An Automated Process for a Sequential Heterocycle/Multicomponent Reaction: Multistep Continuous Flow Synthesis of 5-(Thiazol-2-yl)-3,4-Dihydropyrimidin-2(1H)-ones

Pagano, Nicholas; Herath, Ananda; Cosford, Nicholas D. P.

doi:10.1556/jfchem.2011.00001

Cited by 34 publications

(18 citation statements)

References 26 publications

(17 reference statements)

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“…10 Our methodology provides access to a scaffold with favorable drug-like characteristics and allows the generation of highly varied analogues. The compounds prepared in this way are structurally related to thiazole derivatives such as compound 2 that were initially disclosed in a patent application and subsequently reported in the scientific literature (Fig.…”

Section: Resultsmentioning

confidence: 99%

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An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors

Pagano

Teriete

Mattmann

et al. 2017

Bioorganic & Medicinal Chemistry

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Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanismof action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents.

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Section: Resultsmentioning

confidence: 99%

“…We have exemplified this novel strategy to generate new classes of bio-active compounds based on our ability to rapidly generate diverse dihydropyrimidinone (DHPM) derivatives. 10 …”

Section: Introductionmentioning

confidence: 99%

An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors

Pagano

Teriete

Mattmann

et al. 2017

Bioorganic & Medicinal Chemistry

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“…5-(Thiazol-2-yl)-3,4-dihydropyrimidin-2(1 H )-one ( 41 ) has anti-HIV properties ( Figure 4 ). Thus, combining thiazole and DHPM heterocycles moieties into one structure would constitute an interesting tool to furnish a novel druglike scaffold [49] .…”

Section: -(Thiazol-2-yl)-34-dihydropyrimidin-2(1 H )-One (41)mentioning

confidence: 99%

“…In this unique process, sequential thiazole formation, deketalization and Biginelli three-component reaction provided rapid and effi cient access to a library of novel DHPM derivatives of 41 [49] .…”

Section: -(Thiazol-2-yl)-34-dihydropyrimidin-2(1 H )-One (41)mentioning

confidence: 99%

Micro reactor and flow chemistry for industrial applications in drug discovery and development

Baraldi¹,

Hessel

2012

Green Processing and Synthesis

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In this review, case studies focused on syntheses of active pharmaceutical ingredients, intermediates and lead compounds are reported employing micro reactors and continuous fl ow technology in areas such as medicinal chemistry, chemical development and manufacturing. The advantages of fl ow technology are currently very clear as opposed to conventional batch methods. Most strikingly and relevant for pharmaceutical ' s time-to-market needs, fl ow processing has the important advantage of the ease with which reaction conditions can be scaled. As this technology is new and has major full-process scale implications, we also wanted to point out that this cannot be applied and released to all chemistries yet, thereby also critically mirroring disadvantages and advantages of the step-change technology. However, the positive impact has been dominating and thus pharmaceutical and fi ne-chemical industries have increased their awareness and interest in fl ow chemistry applications. Beyond pharmaceutical syntheses, this review aims to conclude with the special needs of pharmacy on fl ow and micro reactor chemistry, which is not the same as for the fi ne-chemical industry. Here, the needs of Brazil are considered, as the mirroring of micro reactor and fl ow chemistry was done from a European -academic and business -perspective. The hope is to stimulate and promote fl ow developments in emerging developing nations.

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“…The synthesis of α-bromoketones is a useful reaction in organic chemistry, as it provides a convenient pathway towards mono-α-substituted ketones through bromide substitution and towards a variety of heterocycles such as thiazoles [9,10], imidazo[1,2-a]-compounds [11], and indoles through the Bischler-Möhlau synthesis [12]. The ketone substrate used in this model reaction (Scheme 1) is acetophenone (1), which readily undergoes bromination at room temperature within seconds to form the mono-brominated ketone phenacyl bromide (2) [13].…”

Section: Introductionmentioning

confidence: 99%

Optimisation and Scale-up of α-Bromination of Acetophenone in a Continuous Flow Microreactor

Becker¹,

Broek²,

Nieuwland³

et al. 2012

J Flow Chem

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To expand the knowledge base for fundamental organic reactions in continuous flow, the α-bromination of acetophenone was successfully transformed from a known batch procedure to a continuous flow process in 99 % yield through D-optimal optimisation and subsequent scale-up of the validated optimum. Using a preparative scale system, a space-time yield of 0.26 kg/m 3 /s (comparable literature batch reaction 0.24 kg/m 3 /s) was achieved under conditions suitable for laboratory and small-scale industrial application where high yield or purity is required, e.g., when expensive substrates are used.

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An Automated Process for a Sequential Heterocycle/Multicomponent Reaction: Multistep Continuous Flow Synthesis of 5-(Thiazol-2-yl)-3,4-Dihydropyrimidin-2(1H)-ones

Cited by 34 publications

References 26 publications

An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors

An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors

Micro reactor and flow chemistry for industrial applications in drug discovery and development

Optimisation and Scale-up of α-Bromination of Acetophenone in a Continuous Flow Microreactor

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