Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

Abstract

The multistep flow synthesis of complex molecules has gained momentum over the last few years. A wide range of reaction types and conditions have been integrated seamlessly on a single platform including in-line separation as well as monitoring. Beyond merely getting considered as ‘flow version’ of conventional ‘one-pot synthesis’, multistep flow synthesis has become the next generation tool for creating libraries of new molecules. Here we give a more ‘engineering’ look at the possibility of developing a ‘unified multistep flow synthesis platform’. A detailed analysis of various scenarios is presented considering 4 different classes of drugs already reported in the literature. The possible complexities that an automated and controlled platform needs to handle are also discussed in detail. Three different design approaches are proposed: (i) one molecule at a time, (ii) many molecules at a time and (iii) cybernetic approach. Each approach would lead to the effortless integration of different synthesis stages and also at different synthesis scales. While one may expect such a platform to operate like a ‘driverless car’ or a ‘robo chemist’ or a ‘transformer’, in reality, such an envisaged system would be much more complex than these examples.

Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis

“…However, it is worth noting that fully continuous-flow syntheses rarely exceed two steps before offline purification 19 . To realize a fully multistep continuous-flow synthesis is enormously challenging, mainly due to issues originating from solvent and reagent incompatibility, the accumulation of side-products, risk of clogging and mismatch of timescales between steps in a processing chain 20 , 21 . Although in-line purification strategies such as phase separators 12 have been applied (Supplementary Fig.…”

Continuous one-flow multi-step synthesis of active pharmaceutical ingredients

“…54 Flow chemistry allows for a large variety of chemical conversions and specific reaction conditions tailored to the reactants to optimise the synthesis. 55,56 Reaction time, mixing, temperature, stoichiometry, concentration, (side-)product solubility, pressure control and continuous operating modes are a few of the benefits which are widely used in the pharmaceutical industry. 57 Currently, however, numerous biologically relevant molecules are still prepared in a batch fashion, as most of organic chemistry is still focused on this conventional methodology.…”

Low-Cost 3D-Printed Reactionware for the Determination of Fatty Acid Content in Edible Oils using a Base-Catalyzed Transesterification Method in Continuous Flow

“…Reactions in flow have several key advantages compared to conventional batch procedures. These advantages include rapid mixing, efficient heat and mass transfer rates, and faster and safer reactions (Ötvös et al 2012;Akwi and Watts 2018;Sharma et al 2018). To the best of our knowledge, the benefits of continuous flow systems have not been leveraged for fatty acid content analysis from triacylglycerols in edible oils.…”