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The application of modern reactions in large-scale synthesis

Nature Reviews Chemistry volume 5, pages 546–563 (2021)Cite this article

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Abstract

In the past decade, the field of organic synthesis has witnessed tremendous advancements in the areas of photoredox catalysis, electrochemistry, C–H activation, reductive coupling and flow chemistry. While these methods and technologies offer many strategic advantages in streamlining syntheses, their application on the process scale is complicated by several factors. In this Review, we discuss the challenges that arise when these reaction classes and/or flow chemistry technology are taken from a research laboratory operating at the milligram scale to a reactor capable of producing kilograms of product. We discuss how these challenges have been overcome through chemical and engineering solutions. Specifically, this Review will highlight key examples that have led to the production of multi-hundred-gram to kilogram quantities of active pharmaceutical ingredients or their intermediates and will provide insight on the scaling-up process to those developing new technologies and reactions.

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Fig. 1: Photoredox catalysis for late-stage functionalization of complex molecules.
Fig. 2: Application of electrochemical synthesis in large-scale transformations.
Fig. 3: C–H activation has emerged as a state-of-the-art method for the synthesis of complex molecules.
Fig. 4: Process-scale applications of C–H activation protocols towards complex active pharmaceutical ingredients.
Fig. 5: Reductive cross-electrophile coupling for the synthesis of complex active pharmaceutical ingredients.
Fig. 6: Continuous flow manufacturing of pharmaceuticals.
Fig. 7: Process-scale flow chemistry in the pharmaceutical industry.

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Acknowledgements

We thank F. Levesque, K. Xiao, J. Hughes, D. Schultz and D. Lehnherr for their help in reviewing this manuscript.

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  1. Department of Process Research and Development, Merck & Co., Inc., Rahway, NJ, USA

    Kaitlyn Lovato, Patrick S. Fier & Kevin M. Maloney

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K.L., P.S.F. and K.M.M. contributed to the literature search for the article. K.L. contributed to the writing of the article and the preparation of figures. P.S.F. and K.M.M. contributed to the editing of the manuscript, coordinated the project and supervised the writing.

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Glossary

Process mass intensity

(PMI). The ratio between the mass of raw material input and the mass of desired output.

Continuous stirred-tank reactor

(CSTR). A reactor run at steady state with a continuous flow of reactants and products. With continuous stirring, reaction conditions do not change over time.

Plug flow reactors

(PFRs). Tubular reactors run with a constant flow of reactants and products, without stirring and with materials travelling linearly as a plug of fluid.

Immersion well

(IW). A fixed-volume batch reactor with an inner jacketed well to house a light source. The reaction mixture is irradiated from within the reactor set-up.

Undivided cell

An electrochemical cell where the anode and the cathode are housed in the same chamber.

Process greenness score

(PGS). A calculation used by industrial companies to evaluate the potential environmental impact of chemical manufacturing processes. A higher score indicates a greener reaction.

Redox flow batteries

Electrochemical cells that generate chemical energy by pumping separated anolyte and catholyte solutions across an ion-selective membrane placed in between two electrodes.

Turbulent flow

A type of fluid flow characterized by chaotic changes in the direction and magnitude of flow as a result of changes in pressure and flow velocity.

Divided cells

Electrochemical cells where the anode and the cathode are housed in different chambers, separated by an ion-permeable membrane or salt bridge.

Overcharge protectant

A redox shuttle reagent that consumes excess current generated by the system.

Just suspended speed

The impeller speed where no solids remain stationary for more than 2 s. A value used in process scale-up to predict the ideal agitation rate.

Assay yield

(AY). The ratio of reaction selectivity towards the desired product (%) to conversion of the starting material (%).

Scaled up

In flow chemistry, increasing the size of a flow reactor while maintaining the same reactor design.

Scaled out

In flow chemistry, increasing the reaction time of a flow process while maintaining the same reactor size and design.

Numbered up

In flow chemistry, increasing the number of flow reactors of the same size and design to create a system of parallel reactors.

Good manufacturing practices

Regulations implemented by the US Food and Drug Administration that require manufacturers to ensure their products are safe, pure and effective.

Reynolds number

The ratio of density, flow speed and the characteristic length of the system to the dynamic viscosity of the fluid. Used to predict flow patterns.

Transitional flow

A mixture of turbulent flow towards the centre of the pipe and laminar flow, where fluid particles follow smooth paths in layers, on the edges.

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Lovato, K., Fier, P.S. & Maloney, K.M. The application of modern reactions in large-scale synthesis. Nat Rev Chem 5, 546–563 (2021). https://doi.org/10.1038/s41570-021-00288-z

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