手性药物结晶拆分的研究进展

手性是自然界和生物体中广泛存在的一种性质,约半数以上的药物活性成分含有手性中心,受手性分子的空间立体选择性影响,手性对映体药物往往较其外消旋体表现出更高的活性、更低的副作用,因而,精准制备手性单一对映体药物具有非常重要的研究意义。目前,手性外消旋体拆分是制备单一对映体的最高效、便捷的途径,而结晶拆分是实现手性单一对映体分离最为重要且广泛应用的技术。综述了近年来手性药物结晶拆分的研究进展,梳理了结晶拆分研究的发展历程,重点介绍了基于经典拆分方法 (非对映体成盐拆分和优先结晶)和近年来发展的基于优先富集和Viedma熟化的对映体拆分新技术以及结晶拆分的强化方法,并简述了色谱、膜分离等其他手性外消旋体分离方法。最后,对手性药物的结晶拆分方法进行了总结和展望。     

手性化学促进单一对映体药物开发

外消旋体拆分是获取单一对映体药物的主要方法 ,将主 客化学引入化学拆分发明的包结拆分法突破了经典拆分方法的局限 ;酶法拆分目前用的最多的是水解和酯交换反应 ;模拟移动床色谱是商业规模制备色谱最有希望的技术 ;逆流萃取和膜分离技术是近年发展的分离对映体药物或中间体的更为经济的手性分离技术。不对称合成已走出实验室进入工业生产 ,常用的方法有手性源法、不对称催化法和生物转化法     

新型手性拆分膜研究进展

单一对映体手性化合物在食品、医疗和建筑等领域中具有重要的意义.随着对手性对映体的需求日益增多,开发高效手性对映体拆分技术成为近年来研究的热点.膜分离技术具有其高效节能的特点,在分子分离领域日益受到关注.近年来,一些新型的膜材料在手性对映体拆分领域展现出了优异的性能和潜在的应用前景.本文从膜材料结构设计的角度出发,介绍了...     

手性化学工业的发展（一）

传统化学仍是获得单一对映体的主要方法,传统化学也可能达到对映体纯产品的目标,例如结晶动力学拆分制备(R)-氟比洛芬,哌啶诱导构型转换制备L-核糖。手性源和拆分方法仍多于催化不对称合成,而催化不对称合成化学的核心是催化剂的选择,不对称环氧化在工业上取得了巨大成功。     

β-氨基酸消旋体的合成与手性分离

光学纯β-氨基酸是合成拟多肽和β-内酰胺类抗生素等药物的重要中间体,其制备方法通常涉及多步反应,原料昂贵,操作复杂且产率较低。以醛、丙二酸和铵盐为原料,采用“一锅法”合成了5种β-氨基酸消旋体。应用手性配体交换色谱对所合成的氨基酸消旋体进行拆分,获得了光学纯β-氨基酸对映体。结果表明基于“一锅法”合成β-氨基酸消旋体和手性配体交换色谱分离对映体的制备方法具有操作简便,成本低廉,产率较高的特点,适合用于药物高通量筛选不同结构β-氨基酸对映体的快速制备。     

手性萃取剂与液-液萃取拆分对映体技术研究进展

手性对映体的拆分是当前备受关注的一个研究领域。手性对映体的拆分方法有多种, 手性液-液萃取拆分法是其中有较好发展前景的一种手性对映体拆分技术。本文概述了手性液-液萃取技术的基本原理, 并进一步对酒石酸类手性萃取剂、环糊精类手性萃取剂、冠醚类手性萃取剂、金属络合物类手性萃取剂等不同种类手性萃取剂及其研究进展进行了综述。分析表明, 手性液-液萃取拆分技术对外消旋体特别是药物外消旋体的拆分有较好的效果, 随着对手性萃取剂研究的进一步深入, 手性液-液萃取有望成为一种手性化合物拆分的重要方式。     

手性药物及其薄层色谱拆分

手性药物的活性和药效很大程度取决于它们的结构,往往一种对映体有药效而另一种对映体无药效甚至有毒副作用。近年来,色谱法分离对映体已成为重要的和迅速发展的研究领域。本文对薄层色谱法在拆分对映体方面的应用情况作一概述,包括纤维素及其衍生物,β－环糊精及其衍生物,铜和光学活性配位络合物及电荷转移络合物等手性固定相拆分法、手性流动相添加剂的拆分法和某些药物的活性和它们的构象之间关系也被叙述。     

环氧化物生物催化转化的研究进展

环氧化物是合成手性目标产物的高价值中问体。环氧化物生物催化转化包括环氧化物水解酶催化的动力学拆分和对映会聚的酶水解,前者可生成相应二醇和剩余的手性底物,后者可从外消旋混合物中得到高产率的单一对映体。而用选择性的阴离子亲核试剂,卤醇脱卤酶则催化环氧化物非水解型对映选择性开环。这些酶的催化机理包括天门冬氨酸羧酸酯作为亲核试剂的共价催化和酪氨酸作为广义酸碱试剂的非共价催化。本文介绍了环氧化物生物催化转化中的新进展。     

金属催化和生物催化在对映体拆分中的联合应用

随着对单一对映体化合物需求的日益增长，外消旋体向单一对映体的转化(去外消旋化过程)成为研究的主要方面之一，最近在去外消旋化过程中的生物催化和金属催化的联合作用被证明是非常有效的。动态动力学拆分和循环去外消旋化已经对这方面的研究有很大的推动作用。     

手性化合物合成与拆分技术进展

目前，手性物质的生产除了直接进行不对称合成与发酵之外，主要是通过化学合成DL-型外消旋体物质，然后通过各种拆分方法得到所需要的具有光学活性的对映体。当前用于手性化合物拆分的方法主要有结晶法、外消旋拆分法、萃取法等，电合成作为合成手性化合物的方法则一支独秀。     

Preferential crystallization: Multi‐objective optimization framework

A four objective optimization framework for preferential crystallization of D‐L threonine solution is presented. The objectives are maximization of average crystal size and productivity, and minimization of batch time and the coefficient of variation at the desired purity while respecting design and operating constraints. The cooling rate, enantiomeric excess of the preferred enantiomer, and the mass of seeds are used as the decision variables. The optimization problem is solved by using adaptation of the nondominated sorting genetic algorithm. The results obtained clearly distinguish different regimes of interest during preferential crystallization. The multi‐objective analysis presented in this study is generic and gives a simplified picture in terms of three zones of operations obtained because of relative importance of nucleation and growth. Such analysis is of great importance in providing better insight for design and decision making, and improving the performance of the preferential crystallization that is considered as a promising future alternative to chromatographic separation of enantiomers. © 2009 American Institute of Chemical Engineers AIChE J, 2009     

亲和膜手性拆分技术及手性拆分固膜

阐述了亲和膜拆分技术,包括亲和超滤、纳滤、电渗析、渗析及渗透汽化等在手性拆分领域的应用,对基于对映体间亲和性差异的手性选择膜及基于"形状记忆"的分子印迹拆分膜的最新进展进行了综述,并就今后的发展方向提出建议。     

Simultaneous preferential crystallization in a coupled batch operation mode. Part II: Experimental study and model refinement

In the previous part of this series a parametric study was presented to assess theoretically the performance of a novel crystallizer configuration. Complementary, the present work addresses a comprehensive, systematic experimental examination accompanied by an analysis of some relevant process parameters (mass of seeds, CSD of seeds, starting point for the mother liquor exchange, process duration) of two general concepts for preferential crystallization in which the amino acid threonine dissolved in water was used as a model system. In the first step of investigations, the impact of these process parameters was studied for conventional single batch crystallization. The experimental results are discussed and compared with the theoretical ones. Moreover, a configuration consisting of two coupled crystallization vessels was investigated. The specific manipulation of the concentration profiles of each enantiomer in solution as well as of the temperature profiles was found to be suitable to enhance the process performance. This is reflected by higher achievable process productivities and higher product purities.     

Simultaneous kinetic resolution of chiral propylene oxide and propylene glycol in a continuous reactive distillation column

Traditionally kinetic resolutions are conducted by batch processing to recover one of the desired enantiomers of the racemate, while the product formed by the resolution is discarded due to its low purity. However, chiral materials are economically valuable and simultaneously conducting the reaction and separation, using reactive distillation, allows for both a reactant enantiomer and a product enantiomer to be recovered in high enantiomeric excess and yield. A feasible design of a continuous reactive distillation column is presented which performs a simultaneous kinetic resolution of racemic propylene oxide to produce both enantiomerically-pure propylene oxide and propylene glycol.     

手性表面与对映异构体的结晶分离

近年来,手性表面在分离对映异构体方面的重要性引起科学工作者的很大兴趣。手性表面对手性分子的识别和区分能力成为人们最感兴趣的领域之一。文章回顾了用手性自组装单分子层做分离助剂来结晶分离外消旋物的研究进展。     

Resolution by Preferential Crystallization of Proxyphylline by Using Its Salicylic Acid Monohydrate Co-Crystal

The monohydrated co-crystal composed of the chiral active pharmaceutical ingredient proxyphylline, salicylic acid, and water was successfully resolved by preferential crystallization from a water/ethanol mixture. To the best of our knowledge, this is the first report of preferential crystallization applied to such a system and the results reveal that unusually high enantiomeric excess values can be attained in the mother liquor. These robust and reproducible results underline the potential of preferential crystallization to resolve co-crystal systems.     

HPLC法和HPCE法在手性分子拆分领域的应用

对HPLC（高效液相色谱）法和HPCE（高效毛细管电泳）法在手性拆分领域的应用和分展进行了综述,主要论述手性HPLC拆分法中各种手性固定相的情况和手性HPCE拆分法中手性添加剂的选择,并对该领域未来的发展方向作出展望,显示出高效液相色谱和毛细管电泳是进行手性拆分的高效、快速、简便的分离手段。     

溶析结晶研究进展

溶析结晶是一种常见的分离提纯方法,广泛应用于化工、医药、食品等行业。近年来人们拓展了一些新的研究方向,比如显著影响结晶产品性质的溶析剂加入点的混合技术,与超临界流体技术耦合的溶析结晶微粒制造技术。本文从应用开发、动力学、聚集与混合、晶形与多晶型、超临界流体溶析结晶五个方面回顾了溶析结晶的研究进展。     

Chirotechnology: Designing economic chiral syntheses

The increasing awareness of the importance of chirality in the context of biological activity has stimulated a growing demand for efficient methods for the industrial synthesis of pure enantiomers. Various methodologies for the synthesis of pure enantiomers, viz. use of the chiral pool, separation of racemates via crystallization techniques or enzymatic kinetic resolution and catalytic asymmetric synthesis are reviewed and compared. Factors which influence the process economics and, hence, route selection are discussed. In particular the merits and limitations of catalytic asymmetric synthesis versus kinetic resolution are delineated. General guidelines are elaborated regarding the design of economic chiral syntheses and are illustrated by reference to the manufacture of commercially important chiral drugs, e.g. ampicillin and amoxycillin side-chains, naproxen and ibuprofen, captopril and diltiazem. Given the rapidly growing repertoire of cost-effective technologies, the industrial synthesis of chiral pharmaceuticals in enantiomerically pure form is clearly an economically viable proposition. Moreover, as understanding of the general principles involved provides a sound basis for identifying the most attractive process.     

Applications of the crystallization process in the pharmaceutical industry

The applications of the crystallization technique in the pharmaceutical industry as a purification and separation process for the isolation and synthesis of pure active pharmaceutical ingredients (API), co-crystals, controlled release pulmonary drug delivery, and separation of chiral isomers are briefly discussed using a few case studies. The effect of process variables and solvent on the polymorphism and morphology of stavudine is discussed. The implementation of external control in the form of feedback and real-time optimal control using cooling and antisolvent crystallization of paracetamol in water-isopropyl alcohol is introduced. Two methods to prepare micronsized drug particles, namely, micro-crystallization and polymer-coated API-loaded magnetic nanoparticles for pulmonary drug delivery, are discussed. The significance of co-crystals in drug administration is highlighted using the theophylline-nicotinamide co-crystal system. Resolution of chloromandelic acid derivatives, a racemic compound, is achieved using direct crystallization and diastereomeric salts crystallization. The crystal structures of diastereomeric salts of chloromandelic acid and phenylethylamine are determined. The structure comparison between the less soluble and more soluble salts shows that weak interactions such as CH/π interactions and van der Waals forces contribute to chiral recognition when the hydrogen bonding patterns are similar.