Scale-Up of a Continuous Manufacturing Process of Edaravone

Zhou, Shuhao; Hong, Qingxia; Mei, Wenliu; He, Yan; Wu, Chwan-Hwa

doi:10.1021/acs.oprd.1c00228

Cited by 9 publications

(4 citation statements)

References 28 publications

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“…340 Examples of scale-up toward a pilot/manufacturing plant capacity are available in the literature, including a hydrazine condensation study by Lane and co-workers and the edaravone synthesis by Sun and co-workers. 341,342 7.1.2. Alternative Approaches: Numbering Up.…”

Section: Scale-up Considerations Within Reaction Optimizationmentioning

confidence: 99%

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A Brief Introduction to Chemical Reaction Optimization

et al. 2023

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From the start of a synthetic chemist’s training, experiments are conducted based on recipes from textbooks and manuscripts that achieve clean reaction outcomes, allowing the scientist to develop practical skills and some chemical intuition. This procedure is often kept long into a researcher’s career, as new recipes are developed based on similar reaction protocols, and intuition-guided deviations are conducted through learning from failed experiments. However, when attempting to understand chemical systems of interest, it has been shown that model-based, algorithm-based, and miniaturized high-throughput techniques outperform human chemical intuition and achieve reaction optimization in a much more time- and material-efficient manner; this is covered in detail in this paper. As many synthetic chemists are not exposed to these techniques in undergraduate teaching, this leads to a disproportionate number of scientists that wish to optimize their reactions but are unable to use these methodologies or are simply unaware of their existence. This review highlights the basics, and the cutting-edge, of modern chemical reaction optimization as well as its relation to process scale-up and can thereby serve as a reference for inspired scientists for each of these techniques, detailing several of their respective applications.

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Section: Scale-up Considerations Within Reaction Optimizationmentioning

confidence: 99%

“…Design of such plants was described in detail by Whalley . Examples of scale-up toward a pilot/manufacturing plant capacity are available in the literature, including a hydrazine condensation study by Lane and co-workers and the edaravone synthesis by Sun and co-workers. , …”

Section: Scale-up and Manufacturementioning

confidence: 99%

A Brief Introduction to Chemical Reaction Optimization

et al. 2023

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“…A recent publication detailed the need to separate the imine formation and cyclization reaction steps, to minimize the formation of undesired side products. [ 25 ]…”

Section: Resultsmentioning

confidence: 99%

“…A recent publication detailed the need to separate the imine formation and cyclization reaction steps, to minimize the formation of undesired side products. [25] Analysis of the reaction took place after the first and second reaction steps, using inline NMR (Magritek, Spinsolve Ultra 43 MHz) and inline FTIR (Mettler Toledo, ReactIR 15, SiComp flow cell), respectively. The use of high temperatures for the cyclization necessitated elevated pressure to prevent solvent vaporization.…”

Section: Multi-step Self-optimizationmentioning

confidence: 99%

Autonomous Multi‐Step and Multi‐Objective Optimization Facilitated by Real‐Time Process Analytics

et al. 2022

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Autonomous flow reactors are becoming increasingly utilized in the synthesis of organic compounds, yet the complexity of the chemical reactions and analytical methods remains limited. The development of a modular platform which uses rapid flow NMR and FTIR measurements, combined with chemometric modeling, is presented for efficient and timely analysis of reaction outcomes. This platform is tested with a four variable single-step reaction (nucleophilic aromatic substitution), to determine the most effective optimization methodology. The self-optimization approach with minimal background knowledge proves to provide the optimal reaction parameters within the shortest operational time. The chosen approach is then applied to a seven variable two-step optimization problem (imine formation and cyclization), for the synthesis of the active pharmaceutical ingredient edaravone. Despite the exponentially increased complexity of this optimization problem, the platform achieves excellent results in a relatively small number of iterations, leading to >95% solution yield of the intermediate and up to 5.42 kg L −1 h −1 space-time yield for this pharmaceutically relevant product.

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A Boron Scan of Ethyl Acetoacetate Leads to Versatile Building Blocks

Trofimova,

White,

Diaz

et al. 2024

Angewandte Chemie

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Discovered in the 19th century, ethyl acetoacetate has been central to the development of organic chemistry, including its pedagogy and applications. In this study, we present borylated derivatives of this venerable molecule. A boron handle has been installed at either [[EQUATION]]‐ or [[EQUATION]]‐position of acetoacetate by homologation of acyl‐MIDA (N‐methyliminodiacetic acid) boronates with diazoacetates. Either alkyl or boryl groups were found to migrate with regiochemistry being a function of the steric bulk of the diazo species. Boryl [[EQUATION]]‐ketoesters can be further modified into borylated pyrazolones and oximes, thereby expanding the synthetic toolkit and offering opportunities for additional modifications.

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Scale-Up of a Continuous Manufacturing Process of Edaravone

Cited by 9 publications

References 28 publications

A Brief Introduction to Chemical Reaction Optimization

A Brief Introduction to Chemical Reaction Optimization

Autonomous Multi‐Step and Multi‐Objective Optimization Facilitated by Real‐Time Process Analytics

A Boron Scan of Ethyl Acetoacetate Leads to Versatile Building Blocks

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