Automated multistep synthesis of 2-pyrazolines in continuous flow

Labes, Ricardo; Pastre, Julio C.; Ingham, Richard J.; Battilocchio, Claudio; Marçon, Henrique M.; Damião, Mariana C. F. C. B.; Tran, Duc N.; Ley, Steven V.

doi:10.1039/d3re00515a

React. Chem. Eng.

2024

DOI: 10.1039/d3re00515a

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Automated multistep synthesis of 2-pyrazolines in continuous flow

Ricardo Labes,

Julio C. Pastre,

Richard J. Ingham

et al.

Abstract: The synthesis of 2-pyrazolines from aldehydes via cycloaddition of unstabilised diazo species and alkenes is reported, including automated library generation and graphical interface for reaction control.

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Automated Optimization of a Multistep, Multiphase Continuous Flow Process for Pharmaceutical Synthesis

Boyall,

Clarke,

Dixon

et al. 2024

ACS Sustainable Chem. Eng.

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Flow synthesis is becoming increasingly relevant as a sustainable and safe alternative to traditional batch processes, as reaction conditions that are not usually achievable in batch chemistry can be exploited (for example, higher temperatures and pressures). Telescoped continuous reactions have the potential to reduce waste by decreasing the number of separate unit operations (e.g., crystallization, filtration, washing, and drying), increase safety due to limiting operator interaction with potentially harmful materials that can be reacted in subsequent steps, minimize supply chain disruption, and reduce the need to store large inventories of intermediates as they can be synthesized on demand. Optimization of these flow processes leads to further efficiency when exploring new reactions, as with a higher yield comes higher purity, reduced waste, and a greener synthesis. This project explored a two-step process consisting of a threephase heterogeneously catalyzed hydrogenation followed by a homogeneous amidation reaction. The steps were optimized individually and as a multistep telescoped process for yield using remote automated control via a Bayesian optimization algorithm and HPLC analysis to assess the performance of a reaction for a given set of experimental conditions. 2-MeTHF was selected as a green solvent throughout the process, and the heterogeneous step provided good atom economy due to the use of pure hydrogen gas as a reagent. This research highlights the benefits of using multistage automated optimization in the development of pharmaceutical syntheses. The combination of telescoping and optimization with automation allows for swift investigation of synthetic processes in a minimum number of experiments, leading to a reduction in the number of experiments performed and a large reduction in process mass intensity values.

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Automated Optimization of a Multistep, Multiphase Continuous Flow Process for Pharmaceutical Synthesis

Boyall,

Clarke,

Dixon

et al. 2024

ACS Sustainable Chem. Eng.

View full text Add to dashboard Cite

show abstract

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Automated multistep synthesis of 2-pyrazolines in continuous flow

Abstract: The synthesis of 2-pyrazolines from aldehydes via cycloaddition of unstabilised diazo species and alkenes is reported, including automated library generation and graphical interface for reaction control.

Cited by 1 publication

References 50 publications

Automated Optimization of a Multistep, Multiphase Continuous Flow Process for Pharmaceutical Synthesis

Automated Optimization of a Multistep, Multiphase Continuous Flow Process for Pharmaceutical Synthesis

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