Automatic monitoring and on-line chiral separation of chiral drug synthesis

Abstract

Chiral synthesis of single chiral drugs offers high efficiency, controllable costs, and excellent enantioselectivity, making it crucial in the pharmaceutical industry. A significant number of studies on chiral drug synthesis primarily focuses on the design and synthesis of innovative chiral catalysts and ligands with extremely high selectivity, as well as the development of new methods and strategies. Nonetheless, the on-line monitoring of chiral drug synthesis and its underlying mechanisms remain obscure. The principal challenge lies in the diverse synthesis pathways and intricate mechanisms of chiral drugs, with numerous intermediates and by-products. To tackle this issue, employing the chiral drug omeprazole as a breakthrough, we design and establish a reliable and stable analytical method to monitor the synthesis process. By integrating electrokinetic chromatography technology with automatic sequence injection, the chiral synthesis of omeprazole can be comprehensively tracked and monitored throughout its entire process. During the chiral drug synthesis process, all compounds, containing all reagents and products (omeprazole sulfide, R-omeprazole, S-omeprazole, iodobenzene and iodobenzene diacetate) are efficiently separated and simultaneously detected through a single run. The method shows a high resolution greater than 1.2, a wide linear range with a detection limit as low as 0.008 μM, as well as exceptional repeatability in sequence analysis. Therefore, the proposed method has demonstrated significant value in the analysis of chiral drug synthesis and holds potential for extensive application in the industrial production of chiral compound synthesis.