Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry

Bogdan, Andrew R.; Dombrowski, Amanda W.

doi:10.1021/acs.jmedchem.8b01760

Cited by 176 publications

(113 citation statements)

References 168 publications

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Section: Microflow Technology and Photochemistry: A Perfect Matchmentioning

confidence: 96%

“…Moreover, the ease of automation and coupling with inline analysis, separation, and purification methods allows the development of continuous multistep synthesis and automated production platforms. These advantages are nicely showcased in the growing use of flow in the pharmaceutical industry [12][13][14][15][16].The typical flow setup for photochemical processes comprises transparent tubing made of perfluorinated materials (e.g., PFA, ETFE) efficiently coiled around a light source [17], or surrounded by it, for uniform irradiation ( Figure 1E). A more expensive alternative is the use of flat, transparent microreactors with engraved microchannels irradiated from both sides of the plate.…”

mentioning

confidence: 99%

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Flow Photochemistry: Shine Some Light on Those Tubes!

Sambiagio

Noël

2020

Trends in Chemistry

297

223

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Continuous-flow chemistry has recently attracted significant interest from chemists in both academia and industry working in different disciplines and from different backgrounds. Flow methods are now being used in reaction discovery/methodology, in scale-up and production, and for rapid screening and optimization. Photochemical processes are currently an important research field in the scientific community and the recent exploitation of flow methods for these methodologies has made clear the advantages of flow chemistry and its importance in modern chemistry and technology worldwide. This review highlights the most important features of continuous-flow technology applied to photochemical processes and provides a general perspective on this rapidly evolving research field. Microflow Technology and Photochemistry: A Perfect MatchThe use of light to promote chemical reactions has been exploited since the 18th century, but only recently a resurgence has been observed in synthetic organic chemistry, in particular due to the development of visible-light photoredox catalysis [1-5]. All transformations involving light (e.g., Figure 1A-D) must consider, besides classical chemical parameters (i.e., reaction conditions), the photophysical aspects of the sensitizer (see Glossary)/photocatalyst (when used), and the reactor design. The latter, although often neglected by chemists, is a critical aspect for the outcome of the studied chemical transformation. This includes, for example, the size, shape, and material of the reaction vessel, the characteristics and positioning of the light source(s), and heat-transfer properties, particularly when high-intensity lamps are used [6,7]. The engineering and technological aspects of photochemical processes are often at the basis of the irreproducibility and non-scalability of such transformations.According to the Beer-Lambert law, light transmittance decreases exponentially with the distance from the light source ( Figure 1F). For a standard batch reactor (diameter at least in the centimeter range), light intensity decreases considerably from the flask walls to the middle of the reaction mixture, resulting in slow reactions and nonhomogeneous irradiation of the reaction mixture. Performing photochemical reactions in microchannels (ID < 1 mm) allows a higher and more homogeneous photon flux, resulting in shorter reaction times and consequently less side-product formation due to over-irradiation, often observed in batch [8,9]. Another advantage of microflow chemistry, correlated with the large surface:volume ratio, is improved heat and mass transfer, with the possibility to perform mass-transfer-limited multiphasic reactions efficiently [10]. Reactive chemicals and intermediates can be handled more safely in flow than in batch, as no accumulation of dangerous components occurs within the confined reactor volume due to the continuous nature of the process. Together, these result in often faster, safer, and higher-yielding reactions, with the possibility to perform reactions under condition...

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Section: Microflow Technology and Photochemistry: A Perfect Matchmentioning

confidence: 96%

mentioning

confidence: 99%

Flow Photochemistry: Shine Some Light on Those Tubes!

Sambiagio

Noël

2020

Trends in Chemistry

297

223

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“…Such a method of creating flow-batch systems is even more frequently employed in designing flow systems for organic syntheses, which was very well illustrated by a recent comprehensive review on the development of flow synthetic methods for the pharmaceutical industry [154]. In numerous cases, a 2-3-step telescoping process is ended in a batch reactor with a quenching step.…”

Section: Detectors Reactors Manifoldsmentioning

confidence: 99%

“…The latter mode was successfully used in a micro-fluidic system for conducting gas-liquid-solid hydrogenation [47]. Numerous applications of flow syntheses involving gaseous reactants can be found in many review papers [154,195].…”

Section: On-line Processes Supporting Flow Analysis and Flow Synthesismentioning

confidence: 99%

Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications

Trojanowicz

2020

Molecules

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Flow chemistry is an area of contemporary chemistry exploiting the hydrodynamic conditions of flowing liquids to provide particular environments for chemical reactions. These particular conditions of enhanced and strictly regulated transport of reagents, improved interface contacts, intensification of heat transfer, and safe operation with hazardous chemicals can be utilized in chemical synthesis, both for mechanization and automation of analytical procedures, and for the investigation of the kinetics of ultrafast reactions. Such methods are developed for more than half a century. In the field of chemical synthesis, they are used mostly in pharmaceutical chemistry for efficient syntheses of small amounts of active substances. In analytical chemistry, flow measuring systems are designed for environmental applications and industrial monitoring, as well as medical and pharmaceutical analysis, providing essential enhancement of the yield of analyses and precision of analytical determinations. The main concept of this review is to show the overlapping of development trends in the design of instrumentation and various ways of the utilization of specificity of chemical operations under flow conditions, especially for synthetic and analytical purposes, with a simultaneous presentation of the still rather limited correspondence between these two main areas of flow chemistry.

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“…In the broad landscape of enabling technologies in medicinal chemistry, flow chemistry stands out as one of the most powerful techniques to discover new active pharmaceutical ingredients or to set up a streamlined process for their manufacturing. A plethora of articles and reviews well-documented how many chemical processes could benefit from running reactions in flow [5][6][7][8][9]. In particular, this approach has demonstrated to be superior to batch protocols in every case where heat transfer and mixing are important, hazardous or sensitive materials are handled, and high temperatures/pressures are required.…”

Section: Introductionmentioning

confidence: 99%

Flow Synthesis of Biologically-Relevant Compound Libraries

Luque-Navarro

Lanari

2020

Molecules

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Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists' approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be tested for biological properties. The aim of the present review is to comment on some representative examples from the last five years of literature that highlight how flow procedures are becoming of increasing importance for the synthesis of biologically-relevant molecules.Molecules 2020, 25, 909 2 of 12 of urea-based biologically active compounds are present like vestipitant and trimefluor [14,15]. As a continuation of previous work [16], Rutjes and co-workers set up a new procedure for the synthesis in flow of a library made of urea-based molecules based on piperidin-4-ones (Scheme 1) [17]. Optimization studies have been performed using as test compounds ethylisocianate 2a and piperidin-4-one 1a employing a microreactor (100 µL effective volume). After using different solvents, temperatures, and reactants ratios, the authors identified as best reaction conditions those that employed tBuOH as solvent at 50 • C for 17 min. On the other hand, when isocyanate 2c bearing an aryl moiety was allowed to react with 1a, full conversion was obtained only by using 1,2 dichloroethane (1,2 DCE) at 80 • C for 17 min. Such conditions were applied then to isocyanates (2a-c) and piperin-4-ones (1a-c) for the synthesis of 15 urea-based products 3 containing different fluorine moieties as it has been shown that such functionalities could enhance bioactivity and metabolic profile [18]. The urea-based products were obtained with isolated yields values ranging from 55 to 99%. No further chromatography purification was necessary. This methodology, therefore, is suitable for the synthesis of a large number of molecules to be tested for biological activity.

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Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry

Cited by 176 publications

References 168 publications

Flow Photochemistry: Shine Some Light on Those Tubes!

Flow Photochemistry: Shine Some Light on Those Tubes!

Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications

Flow Synthesis of Biologically-Relevant Compound Libraries

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