GABRIELE MENGES-FLANAGAN*, EVA DEITMANN, LARS GÖSSL
*Corresponding author
Fraunhofer-Institute for Microengineering and Microsystems IMM, Mainz, Germany

Abstract

The benefits of using flow chemistry for fast, very exothermic, and dangerous processes has been widely acknowledged and demonstrated within the last few decades. Discussed in this article are the particular advantages that can be gained when using continuous processing for the formation and consumption of magnesium and zinc organometallic intermediates especially considering significant process improvements in terms of safety, scalability, selectivity, and sustainability. Appropriate technology applicable to the process, its scalability, and its application for a particular magnesium- and zinc-based reagent emphasizes that continuous processing can be used for either metal interchangeably depending on reagent processing needs.

Introduction
For more than a century, organometallic reagents, initially based on direct insertion of zinc as a metal (1) and later complemented and expanded by magnesium-based compounds (Grignard reagents) (2), have been a very valuable and intricate tool for process chemists in the formation of novel carbon-carbon bonds. Particularly in the synthesis of Active Pharmaceutical Ingredients (API), Grignard reagents and zinc reactive intermediates are regularly employed and 50 % of the Grignard reagent market is taken up by the use in the pharmaceutical sector (3, 4).
However, organometallic reagent handling is flawed by a sensitivity to water and oxygen and their formation is challenging because of variable length incubation periods due to metal surface passivation, in many cases high exothermicities in the formation that have to be appropriately managed, and a tendency for side product formation. Since the overall market for Grignard reagents is expected to grow over the next years, production capacities and product variety will increase (3). A modular continuous production process allows for tight process control, reduced storage times, and provid ...