Application of Flow Chemistry to Macrocyclization of Crown Ethers

Fődi, Tamás; Kupai, József; Túrós, György István; Németh, Tamás; Rojik, Eszter; Riethmüller, Eszter; Balogh, György Tibor; Huszthy, Péter

doi:10.1556/1846.2016.00033

Cited by 6 publications

(5 citation statements)

References 37 publications

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“…Although the use of packed bed reactors using inorganic bases has been formerly reported, , the partial solubility of Cs 2 CO 3 in CH 3 CN hampered this approximation, as some leaching could not be avoided. Thus, to develop this macrocyclization under continuous-flow, the design of an appropriate immobilized base to substitute the Cs 2 CO 3 was envisaged.…”

Section: Results and Discussionmentioning

confidence: 99%

“…In the search of alternative approaches and to provide an easier scale-up for the synthesis of these pseudopeptidic macrocyclic cyclophanes (3), the use of flow chemistry was considered. Although the use of packed bed reactors using inorganic bases has been formerly reported, 12,13 the partial solubility of Cs 2 CO 3 in CH 3 CN hampered this approximation, as some leaching could not be avoided. Thus, to develop this macrocyclization under continuous-flow, the design of an appropriate immobilized base to substitute the Cs 2 CO 3 was envisaged.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…In the case of intermolecular macrocyclizations, different chiral and achiral pyridino-18-crown-6 ethers were synthesized by alkylation of various alcohols in the presence of pyridine diiodides in a continuous-flow Williamson type synthesis using KOH as the base in a packed bed reactor. This provided a cheaper and less dangerous method with higher yields and in shorter times than the ones reported using NaH as a base in batch conditions . In a similar manner, the use of a K 2 CO 3 packed bed reactor enabled the preparation in high yields and high purities of C 2 -symmetric chiral PyBox.…”

Section: Introductionmentioning

confidence: 81%

“…This provided a cheaper and less dangerous method with higher yields and in shorter times than the ones reported using NaH as a base in batch conditions. 12 In a similar manner, the use of a K 2 CO 3 packed bed reactor enabled the preparation in high yields and high purities of C 2 -symmetric chiral PyBox. The macrocyclization reaction relied on amide formation of chlorinated chelidamic acids in the presence of different amino alcohols, and the results obtained by flow processes were not attainable under batch conditions.…”

Section: Introductionmentioning

confidence: 99%

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Continuous Flow Processes as an Enabling Tool for the Synthesis of Constrained Pseudopeptidic Macrocycles

et al. 2022

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Herein we report our efforts to develop a continuous flow methodology for the efficient preparation of pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo-[3,4-f]-isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Appropriate design of a supported base permitted the continuous production of the macrocycles even at large scales, taking advantage of the positive template effect promoted by the bromide anions. In addition, the use of flow protocols allowed a ca. 20-fold increase in productivity as well as reducing the environmental impact almost 2 orders of magnitude, in comparison with the related batch macrocyclization process.

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Section: Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Continuous Flow Processes as an Enabling Tool for the Synthesis of Constrained Pseudopeptidic Macrocycles

et al. 2022

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“…The main advantage of this flow system proved to be the considerable reduction in reaction time (t R =30 min vs . 3–120 h under batch conditions) …”

Section: Heterocyclic Synthesismentioning

confidence: 99%

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

2019

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Flow Chemistry is a revolutionary field in Organic Chemistry. By changing the conventional methods and apparatus applied in the chemical synthesis, flow chemistry emerges as a game changer for organic synthesis laboratories, in both academia and industries. Considered as a sustainable practice, flow processes play an important role in the development of fine chemical products and in drug discovery development pro- [a] The main advantages of flow chemistry are that it allows the reaction to be carried out safely with high selectivity, high reproducibility and reduced energy consumption/carbon footprint. These features make this emerging technology for organic synthesis desirable for green and sustainable chemical synthesis, giving the chemist time for work planning and design, instead of using it in repetitive tasks, [5b,12] as expressed by the CHEM21 project by awarding a green flag for continuousflow reactions, in opposition to an amber flag for those performed under batch conditions. [13] Pedro Brandão received his MSc in Pharmaceutical Sciences from the Faculty of Pharmacy -University of Porto, in 2011. Pursuing his passion on studies in the field of Drug Discovery and Development, he is currently undergoing his PhD studies in Chemistry, in the field of Catalysis and Sustainability. His main focus of work is the discovery of new drug candidates through sustainable techniques. Marta Pineiro received her Ph.D. in Organic Chemistry in 2003 in the University of Coimbra, Portugal, and since 2002 has been enrolled at the University of Coimbra, being at present Auxiliary Professor. Her research interests are in the area of sustainable organic synthesis, microwave-assisted organic synthesis and synthesis and biological applications of tetrapyrrolic macrocycles. Teresa M. V. D. Pinho e Melo studied Chemistry at the University of Coimbra, where she graduated in 1985, got her M. 7191CPBA) as the oxidizing agent, avoiding the handling of this expensive and explosive reagent. [25] Recently, Morodo et al. explored the synthesis of two very important oxiranes (epichlorohydrin and glycidol) from biobased glycerol, under flow conditions. As depicted in Scheme 1, and using pimelic acid as the catalyst (10 mol-%), a sequential hydrochlorination/dichlorination process allows high conversion of glycerol (> 99 %) into 1,3-dichloro-2-propanol, followed by the quantitative conversion into a separable mixture of glycidol and epichlorohydrin (2:3). The separation of these two products is performed by an in-line membrane separation system, which allows the first product to be collected in the aqueous phase, while the second is collected in MTBE. This heterocycle can be further used as a synthetic precursor to relevant APIs bearing -amino alcohol moieties (e.g., propranolol, alprenolol and naftopidil). [26] Scheme 1. Sequential flow setup for the preparation of glycidol and epichlorohydrin, important APIs synthetic intermediates.Scheme 3. Synthesis and inline purification of a bicyclic aziridine (SGMR = silicon-glass microfluidic react...

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Continuous Synthesis of a Macrocyclic Sulfite of Polyethylene Glycol by Cascaded Continuous Stirred Tank Reactors (CSTRs)

Wei,

Liu,

Sun

et al. 2024

Chemistry A European J

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Many macrocyclic compounds are attractive drug‐like molecules or intermediates due to their special properties. However, the bulk synthesis of such compounds are hindered by the necessity of using diluted solutions, in order to prevent intermolecular reactions that yields oligomer impurities, thereby resulting in a low production efficiency. Such challenge can be adequately addressed by using continuous reactors, allowing improved efficiency with smaller space footprints. In this work, we proposed a novel continuous process for the synthesis of a macrocyclic sulfite of tetraethylene glycol (PEG4‐MCSi), which is a precursor to a very useful building block, PEG4‐macrocyclic sulfate (PEG4‐MCS). The basic reaction parameters, including stoichiometry and temperature, were first confirmed with small batch reactions, and the effectiveness of coiled reactors and continuous stirred tank reactors (CSTRs) were compared. Cascaded CSTRs were proven to be suitable, and the reaction parameters were subject to further optimization to give a robust continuous process. The process was then tested with 4 parallel runs for up to 64 h. Finally, the merits and demerits of batch and continuous reactions were also compared, demonstrating the suitability of latter in the bulk production of macrocyclic PEG‐MCSi compounds.

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Application of Flow Chemistry to Macrocyclization of Crown Ethers

Cited by 6 publications

References 37 publications

Continuous Flow Processes as an Enabling Tool for the Synthesis of Constrained Pseudopeptidic Macrocycles

Continuous Flow Processes as an Enabling Tool for the Synthesis of Constrained Pseudopeptidic Macrocycles

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

Continuous Synthesis of a Macrocyclic Sulfite of Polyethylene Glycol by Cascaded Continuous Stirred Tank Reactors (CSTRs)

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