Creating chemical diversity with flow chemistry

Flow chemistry techniques are increasingly being used in drug discovery to provide cost-effective access to a wide range of structurally diverse small molecule analogs, as well as access to previously underused or inaccessible chemistries. There are several ways that this powerful technique can be used to increase structural diversity when building candidate molecules, including linear progression from diverse starting materials, multicomponent reactions around core structural motifs, synthesis of uncommon low diversity starting material sub-sets, and convergent synthesis approaches. The diversity of the starting components is a key consideration when deciding the most suitable strategy for each specific application, but the development of automated, modular flow chemistry systems has made all these approaches far easier to achieve. Here we outline the various methods and provide real-world examples of how flow chemistry is being used in the industry, as well as highlighting the key flow chemistry set-up considerations.

Linear reaction sequence

The most common method for building molecules is by using a traditional linear reaction sequence, where one reaction is performed, and then the target molecule is worked-up and isolated before performing the next step. Traditional batch methods are typically time consuming and result in lower yields due to losses that occur at each step of the sequence. See Figure 1 below:

Figure 1. Linear synthesis using traditional batch techniques

In contrast, automated flow chemistry can telescope reactions in a linear sequence offering higher yields by providing better selectivity and reducing losses during work-up. Diversity is created by varying the building blocks throughout the sequence as shown in. Figure 2..

Figure 2. Linear synthesis using flow chemistry techniques

Multicomponent reactions

Multicomponent reactions (MCRs) – such as Hantzsch, Biginelli or Passerini reactions – are used to produce a single product from three or more reactants through a cascade of reactions in a single vessel. Automated flow chemistry systems can be used to introduce a range of diverse starting materials to perform these one-pot MCRs. This process can be taken further by tailoring the addition of these components to introduce reagents in the specific mechanistic sequence.

Generation of uncommon low diversity starting materials using flow chemistry

Flow chemistry techniques allow chemists to generate diverse sub-sets of compounds by synthesizing and reacting unstable intermediates on-demand. For example, aryl boronic acids are commercially available in huge numbers, but their heteroaryl counterparts are not, whereas the equivalent heteroaryl halides are available with wide structural diversity. Using the method shown in figure 3 below, flow chemistry platforms can interconvert the halides to boronic acids by automating the addition of aryl halides (See Figure 3: A), generating heteroaryl boronic acids (figure 3: B), then performing cross-coupling reactions.

Figure 3. Generating diverse starting materials using flow chemistry

Convergent synthesis using flow chemistry

Convergent synthesis fragments the desired product using a set of parallel reactions, then combining them via another set of reactions to offer enhanced efficiency and higher yields compared to linear transformations. The modularity of flow chemistry systems enables continuous convergent synthesis, and automation allows chemical diversity to be generated in parallel fragment components, then brought together in a convergent reaction as shown in Figure 4.

Figure 4. Convergent synthesis using flow chemistry techniques

Case study: Applying flow chemistry to oxadiazole synthesis

Researchers at the Sanford Burnham Institute have demonstrated the power of flow chemistry for the synthesis of highly functionalized 1,2,4-oxadiazoles from carboxylic acids.1 The team used continuous flow approaches to create chemical diversity with the generation of diverse intermediates from simple starting materials, to perform linear and convergent synthesis, and to direct scale-up of hit compounds. This study involved the synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles using a three reactor, multistep continuous flow system without isolation of intermediates. An optimized oxadiazole ring-closure procedure was combined with the synthesis of a diverse set of amidoximes, using modifications to the flow reaction conditions to generate a variety of 1,2,4-oxadiazoles, as shown in figure 5.

Figure 5. Synthesis of 1,2,4-oxadiazoles via a continuous microreactor sequence from arylnitriles and carboxylic acids

The next stage required the continuous flow synthesis of imidazo[1,2-a]pyridine-2-carboxylic acids from diverse sets of heteroaromatic amines and α-bromo esters (figure 6), providing an excellent example of generating low-diversity intermediates.

Finally, both processes were combined to deliver a continuous convergent process, allowing rapid screening of a diverse array of drug-like heterocycles with high yields. The greatest advantage of using this continuous flow approach was the ability to scale up the production of larger quantities of hits without the need for process re-optimization. The authors were also able to incorporate in-line liquid-liquid extraction technology – Asia Flow Liquid Liquid Extraction (Syrris) – into the set-up to remove the high boiling point solvent used in synthesis, enabling an easier work-up (Figure 7). This made it possible to isolate compounds on a gram scale for downstream in vitro or in vivo assessments.

Flow chemistry system requirements

Modular flow chemistry systems – such as Asia Flow Chemistry System – can be used to create chemical diversity and expand the chemical space available to research chemists, while offering the flexibility to be configured in any orientation as laboratory and project needs change. Advanced platforms can incorporate both heating and cooling devices, as well as devices for electrochemical- and photochemical-initiated reactions, and be combined with automated reagent injectors to aid exploration of a wide range of reactants to create complex libraries of compounds. Easy-to-use software is essential to take full advantage of these setups, allowing fully automated, walk-away control of virtually any configuration.

Conclusion

Flow chemistry is becoming increasingly valuable for the creation of chemical diversity in drug discovery, and automation of synthesis and purification is helping researchers to perform complex reactions more efficiently. Automated reagent injectors and versatile flow chemistry platforms enable the rapid generation of diverse compound sets, whether generating bespoke monomers or carrying out complex convergent synthesis.

References

1. 

   Andrew Mansfield

   Herath, A.; Cosford, N. D. P. Continuous-Flow Synthesis of Highly Functionalized Imidazo-Oxadiazoles Facilitated by Microfluidic Extraction. Beilstein J. Org. Chem. 2017, 13, 239–246. https://doi.org/10.3762/bjoc.13.26

Andrew Mansfield is the Flow Chemistry Leader at Syrris. Andrew has a background in implementing new chemical technologies across pharma and academia, with a major interest in the application of flow chemistry. At Syrris, Andrew manages and develops the flow chemistry portfolio.