Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability

Boros, Zoltán; Nagy-Győr, László; Kátai-Fadgyas, Katalin; Kőhegyi, Imre; Nagy, Tamás; Iványi, Zoltán; Olah, Mark J.; Ruzsics, György; Temesi, Ottó; Volk, Balázs

doi:10.1007/s41981-019-00036-x

Cited by 10 publications

(4 citation statements)

References 26 publications

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“…Iodination could also be achieved under aqueous surfactant conditions, thereby reducing the amount of NMP by 90 % relative to the literature route [23] . Further extension to key precursor 46 of the antidepressant vortioxetine [24] ( 47 ; Scheme 1 b) could also be realized in 71 % yield. Similar analysis of this product indicated only 1.0 ppm residual nickel.…”

Section: Resultsmentioning

confidence: 99%

Safe, Scalable, Inexpensive, and Mild Nickel‐Catalyzed Migita‐Like C−S Cross‐Couplings in Recyclable Water

Pang

Yi-lin

et al. 2020

Angewandte Chemie

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A new approach to C−S couplings is reported that relies on nickel catalysis under mild conditions, enabled by micellar catalysis in recyclable water as the reaction medium. The protocol tolerates a wide range of heteroaromatic halides and thiols, including alkyl and heteroaryl thiols, leading to a variety of thioethers in good isolated yields. The method is scalable, results in low residual metal in the products, and is applicable to syntheses of targets in the pharmaceutical area. The procedure also features an associated low E Factor, suggesting a far more attractive entry than is otherwise currently available, especially those based on unsustainable loadings of Pd catalysts.

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Section: Resultsmentioning

confidence: 99%

Safe, Scalable, Inexpensive, and Mild Nickel‐Catalyzed Migita‐Like C−S Cross‐Couplings in Recyclable Water

Pang

Yi-lin

et al. 2020

Angewandte Chemie

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show abstract

“…Iodination could also be achieved under aqueous surfactant conditions, thereby reducing the amount of NMP by 90% relative to the literature route. [23] Further extension to key precursor 46 of the antidepressant vortioxetine [24] (47; Scheme 1b) could also be realized in 71% yield. Similar analysis of this product indicated only 1.0 ppm residual nickel.…”

Section: Author Manuscriptmentioning

confidence: 99%

Safe, Scalable, Inexpensive, and Mild Nickel‐Catalyzed Migita‐Like C−S Cross‐Couplings in Recyclable Water

Pang

Yi-lin

et al. 2020

Angew Chem Int Ed

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“…Boros et al (2019) considered the flow synthesis of vortioxetine (an antidepressant API) from an intermediate, comparing the effects of temperature and residence time on process yield [54]. Their design space investigation vs. different batch configurations showed improvements with respect to product yield and purity, illustrating the benefit of design space investigation in order to maximize the benefits of CPM compared to existing batch processes ( Figure 3).…”

Section: Continuous Flow Synthesismentioning

confidence: 99%

“…Reaction optimization for vortioxetine synthesis. Reproduced with permission from Boros et al, Journal of Flow Chemistry; published by Springer Nature, 2019[54].…”

mentioning

confidence: 99%

Design Space Identification and Visualization for Continuous Pharmaceutical Manufacturing

Diab¹,

Gerogiorgis²

2020

Pharmaceutics

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Progress in continuous flow chemistry over the past two decades has facilitated significant developments in the flow synthesis of a wide variety of Active Pharmaceutical Ingredients (APIs), the foundation of Continuous Pharmaceutical Manufacturing (CPM), which has gained interest for its potential to reduce material usage, energy and costs and the ability to access novel processing windows that would be otherwise hazardous if operated via traditional batch techniques. Design space investigation of manufacturing processes is a useful task in elucidating attainable regions of process performance and product quality attributes that can allow insight into process design and optimization prior to costly experimental campaigns and pilot plant studies. This study discusses recent demonstrations from the literature on design space investigation and visualization for continuous API production and highlights attainable regions of recoveries, material efficiencies, flowsheet complexity and cost components for upstream (reaction + separation) via modeling, simulation and nonlinear optimization, providing insight into optimal CPM operation.

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Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability

Cited by 10 publications

References 26 publications

Safe, Scalable, Inexpensive, and Mild Nickel‐Catalyzed Migita‐Like C−S Cross‐Couplings in Recyclable Water

Safe, Scalable, Inexpensive, and Mild Nickel‐Catalyzed Migita‐Like C−S Cross‐Couplings in Recyclable Water

Safe, Scalable, Inexpensive, and Mild Nickel‐Catalyzed Migita‐Like C−S Cross‐Couplings in Recyclable Water

Design Space Identification and Visualization for Continuous Pharmaceutical Manufacturing

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