PREPARATIVE ELECTROPHORETIC CHIRAL SEPARATIONS

众所周知，对映体的分离对制药工业具有重要意义。尽管在许多情况下，一个对映体具有所需的药理活性，而另一个对映体可能导致不良副作用，这一事实引起了人们的极大关注，但经常被忽视的一点是，在某些情况下，两种对映体都可能具有治疗价值……只是对同一种疾病状态不同。因此，开发经济的制备和半制备规模的手性分离方法是非常必要的，特别是对于R和D环境，在开发成本更高、效率更低的立体专一性合成策略之前，可能只需要少量的材料来启动筛选。该项目的具体目标是解决这一关键需求，以开发制备手性分离。我们的方法是探索基于连续自由流动电泳法的手性分离方法，在缓冲液中使用磺化环糊精作为手性添加剂。连续自由流动电泳法在水相手性分离中的应用是一种新颖的方法，有可能获得水溶液中手性药物的纯对映体从mg到g/小时的数量，对许多不同类别的手性药物以及手性中间体或代谢物具有广泛的适用性。实验设计允许手性选择剂的潜在回收和重复使用(通常昂贵和/或稀有)，从而增加了该方法的经济吸引力。

It is well recognized that the separation of enantiomers is important to the pharmaceutical industry. Although much attention has been paid to the fact that in many cases, one enantiomer has the desired pharmacological activity whereas the other enantiomer may be responsible for undesirable side-effects, a point that often gets lost is that in some cases, both enantiomers may have therapeutic value...just not for the same disease state. Thus the development of economical methods for preparative and semipreparative scale chiral separations is highly desirable, particularly for an R and D setting, where only small amounts of material may be required to initiate screening prior to developing more costly, less efficient stereospecific synthetic strategies. The specific aim of the project is to address this critical need for the development of preparative chiral separations. Our approach is to explore preparative chiral separation methods based on continuous free flow electrophoresis using a sulfated cyclodextrin as the chiral additive in the buffer. The application of continuous free flow electrophoresis to bulk scale aqueous chiral separations is novel and has the potential for obtaining mg to g/hour quantities of both pure enantiomers of chiral drugs in aqueous solution, with wide applicability for a broad range of chiral drugs from many different categories as well as chiral intermediates or metabolites. The experimental design allows for the potential recovery and reuse of the chiral selector (typically expensive and/or rare), thereby increasing the economic appeal of this approach.