. Competitive loading capacity (20 mg of methionine per g of chiral stationary phase (CSP)) and SMB productivity (1 g of D-methionine per g of CSP per day) were predicted. The applied transport-dispersive model based on a competitive Bi-Langmuir isotherm was validated and its parameter estimated by model-based experimental analysis.     

Experimental investigation of the behavior of gas phase simulated moving beds

The preparative, continuous gas chromatographic separation of the enantiomers of the inhalation anaesthetic enflurane has been studied on a chiral stationary phase based on octakis(3-O-butanoyl-2,6-di-O-n-pentyl)-gamma-cyclodextrin, dissolved in polysiloxane SE-54 and coated on Chromosorb particles. This has been carried out in a gas chromatographic simulated moving bed (GC-SMB) unit, equipped with eight columns, yielding a total volume of 1.128 l. With reference to this particular system, the separation performance and the behavior of GC-SMB units have been analyzed in depth. We have varied the internal flow-rates in the four sections of the unit in the range between about 1 and about 5 std l/min, the temperature between 20 and 45 degrees C, the switch time between about 2 and about 14 min, and the feed concentration in the range 0.32-0.90 mol%. Similarities and differences in the behavior of GC-SMBs as compared to conventional liquid phase SMBs have been described, and discussed. Operating conditions leading to more than 99% purity in one or both outlet stream have been identified, together with those achieving optimal throughput. Under such optimal conditions, about 20 g of each enflurane enantiomer with enantiomeric purity larger than 98% have been prepared.     

Resolution of (D,L)-Phenylalanine in Biphasic System by α-Chymotrypsin Immobilized on Superparamagnetic Nanogels

α-Chymotrypsin immobilized on super paramagnetic nanogels covered with carboxyl groups, exhibited high stereoselectivity in kinetic resolution of racemic phenylalanine in toluene/water biphasic system, and even improved reusability over its parent free enzyme. The results also showed that the addition of ionic liquid to water phase could enhance the stereoselectivity of the immobilized enzyme to a certain extent while the conversion yield decreased. The long-term stability allows the supported enzyme with nano-scaled dimension to use in continuous chiral resolution reaction, which opens a new horizon for enzymatic chiral resolution in large-scale production.     

模拟移动床色谱在手性药物大规模拆分中的应用

模拟移动床色谱作为手性药物大规模拆分领域中的强有力工具,越来越受到人们的重视,该文介绍了模拟移动床色谱技术的发展情况及其工作原理,对描述模拟移动床色谱分离行为的理论模型和分离操作中操作参数的确定也作了介绍。     

Preparative enantioseparation by simulated moving bed chromatography

Simulated moving bed (SMB) chromatography was invented in the 1960s in the petrochemical industry and has since then been widely used to produce petrochemicals and sugars at the multi-ton scale. In the early 1990s its principle could be successfully adapted to chromatographic enantioseparation, due to developments in system design, chiral stationary phase synthesis and improvements in modelling and simulation of non-linear chromatographic behaviour. Since then a lot of separation systems have been brought into production, which are reviewed. In addition new developments are outlined in the field of system design and stationary phase development.     

高效液相色谱法测定手性四面体金属簇合物对映体过量值

在自制的直链淀粉-三(苯基氨基甲酸酯)(ATPC)高效液相色谱手性固定相(HPLC—CSP)上，优化了手性四面体金属簇合物的手性分离条件，测定了不同合成条件下得到的手性四面体金属族合物CoMo(C0)5C5H4C(O)CH3(μη^2-HC≡CCH2OH)的对映体过量值(e.e)。结果表明：高效液相色谱手性固定相法是拆分这类化合物的一种理想方法。     

色谱法测定手性四面体金属簇合物对映体过量值

在自制的直链淀粉-三(苯基氨基甲酸酯)(ATPC)高效液相色谱手性固定相(HPLC-CSP)上,优化了手性四面体金属簇合物的手性分离条件,测定了不同合成条件下得到的手性四面体金属簇合物C0M0(CO)5C5H4C(O)CH3(μη^2-HC≡CCH2OH)的对映体过剩值(ee)。结果表明,高效液相色谱手性固定相法是拆分这类化合物的一种理想方法。     

Coupling of simulated moving bed chromatography and fractional crystallisation for efficient enantioseparation

An optimised coupling of liquid chromatography and fractional crystallisation is suggested for efficient enantioseparation. As a first stage, a chromatographic separation, preferably simulated moving bed (SMB) chromatography, is applied to achieve an enantiomeric enrichment sufficient for a subsequent crystallisation. First results of the experimental and modelling work for the model system (+)-/(-)-mandelic acid in an aqueous solution are described. Chromatographic investigations involve the estimation of adsorption isotherms on a suitable chiral stationary phase and the simulation and optimisation of a corresponding SMB process. From the ternary phase diagram measured for the (+)-/(-)-enantiomer/ solvent system, the conditions required to crystallise a pure enantiomer from an asymmetric mixture can be derived. The productivity gains achievable from the combined process compared to the application of chromatography alone are discussed.