Drug manufacture can benefit from flow synthesis, in which raw materials are fed into a sequence of reactors, producing the drug as a continuous output. A flow strategy that capitalizes on solid catalysts has now been realized. See Letter p.329

The active ingredients of pharmaceuticals are typically structurally complex organic molecules that have precise arrangements of chemical groups. They are made using sequences of organic reactions that build complexity, starting with commercially available compounds and proceeding through typically six to ten chemical steps. Each step is most commonly run in a separate batch reactor — a vessel akin to a laboratory flask, but larger and more sophisticated, to enable the production of active pharmaceutical ingredients (APIs) on kilogram to tonne scales, as required. But on page 329 of this issue, Tsubogo and colleagues1 describe a different approach to making the anti-inflammatory drug (R)-rolipram: a fully continuous synthesis in which the raw materials flow through a sequence of solid catalysts.

In batch processes for manufacturing chemicals, each step of a synthesis requires specific operations: to combine the reagents under particular reaction conditions, to stop (quench) the reaction, and then to separate the desired product from any components that cannot be taken into the next step, often by isolating and purifying compounds formed at intermediate stages. This can be an arduous process, so there has been increasing interest in flow chemistry and continuous processing2,3. In these approaches, starting materials and reagents for a reaction are continuously fed into a reactor such as a tube, so that the resulting intermediate is constantly produced. The products can be directly flowed into the quench, separation and purification steps to streamline the overall synthesis.

Ideally, different flowing synthetic steps are linked (telescoped), so that intermediates do not have to be isolated, with the ultimate goal being a flow process for the entire synthetic sequence: raw materials and reagents are flowed into a series of reactors, producing the API as the output4,5. Such a sequence of flowing steps must be kept in balance to manufacture high-purity APIs; this can be achieved by adding chemical engineering controls and streamlining the underlying chemistry.

As Tsubogo and colleagues describe, flow chemistry can be classified into four types depending on whether the reactants and catalysts are flowed into the reactor together, or whether the flowing reagents pass through solid reagents or catalysts contained in the reactor. This distinction is important when an entire API synthesis is telescoped, because any by-products or excess reagents from one step must be removed before, or tolerated by, the next step. The cleaner the effluent from one step, the simpler the intervening processing required between subsequent steps. And the more tolerant the chemistry of a step is to reagent ratios and to chemical species flowing downstream from previous steps, the simpler are the engineering controls required for that step. This simplicity can be achieved by flowing reagents through solid catalysts (a type IV process as classified by Tsubogo et al.), especially if any by-products or unreacted reagents are innocuous and volatile6. Ideally, the solid catalysts stay in the reactor, neither being consumed nor interfering with the chemistry downstream.

Various processes, including oxidations7, hydrolyses8 and reactions with hydrogen9, have previously been reported in which reactants flow through solid catalysts. However, Tsubogo and co-workers are the first to achieve an entire API synthesis by flowing starting materials and reagents through a sequence of such catalysts (Fig. 1). Notably, one of the catalysts was chiral, and so a small amount of this species bound in the reactor tube imparts 'handedness' to a large quantity of intermediate molecules flowing downstream, ultimately contributing to the three-dimensional geometry of the resulting APIs. The researchers demonstrated their system on a laboratory scale, using it to produce gram quantities of drug per day and demonstrating stable operation for at least a week. They are now scaling up the system to the multi-kilogram scale. Figure 1: Flow synthesis of the anti-inflammatory drug (R)-rolipram. Tsubogo et al.1 have prepared (R)-rolipram by passing a solution of the starting material on the left constantly through a sequence of four solid catalysts, with the added reagents shown above the arrows. The drug emerges as a continuously flowing solution, and as a single product. Me, methyl group. Full size image

The authors' process is inherently modular and flexible, which means that a series of analogues of the original drug can be prepared by simply swapping starting materials or catalysts with structurally different but functionally similar species. Tsubogo et al. demonstrated this by modifying their synthesis to prepare phenibut, a drug from the same family as rolipram.

Kilogram-scale production systems based on Tsubogo and co-workers' system should be small enough to operate in walk-in fume hoods, thus requiring smaller and cheaper infrastructure than is used for conventional batch manufacturing facilities. They might even be small and modular enough to be shipped to a different manufacturing facility, if required for business needs; alternatively, processes could be easily set up to run on an identical but remote sister set-up. Larger quantities of APIs could be achieved by judiciously 'scaling up and scaling out' — increasing reactor sizes within the range that would not require re-engineering and increasing the number of systems run in parallel, within practical constraints. As new APIs become ever more potent, selective and personalized, smaller manufacturing volumes will be needed, making portable, continuous, miniature and modular (PCMM) manufacturing processes such as these particularly attractive (for a discussion of PCMM applied to drug formulation, see ref. 10).

Streamlined drug manufacture using type IV flow systems will require robust catalysts that maintain their chemical activity over time. Alternatively, catalysts that have well-understood deactivation profiles will need to be used at elevated loadings, in tandem with a catalyst-replacement schedule. Most importantly, the range of reactions that are amenable to flowing through solid catalysts must be expanded. This provides a valuable target for future catalyst development, which may in part be met by solid-supported enzymes (see, for example, ref. 11).

Notes

References 1 Tsubogo, T., Oyamada, H. & Kobayashi, S. Nature 520, 329–332 (2015). 2 Pastre, J. C., Browne, D. L. & Ley, S. V. Chem. Soc. Rev. 42, 8849–8869 (2013). 3 Baxendale, I. R. et al. J. Pharm. Sci. 104, 781–791 (2015). 4 Hopkin, M. D., Baxendale, I. R. & Ley, S. V. Chem. Commun. 46, 2450–2452 (2010). 5 Snead, D. R. & Jamison, T. F. Angew. Chem. Int. Edn 54, 983–987 (2015). 6 Battilocchio, C., Hawkins, J. M. & Ley, S. V. Org. Lett. 15, 2278–2281 (2013). 7 Chorghade, R., Battilocchio, C., Hawkins, J. M. & Ley, S. V. Org. Lett. 15, 5698–5701 (2013). 8 Battilocchio, C., Hawkins, J. M. & Ley, S. V. Org. Lett. 16, 1060–1063 (2014). 9 Ouchi, T., Battilocchio, C., Hawkins, J. M. & Ley, S. V. Org. Process Res. Dev. 18, 1560–1566 (2014). 10 Markarian, J. Pharm. Technol. 38(11), 52–54 (2014). 11 Truppo, M. D., Janey, J. M. & Hughes, G. US patent application US20140106413 A1 (2014). Download references

Author information Affiliations Joel M. Hawkins is in Chemical Research and Development, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, USA. Joel M. Hawkins Authors Joel M. Hawkins View author publications You can also search for this author in PubMed Google Scholar Corresponding author Correspondence to Joel M. Hawkins.

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