Chiral resolution of racemic amines in µ-reactor-crystallizer

Abstract

• A semi-continuous microfluidic platform for the chiral separation process is developed. • The crystal is formed in µ-Crystallizer ∼ 33 times faster than the batch process. • The obtained diastereomeric salt from µ-Crystallizer is purer than the batch process. • A parametric map with concentration and flow rate is presented for the desired crystal. • The microfluidic process demonstrated here can be adopted for industrial application. The production of pure chiral drugs in a continuous manner is one of the major issues for pharmaceutical industries. A micro continuous process is developed for chiral separation of racemic molecules exploiting a “classical” method of diastereomer formation and subsequent crystallization. A flexible µ-reactor and µ-crystallizer are fabricated for the continuous production of diastereomer salt crystals from racemic α-phenylethylamine (I) where optically active L-(+)-tartaric acid (II) is used as a resolving agent. CD spectroscopy, UV–Vis spectroscopy, and other characterizations confirm that the diastereomeric salt obtained from the micro-continuous process is similar in quality if not better than that obtained from a conventional batch process. The process described here is capable to produce crystals at ∼ 33 times faster than the batch process at identical feed concentrations. The better control over crystals and faster resolution in this low-cost micro-continuous process offer industries a potential route for production through very-large-scale integration (VLSI).