In-Line Purification: A Key Component to Facilitate Drug Synthesis and Process Development in Medicinal Chemistry

Abstract

In-line purification is an important tool for flow chemistry. It enables effective handling of unstable intermediates and integration of multiple synthetic steps. The integrated flow synthesis is useful for drug synthesis and process development in medicinal chemistry. In this article, we overview current states of in-line purification methods. In particular, we focus on four common methods: scavenger column, distillation, nanofiltration, and extraction. Examples of their applications are provided.

Figure 1

Schemes show different approaches for operating multistep synthesis in flow: (1) telescoping, (2) integration with off-line purification, (3) integration with in-line purification.

Figure 2

(a) Scheme of the triazoles synthesis with scavenger resins to remove impurities. (b) Vaportec R2+/R4 with scavengers in glass columns. Adapted with permission from ref (30). Copyright 2009 Wiley-VCH.

Figure 3

(a) Microfluidic distillation for in-line solvent switch. Adapted with permission from ref (33). Copyright 2010 Wiley-VCH. (b) Hickman still head setup for continuous reactive distillation. Reproduced from ref (34) with permission from The Royal Society of Chemistry. (c) Prototype glass column for solvent switch. Adapted from ref (35) with permission from The Royal Society of Chemistry.

Figure 4

(a) Continuous-flow reactor/separator cell assembly for performing Heck coupling reactions and separating Pd catalysts. Adapted with permission from ref (43). Copyright 2013 American Chemical Society. (b) Nanofiltration module for separating metathesis catalysts. Reprinted with permission from ref (45). Copyright 2014 Wiley-VCH.

Figure 5

Integrated multistep synthesis of fluoxetine with in-line membrane separations. From ref (24). Reprinted with permission from AAAS.

Figure 6

(a) High-efficiency extraction device in a glass column. Adapted with permission from ref (53). Copyright 2016 American Chemical Society. (b) Use of electrical impedance probe to monitor the phase separation in a glass tube. Adapted by permission from Springer, Journal of Flow Chemistry, Sprecher, H.; Payán, M. N. P.; Weber, M.; Yilmaz, G.; Wille, G., Copyright 2012. (c) Flow setup with a camera-based separator for hydrozone formations. Adapted from 55 with permission from The Royal Society of Chemistry.

Figure 7

(a) Prototyped membrane separator with self-tuning pressure control. Reprinted with permission from ref (65). Copyright 2013 American Chemical Society. (b) Membrane separators as commercialized by Zaiput Flow Technologies. Copyright Andrea Adamo. Used with permission. (c) Continuous-flow multistage extraction setup. Reprinted with permission from ref (73). Copyright 2017 American Chemical Society. (d) Multistage setup on market by Zaiput Flow Technologies. Copyright Andrea Adamo. Used with permission.