Electrophilic Bromination in Flow: A Safe and Sustainable Alternative to the Use of Molecular Bromine in Batch

Kerrebroeck, Reinout Van; Naert, Pieter; Heugebaert, Thomas S. A.; D’hooghe, Matthias; Stevens, Christian V.

doi:10.3390/molecules24112116

Cited by 16 publications

(4 citation statements)

References 37 publications

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“…Excess Br 2 was quenched in-line with sodium thiosulfate (Na 2 S 2 O 3 ). Similar Br 2 generators using either NaOCl 16 or H 2 O 2 17 as oxidant have also been reported. Along similar lines, elemental chlorine (Cl 2 ) can be generated.…”

Section: Generators For Stable Reagentssupporting

confidence: 70%

The Concept of Chemical Generators: On-Site On-Demand Production of Hazardous Reagents in Continuous Flow

2020

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Conspectus In recent years, a steadily growing number of chemists, from both academia and industry, have dedicated their research to the development of continuous flow processes performed in milli- or microreactors. The common availability of continuous flow equipment at virtually all scales and affordable cost has additionally impacted this trend. Furthermore, regulatory agencies such as the United States Food and Drug Administration actively encourage continuous manufacturing of active pharmaceutical ingredients (APIs) with the vision of quality and productivity improvements. That is why the pharmaceutical industry is progressively implementing continuous flow technologies. As a result of the exceptional characteristics of continuous flow reactors such as small reactor volumes and remarkably fast heat and mass transfer, process conditions which need to be avoided in conventional batch syntheses can be safely employed. Thus, continuous operation is particularly advantageous for reactions at high temperatures/pressures (novel process windows) and for ultrafast, exothermic reactions (flash chemistry). In addition to conditions that are outside of the operation range of conventional stirred tank reactors, reagents possessing a high hazard potential and therefore not amenable to batch processing can be safely utilized (forbidden chemistry). Because of the small reactor volumes, risks in case of a failure are minimized. Such hazardous reagents often are low molecular weight compounds, leading generally to the most atom-, time-, and cost-efficient route toward the desired product. Ideally, they are generated from benign, readily available and cheap precursors within the closed environment of the flow reactor on-site on-demand. By doing so, the transport, storage, and handling of those compounds, which impose a certain safety risk especially on a large scale, are circumvented. This strategy also positively impacts the global supply chain dependency, which can be a severe issue, particularly in times of stricter safety regulations or an epidemic. The concept of the in situ production of a hazardous material is generally referred to as the “generator” of the material. Importantly, in an integrated flow process, multiple modules can be assembled consecutively, allowing not only an in-line purification/separation and quenching of the reagent, but also its downstream conversion to a nonhazardous product. For the past decade, research in our group has focused on the continuous generation of hazardous reagents using a range of reactor designs and experimental techniques, particularly toward the synthesis of APIs. In this Account, we therefore introduce chemical generator concepts that have been developed in our laboratories for the production of toxic, explosive, and short-lived reagents. We have defined three different classes of generators depending on the reactivity/stability of the reagents, featuring reagents such as Br 2 , HCN, peracids, diazomethane (CH ...

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Section: Generators For Stable Reagentssupporting

confidence: 70%

The Concept of Chemical Generators: On-Site On-Demand Production of Hazardous Reagents in Continuous Flow

2020

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“…To enhance the extraction yields of specific compounds, COSMOquick was used to screen which solvents were suitable for extraction [60]. Six compounds were evaluated in six different solvents, including water, ethanol, methanol, chloroform, acetone, and tetrahydrofuran (THF).…”

Section: Solvent Considerations For Selected Compoundsmentioning

confidence: 99%

Computational study and in vitro alpha-glucosidase inhibitory effects of medicinal plants from a Thai folk remedy

Eawsakul

Panichayupakaranant

Ongtanasup

et al. 2021

Heliyon

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The number of patients with type 2 diabetes mellitus (T2DM) has increased worldwide. Although an instant cure was achieved with the standard treatment acabose, unsatisfactory symptoms associated with cardiovascular disease after acabose administration have been reported. Therefore, it is important to explore new treatments. A Thai folk recipe has long been used for T2DM treatment, and it effectively decreases blood glucose. However, the mechanism of this recipe has never been proven. Therefore, the potential anti-T2DM effect of this recipe, which is used in Thai hospitals, was determined to involve alpha-glucosidase (AG) inhibition with a half maximal inhibitory concentration (IC 50 ). In vitro experiments showed that crude Cinnamomum verum extract (IC 50 ¼ 0.35 AE 0.12 mg/mL) offered excellent inhibitory activity, followed by extracts from Tinospora crispa (IC 50 ¼ 0.69 AE 0.39 mg/ mL), Stephania suberosa (IC 50 ¼ 1.50 AE 0.17 mg/mL), Andrographis paniculate (IC 50 ¼ 1.78 AE 0.35 mg/mL), and Thunbergia laurifolia (IC 50 ¼ 4.66 AE 0.27 mg/mL). However, the potencies of these extracts were lower than that of acabose (IC 50 ¼ 0.55 AE 0.11 mg/mL). Therefore, this study investigated and developed a formulation of this recipe using computational docking. Among 61 compounds, 7 effectively inhibited AG, including chlorogenic acid (IC 50 ¼ 819.07 pM) through 5 hydrogen bonds (HBs) and 2 hydrophobic interactions (HIs); β-sitosterol (IC 50 ¼ 4.46 nM, 6 HIs); ergosterol peroxide (IC 50 ¼ 4.18 nM, 6 HIs); borapetoside D (IC 50 ¼ 508.63 pM, 7 HBs and 2 HIs); borapetoside A (IC 50 ¼ 1.09 nM, 2 HBs and 2 His), stephasubimine (IC 50 ¼ 285.37 pM, 6 HIs); and stephasubine (IC 50 ¼ 1.09 nM, 3 HBs and 4 HIs). These compounds bind with high affinity to different binding pockets, leading to additive effects. Moreover, the pharmacokinetics of six of these seven compounds (except ergosterol peroxide) showed poor absorption in the gastrointestinal tract, which would allow for competitive binding to AG in the small intestine. These results indicate that the development of these 6 compounds into oral antidiabetic agents is promising.

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“…e bromination process in Scheme 3.4 as described by Zhao and coworkers was followed, replacing the starting material with the 'clicked' product in general procedure 2 [12].…”

Section: General Procedures 3: Bromination Of the 123-triazolesmentioning

confidence: 99%

Synthesized Phosphonium Compounds Demonstrate Resistant Modulatory and Antibiofilm Formation Activities against Some Pathogenic Bacteria

Amengor

Danquah

Adusei

et al. 2022

Heteroatom Chemistry

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A library of six compounds with new hybrids in a single molecule triazole ring attached to the phosphonium salts was synthesized. Click chemistry was, however, used to synthesize the 1-, 2-, and 3-triazole intermediates as a tether for the hybrid phosphonium salts. Their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and Mycobacterium smegmatis mc2155 was determined using the HT-SPOTi assay. Compound 2 showed the most effective antimicrobial activity as it inhibited the growth of Pseudomonas aeruginosa and Staphylococcus aureus at 0.0125 µg/mL and 31.25 µg/mL, respectively. From the FICI data, compounds 2ET-TOL (2) and RABYL-TOL (4) successfully modulated the activities of amoxicillin against Pseudomonas aeruginosa and Staphylococcus aureus. All the test compounds exhibited a concentration-dependent biofilm formation inhibition against S. aureus, except P-Z (compound 6). Compounds P-MEOXY (1) and 2ET-TOL (2) exhibited mild activity against P. aeruginosa with compound 4 showing antimycobacterial activity at 500 µg/mL.

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Electrophilic Bromination in Flow: A Safe and Sustainable Alternative to the Use of Molecular Bromine in Batch

Cited by 16 publications

References 37 publications

The Concept of Chemical Generators: On-Site On-Demand Production of Hazardous Reagents in Continuous Flow

The Concept of Chemical Generators: On-Site On-Demand Production of Hazardous Reagents in Continuous Flow

Computational study and in vitro alpha-glucosidase inhibitory effects of medicinal plants from a Thai folk remedy

Synthesized Phosphonium Compounds Demonstrate Resistant Modulatory and Antibiofilm Formation Activities against Some Pathogenic Bacteria

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