厚体液膜拆分克伦特罗外消旋体及其动力学研究

以D-( )-二苯甲酰酒石酸(D-( )-DBTA)为流动载体,研究了克伦特罗(clenbuterol,Cle)对映体的厚体液膜法拆分,建立了手性拆分条件和动力学拆分模型。考察了D-( )-DBTA浓度、缓冲液pH值对手性拆分性能的影响,进行了动力学分析,并测定了膜-料液界面的萃取反应表观速率常数k1和膜-反萃相界面的反萃取表观速率常数k2。结果表明:在优化的实验条件下(pH为7,手性载体与Cle浓度比为1∶4),Cle外消旋体能被含有手性载体D-( )-DBTA的厚体液膜有效拆分,分离因子大于1.08;Cle单体的跨膜迁移过程可以用两个串联的准一级不可逆过程进行描述。     

组合手性萃取拆分克伦特罗外消旋体

以D-二苯甲酰酒石酸(D-DBTA)和D-二对甲苯甲酰酒石酸(D-DTTA)的组合作为手性选择剂,研究克伦特罗对映体在水相和有机相中的萃取分配行为,优化了手性萃取条件,考察了组合手性选择剂的不同摩尔浓度比、有机溶剂、水相pH值和亲脂性阴离子BPh4-对手性萃取性能的影响,并测定了手性萃取拆分过程中的热力学函数.在优化的手性萃取条件下,有机相中的对映体过量值(e.e.%)可大于10%,而所使用的选择剂量相对大为降低.热力学数据分析表明,该手性萃取过程为焓控过程.     

双相(O/W)识别手性萃取分离α-环己基扁桃酸对映体

提出一种新的手性分离技术双相(O/W)识别手性萃取. 研究了α-环己基扁桃酸对映体在D(L)-酒石酸异丁酯1,2-二氯乙烷有机相和β-环糊精衍生物水相萃取体系中的分配行为; 考察了β-环糊精衍生物种类和浓度、酒石酸酯构型和浓度、水相pH 值等因素对萃取性能的影响. 实验结果表明, 双相(O/W)识别手性萃取具有很强的手性分离能力, 羟丙基β-环糊精、羟乙基β-环糊精、甲基β-环糊精均对S-α-环己基扁桃酸对映体的识别能力大于对R-α-环己基扁桃酸对映体的识别能力, 其中以羟丙基β-环糊精的识别能力最强; 而D-酒石酸异丁酯的识别能力刚好相反; 在羟丙基β-环糊精和D-酒石酸异丁酯萃取体系中, α-环己基扁桃酸外消旋体一次萃取分离后, 水相中S-对映体e.e.%达到27.6%, R-和S-对映体的分配系数(k_R和k_S)分别为2.44和0.98, 分离因子(α)达2.49; 同时pH值和萃取剂浓度对手性分离能力有显著影响. 双相(O/W)识别手性萃取对外消旋体化合物的制备性分离有着十分重要的意义.     

手性酯类萃取剂萃取拆分α-环己基扁桃酸外消旋体

研究了α-环己基扁桃酸对映体在含有疏水性D酒石酸酯手性选择体的1,2-二氯乙烷和水两相系统萃取分配行为,考察了酒石酸酯烷基链长度、pH值和D酒石酸酯浓度对分配比和分离因子的影响。实验表明：D酒石酸酯与R-α-环己基扁桃酸对映体比与S—α-环己基扁桃酸对映体形成更稳定的非对映体复合物;随着pH值增大,分配比减小,分离因子也随之降低;同时,D酒石酸酯浓度的影响也比较大。     

反式第一菊酸对映体的手性选择剂立体选择性分离

研究反式第一菊酸(trans-CA)对映体在含有手性选择剂酒石酸酯的水-有机相双相体系中的萃取分配行为,考察有机相的种类、酒石酸酯烷基链长度、水相的pH值和酒石酸酯的浓度对分配系数K和分配因子α的影响.研究结果表明:1,2-二氯乙烷作为有机相效果较好,D-酒石酸酯与( )-反式第一菊酸对映体形成的复合物稳定性比与(-)-反式第一菊酸对映体形成的复合物稳定性要大,而L-酒石酸酯的萃取性能与此相反,它与(-)-反式第一菊酸对映体形成的复合物稳定性比与( )-反式第一菊酸对映体形成的复合物稳定性要大.酒石酸酯取代烷基链长对分配系数K和分离因子α有很大影响;分配系数K和分离因子α均随pH的升高而降低;分配系数K随着酒石酸酯浓度的增大而增大,分离因子α先随浓度增大而稳定上升,后随浓度增大而缓慢下降.     

疏水性L-酒石酸异丁酯立体选择性萃取拆分氰戊菊酸对映体

合成了萃取拆分氰戊菊酸(FA)对映体的手性选择体L-酒石酸异丁酯.研究了氰戊菊酸对映体在含有手性选择体L-酒石酸异丁酯的水-有机相双相体系中的萃取分配行为.考察了有机稀释剂类型、L-酒石酸异丁酯浓度、pH值和磷酸盐浓度诸因素对分配系数(K)和分离因子(α)的影响.研究结果表明:L-酒石酸异丁酯与S对映体形成的复合物稳定性比与R对映体形成的复合物要好;1,2-二氯乙烷作为有机稀释剂更有利于萃取分离;随着L-酒石酸异丁酯浓度的增大,K逐渐增大,α先增大后减小,当L-酒石酸异丁酯浓度为0.30 mol\5L-1时,α达最大;pH值增大,K和α都降低;磷酸盐浓度对分配系数和分离因子也有较大影响.     

酒石酸酯固载薄层色谱法拆分盐酸克伦特罗对映异构体

药物对映体的各个单体通常具有不同的生物活性、药理活性,所以需要对它们进行拆分以得到旋光单体。D-和L-酒石酸是廉价的手性原料,（2R,3R）-酒石酸可直接从自然界获取。选择酒石酸衍生物例如酒石酸二酯、酒石酸单酰胺、酒石酸二酰胺等用于对映体拆分,效果比较令人满意。本工作将（2R,3R）-酒石酸-二环己酯固载在硅胶GF254板上,成功地拆分了盐酸克伦特罗对映体,并对其拆分机理进行了探讨。     

立体选择性萃取分离反式DV菊酸对映体

研究了反式DV菊酸对映体在含有手性选择体酒石酸酯的水-有机相双相体系中的萃取分配行为,考察了有机稀释剂种类、酒石酸酯的浓度、温度、水相的pH值、酒石酸酯烷基链长度对分配系数(D)和分配因子(α)的影响.研究表明:三氯甲烷作稀释剂时萃取分离效果较好;温度升高使分配系数增大,分离因子减小;分配系数随pH的升高而降低,随着酒石酸酯浓度的增大而增大,分离因子随pH的升高和酒石酸酯浓度的增大先增加后降低,pH和酒石酸酯浓度分别为4.50和0.40mol/L时取得较好的分离效果;取代烷基链长对分配系数(D)和分离因子(α)亦有较大影响.     

手性溶剂萃取分离顺式二氯菊酸对映体

研究了顺式二氯菊酸(cis-PA)对映体在含有酒石酸酯手性选择体的水-1-2-二氯乙烷两相溶液中的萃取分配行为,考察了有机相种类、L-酒石酸酯浓度、水相pH、L-酒石酸酯烷基链长度和萃取温度等因素对萃取分离效果的影响.结果表明,L-酒石酸酯与II对映体形成的复合物稳定性比与I对映体形成的复合物要好;1.2-二氯乙烷作为有机相效果较好;随着L-酒石酸酯浓度的增大,分配系数K逐渐增大,而分离因子α先增大然后开始减小;随着pH的增大,K和α都降低;L-酒石酸酯烷基链长度及萃取温度对K和α有较大影响.     

基于手性配体交换反应立体选择性萃取分离氧氟沙星对映体

基于配体交换反应,研究了氧氟沙星对映体在含有Cu²⁺和N-n-十二烷基-L-脯氨酸手性配体(L)两相体系中的分配平衡.在不同pH条件下,考察了Cu²⁺在含有N-n-十二烷基-L-脯氨酸两相中的分布;研究了pH,Cu²⁺浓度,手性配体浓度等因素对氧氟沙星对映体在两相中的分配系数(K)和分离因子(α)的影响.实验结果表明,N-n-十二烷基-L-脯氨酸对R-氧氟沙星对映体萃取能力大于对S-对映体的萃取能力;pH对K和α的影响很大,在pH值小于3.5时,L₂Cu二元配合物的生成在热力学上看是不适宜的,萃取时pH宜大于3.5;手性配体和Cu²⁺摩尔比为2:1,K和α最佳;使用2×1中空纤维膜对氧氟沙星对映体进行萃取分离,出口水相氧氟沙星对映体浓度比值(S/R)约为1.72.     

Facilitated Transport of Penicillin G by Bulk Liquid Membrane with TBP as Carrier

The facilitated transport of penicillin G from aqueous solutions to the stripping phase through bulk liquid membrane (BLM) containing TBP in 3% iso-octanol and n-butyl acetate was studied. Na₂CO₃ solution was used as the stripping phase. Experiments were performed as a function of stirring rate, TBP concentration and type of diluent in the liquid membrane phase, pH, and initial penicillin G concentration in the feed phase, Na₂CO₃ concentration in the stripping phase, etc. The results showed that the BLM process could carry out the simultaneous separation and concentration of penicillin G from dilute aqueous solutions, and arise “up-hill” effect due to the characteristic of non-equilibrium mass transfer. The diffusion of penicillin G complex in the liquid membrane phase played an important role in BLM process. The mass transfer mechanism of BLM for this system was also discussed.     

Carrier-facilitated bulk liquid membrane transport of iron(III)-siderophore complexes utilizing first coordination sphere recognition

Carrier-facilitated bulk liquid membrane (BLM) transport from an aqueous source phase through a chloroform membrane phase to an aqueous receiving phase was studied for various hydrophilic synthetic and naturally occurring Fe(III)-siderophore complexes using first coordination sphere recognition. Iron transport systems were designed such that two cis coordination sites on a hydrophilic Fe(III) complex are occupied by labile aquo ligands, while the other four coordination sites are blocked by strong tetradentate ligands (siderophores). The labile aquo coordination sites can be "recognized" by a liquid membrane-bound hydrophobic bidentate ligand, which carries the hydrophilic Fe(III)-siderophore complex across the hydrophobic membrane to an aqueous receiving phase. The system is further designed for uphill transport of Fe(III) against a concentration gradient, driven by anti-port H(+) transport. Three tetradentate siderophore and siderophore mimic ligands were investigated: rhodotorulic acid (H(2)L(RA)), alcaligin (H(2)L(AG)), and N,N'-dihydroxy-N,N'-dimethyldecanediamide (H(2)L(8)). Flux values for the transport of Fe(L(x))(OH(2))(2)(+) (x = RA, AG, 8) facilitated by the hydrophobic lauroyl hydroxamic acid (HLHA) membrane carrier were the highest when x = 8, which is attributed to substrate lipophilicity. Ferrioxamine B (FeHDFB(+)) was also selectively transported through a BLM by HLHA. The process involves partial dechelation of ferrioxamine B to produce the tetradentate form of the complex (Fe(H(2)DFB)(OH(2))(2)(2+)), followed by ternary complex formation with HLHA (Fe(H(2)DFB)(LHA)(+)) and transport across the membrane into the receiving phase. Uphill transport of ferrioxamine B was confirmed by increased flux as [H(+)](source phase) < [H(+)](receiving phase). The membrane flux of ferrioxamine B occurs near neutral pH, as evidence that ternary complex formation and ligand exchange are viable processes at the membrane/receptor surface of microbial cells.     

Transport and separation of carboxylic acids through bulk liquid membranes containing tributylamine

In this study, transport and separation of carboxylic acids (formic, acetic, propionic, and butyric acids) from their aqueous solutions through bulk liquid membrane (BLM) containing tributylamine (TBA) and the parameters affecting the transport were investigated. The influence of the parameters on the separation process such as the stirring of membrane phase, the stripping phase type and concentration, the feed phase type, and the feed:membrane:stripping phase ratio (F/M/S phase ratio) were examined. In the experiments, 10% (w/w) acid solutions (formic, acetic, propionic, and butyric acids) were used as the feed phase, different concentrations of NaOH solutions within the range of 0–2?N were used as the stripping phase, and 0.5?mol/lt TBA, dissolved in oleyl alcohol, was used as the membrane phase. It was determined that the stirring of the membrane phase increases the transport of acids. In the case of 2 N NaOH solution in the stripping phase and F/M/S phase ratio 1:2:1 gave the best recovery (96.75%) for butyric acid. It was observed that BLM was an effective technique for the separation of carboxylic acids from aqueous solutions.     

A supported liquid membrane encapsulating a surfactant-lipase complex for the selective separation of organic acids

We have developed a novel, lipase-facilitated, supported liquid membrane (SLM) for the selective separation of organic acids by encapsulating a surfactant-lipase complex in the liquid membrane phase. This system exhibited a high transport efficiency for 3-phenoxypropionic acid and enabled the selective separation of organic acids due to the different solubilities of the acids in the organic phase and the variable substrate specificity of the surfactant-lipase complex in the liquid membrane phase. We found that various parameters, such as the amount of surfactant-lipase complex in the SLM, the lipase concentration in the receiving phase, and the ethanol concentration in the feed phase, affected the transport behavior of organic acids. The optimum conditions were 5 g L(-1) of the surfactant-CRL complex in the SLM (CRL=lipase from Candida rugosa), 8 g L(-1) of PPL in the receiving phase (PPL=lipase from porcine pancreas), and an ethanol concentration of 50 vol %. Furthermore, we achieved high enantioselective transport of (S)-ibuprofen attributable to the enantioselectivity of the surfactant-CRL complex.     

Efficient resolution of racemic N-benzyl beta3-amino acids by iterative liquid-liquid extraction with a chiral (salen)cobalt(III) complex as enantioselective selector

The efficient (up to 93% ee) resolution of racemic N-benzyl beta(3)-amino acids has been achieved by an iterative (two cycle) liquid-liquid extraction process using a lipophilic chiral (salen)cobalt(III) complex [Co(III)(1)(OAc)]. As a result of the resolution by extraction, one enantiomer of the N-benzyl beta(3)-amino acid predominated in the aqueous phase, while the other enantiomer was driven into the organic phase by complexation to cobalt. The complexed amino acid was then quantitatively released into an aqueous phase, by a reductive (Co(III)--> Co(II)) counter-extraction using l-ascorbic acid. The reductive cleavage allowed for the recovery of the cobalt(II) selector in up to 90% yield (easily re-oxidable to Co(III) with air/AcOH).     

Evaluation of the interaction between sitagliptin and cyclodextrin derivatives by capillary electrophoresis and nuclear magnetic resonance spectroscopy

An aqueous capillary electrophoretic method was developed for chiral analysis of the novel anti-diabetic drug, sitagliptin. The acid-base profiling of the analyte was carried out using both capillary electrophoresis and nuclear magnetic resonance pH titrations. The apparent complex stability and chiral separation properties were investigated with 30 different cyclodextrins under acidic conditions. The effect of concentration and pH of the BGE, temperature of the capillary, and the type and concentration of the chiral selector on the enantiomer resolution were thoroughly investigated. The effects of dual cyclodextrin systems on separation were also extensively studied. Complete separation of racemic sitagliptin with good resolution (R(S)=2.24) was achieved within a short time (15 min) with optimized parameters (10°C, pH=4.4, 40 mM phosphate buffer) of a sulfobutylether-β-cyclodextrin (averaged degree of substitution ~4) and native β-cyclodextrin dual system. The averaged stoichiometry of the inclusion complex was determined using the Job plot method with both (1)H and (19)F NMR experiments and resulted in a 1:1 complex. The structure of the inclusion complex was elucidated using 2-D ROESY NMR experiments.     

Synthesis of a nano‐sized chiral imprinted polymer and its use as an (S)‐atenolol carrier in the bulk liquid membrane

In this work, nanosized chiral imprinted polymers containing (S)‐atenolol ((S)‐ATN) selective sites were synthesized by using suspension polymerization in silicon oil. (S)‐ATN, methacrylic acid, and ethylene glycol dimethacrylate were used as enantiomerically pure template, functional monomer, and cross‐linker, respectively. The prepared chiral imprinted polymers were used as the carrier elements in a bulk liquid membrane (BLM). (S)‐ATN transport capability of the chiral imprinted polymers was compared with that of the nonimprinted polymer. It was shown that chiral imprinted polymers could transport (S)‐ATN through the BLM more effectively than (R)‐ATN, whereas no difference in the facilitated transport was observed between (R)‐ATN and (S)‐ATN when using nonimprinted polymer particles as the carrier element in the BLM. A kinetic model was proposed for the transportation of (S)‐ATN through the chiral imprinted polymers based BLM. It was found that the extraction of ATN from the source to the membrane controls the chiral separation process. It was also found that the pH of source and receiving phases as well as the racemic ATN concentration in source phase had very crucial effect on the chiral separation efficiency.     

Electrochemical elucidation on the mechanism of uncoupling caused by hydrophobic weak acids

Uncoupler-mediated cation transport has been investigated by cyclic voltammetry for the ion transfer from one aqueous phase (W1) to another (W2) across a bilayer lipid membrane (BLM) in the presence of typical uncouplers, 3,5-di(tert-butyl)-4-hydroxybenzylidenemalononitril (SF6847) and 2,4-dinitrophenol (DNP). The voltammograms for the ion transfer were in a steady state and exhibited a rotated sigmoidal shape that was almost symmetrical about the origin (0 V, 0 A). The plot of the ion transfer current against pH was a bell-type curve centered on pH approximately = pK(a) + 1, K(a) being the dissociation constant of the uncouplers in the aqueous phase. Taking into account the ion transfer reactions at the W1|BLM and the BLM|W2 interfaces, these properties were well explained by our proposed model which considers that the ion transfer current is attributable to the facilitated transfers of H(+) and Na(+). The buffer action in the aqueous phase was found to play an important role in the facilitated H(+)-transfer across the BLM. The nature of the pH-dependence of the ion transfer current was reasonably explained from an electrochemical viewpoint based on the distribution coefficient of the anionic and neutral forms of SF6847, as estimated from its absorption spectra in liposomal membrane. The proposed model is also valuable for understanding the pH-dependence of uncoupling activity in mitochondria in the literature.     

Voltammetric study on ion transport across a bilayer lipid membrane in the presence of a hydrophobic ion or an ionophore

This review describes voltammetric studies on ion transport from one aqueous phase (W1) to another (W2) across a bilayer lipid membrane (BLM) containing a hydrophobic ion, valinomycin (Val) or gramicidin A (GA). In particular, the ion transport mechanisms are discussed in terms of the distribution of a pair of ions between aqueous and BLM phases. By addition of a small amount of hydrophobic ion into W1 and/or W2 containing a hydrophilic salt as a supporting electrolyte, the hydrophobic ion was distributed into the BLM with the counter ion to maintain electroneutrality within the BLM phase. It was found that the counter ion was transferred between W1 and W2 across the BLM by applying a membrane potential. Facilitated transport of alkali ions across a BLM containing Val as an ion carrier compound, could be interpreted by considering not only the formation of the alkali metal ion–Val complex but also the distribution of both the objective cation and the counter ion. In the case of addition of GA as a channel-forming compound into the BLM, the facilitated transport of alkali ions across the BLM depended on the ionic species of the counter ions. It was discovered that the influence of the counter ion on the facilitated transport of alkali ions across the BLM could be explained in terms of the hydrophobicity and the ionic radius of the counter ion.     

以羟丙基-β-环糊精为手性添加剂拆分2-取代芳基丙酸:取代基对手性识别的影响（英文）

以羟丙基-β-环糊精为手性添加剂,采用反相高效液相色谱法对2-取代芳基丙酸类物质进行了手性拆分。考察了流动相的组成,包括缓冲溶液、有机改性剂以及添加剂的浓度等。缓冲溶液的pH值、有机改性剂的种类与浓度,以及添加剂的浓度对色谱峰的保留时间和分离度均有较大的影响。以YMC ODS-C_(18)(150 mm×4.6 mm,5μm)为色谱柱,乙腈-0.10 mol/L磷酸盐缓冲液(pH 3.3,含25 mmol/L添加剂)为流动相,测定了各2-取代芳基丙酸与羟丙基-β-环糊精的包结常数,考察了羟丙基-β-环糊精对各物质的包结形式。实验结果表明,羟丙基-β-环糊精与各对映体均以1∶1的形式包结,同时发现推电子取代基更有利于羟丙基-β-环糊精的包结行为,为羟丙基-β-环糊精对手性拆分的影响提供了一个有利的参考因素。