A continuous-flow synthesis of 1,4-benzodiazepin-5-ones, privileged scaffolds for drug discovery

Viviano, Monica; Milite, Ciro; Rescigno, Donatella; Castellano, Sabrina; Sbardella, Gianluca

doi:10.1039/c4ra13392g

Cited by 25 publications

(12 citation statements)

References 21 publications

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“…This scaffold has been targeted in treatments for tuberculosis [36] and control of the melanocortin receptors implicated in appetite control [37] and was readily accessed under flow conditions (THF, 0.3 mL min −1 , 50 bar and 80°C). Isolated yields of up to 94% (45) requiring no purifications were noted [38]. In a similar manner, H-cube mediated nitro reduction and lactam cyclisation of γ-nitro-αamino esters with in situ cyclisation afforded, quantitatively, the corresponding γ-lactams (47) (Figure 15).…”

Section: Scaffold Formationmentioning

confidence: 77%

Recent Developments in the Use of Flow Hydrogenation in the Field of Medicinal Chemistry

Russell¹,

Baker²,

Cossar³

et al. 2017

New Advances in Hydrogenation Processes - Fundamentals and Applications

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This chapter focuses on recent applications of flow hydrogenation in medicinal chemistry. Flow reactors can enhance laboratory safety, reducing the risks associated with pyrophoric catalysts, due to their containment in catalyst cartridges or omnifit columns. Flow hydrogenation reduces the risks arising from hydrogen gas, with either hydrogen generated in situ from water, or precise management of the gas flow rate through tube-in-tube reactors. There is an increasing body of evidence that flow hydrogenation enhances reduction outcomes across nitro, imine, nitrile, amide, azide, and azo reductions, together with de-aromatisation and hydrodehalogenation. In addition, olefin, alkyne, carbonyl, and benzyl reductions have been widely examined. Further, protocols involving multistage flow reactions involving hydrogenation are highlighted.

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Section: Scaffold Formationmentioning

confidence: 77%

Recent Developments in the Use of Flow Hydrogenation in the Field of Medicinal Chemistry

Russell¹,

Baker²,

Cossar³

et al. 2017

New Advances in Hydrogenation Processes - Fundamentals and Applications

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“…The synthetic protocol for the preparation of compounds 12a , 12b , 13a , and 13b is reported in Scheme . The key scaffolds for the preparation of the target compounds were the 3,4-dihydro-5 H -benzo[1,4]diazepin-5-ones 16a and 16b , which were obtained in high yields starting from 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 15 using a continuous flow protocol previously developed by us . The removal of the benzyl group from 16a and 16b was accomplished under strong acidic conditions and yielded the unprotected derivatives 17a and 17b .…”

Section: Resultsmentioning

confidence: 99%

Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure

et al. 2019

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Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of nonquinazoline inhibitors of H3K9-specific methyltransferases G9a and G9a-like protein (GLP) have been reported. Herein, we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-aminoand 2-aryl-5-amino-substituted 3H-benzo[e][1,4]diazepine scaffold. Our research efforts resulted in the identification 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNA methyltransferase 1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both parallel artificial membrane permeability assay (PAMPA) and blood−brain barrier-specific PAMPA, and therefore might potentially be a better candidate for animal studies. Finally, the co-crystal structure of GLP in complex with 12a provides the basis for the further development of benzodiazepine-based G9a/GLP inhibitors.

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“…The privileged scaffold 1,4‐benzodiazepin‐5‐one was prepared under flow conditions by Viviano et al ., through a continuous hydrogenation (H‐Cube reactor) of 2‐nitrobenzamides. The products were achieved with high selectivity and yields (3 examples ‐ 92–94 % yield) …”

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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A continuous-flow synthesis of 1,4-benzodiazepin-5-ones, privileged scaffolds for drug discovery

Cited by 25 publications

References 21 publications

Recent Developments in the Use of Flow Hydrogenation in the Field of Medicinal Chemistry

Recent Developments in the Use of Flow Hydrogenation in the Field of Medicinal Chemistry

Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

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