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As a sustainable alternative for conventional batch-based synthetic techniques, the concept of continuous flow processing has emerged in the synthesis of fine chemicals. Systematic tuning of the residence time, a key parameter of continuous reaction technology, can govern the outcome of a chemical reaction by determining the reaction rate and the c...
Citations
... Since full conversion was not obtained in the two-feed approach yet, the residence time and temperature were varied to push the reaction towards completion and maximize the yield (Table 5). However, prolonging the residence time at 100 °C led to a higher conversion rate but a significant drop in NMR yield, accompanied by increased formation of side products (see further) [39]. Similar patterns were noted when the residence time was reduced at higher temperatures (110 °C). ...
The 𝛼-hydroxymethylation reaction hold a significant position within the pharmaceutical industry due to their intriguing nature. Despite numerous reported methods, they often entail prolonged reaction times and moderate yields. Moreover,...
... Therefore, the residency time of the reactor is significant. The nitration reaction may produce by-products that are difficult to handle, and how to deal with these by-products is very important [17]. ...
The paper introduced the principle of nitration reaction and flow chemistry, beginning with background information and the reaction mechanism of nitration. Then the correlation between nitration and flow chemistry is further explored by comparing the nitration reaction in conventional batch mode and under continuous flow. As the dangerous corrosive acids and strong exotherms make the reaction especially difficult to increase production scale, flow chemistry is utilized and proved to be a better alternative to the conventional production method to perform nitration. Using flow chemistry to scale up the exothermic and hazardous nitration reactions offer advantages including better yield, higher production rate, enhanced safety, etc.
... Furthermore, the slowest flow rate is 6 mL/min, equivalent to a residence time of 35 minutes. Increasing the flow rate causes a decrease in residence time (Mándity et al., 2015). These results in suboptimal molecular contact in HS-CSTR reactor, leading to a decrease in MDAG concentration. ...
Glycerolysis-interesterification can be used for the synthesis of products containing high total Mono- and Diacylglycerol (MDAG). Therefore, this study aimed to evaluate the synthesis of products rich in MDAG content using glycerolysis-interesterification method in High Shear Continuous Stirred Tank Reactor (HS-CSTR). The impact of varying material flow rates (6, 10, 14, 18, and 22 mL/min) and processing time on the concentration of MDAG, physical properties of the resulting product, and consistency of product quality throughout the process were assessed. Furthermore, glycerolysis-interesterification reaction was performed at a temperature of 120 °C, with a glycerol and oil mixture mole ratio of 1:5 (mol/mol), 3% NaOH, and a stirring speed of 2000 rpm. Oil mixture consisted of Palm Stearin (PS) and Nyamplung oil (Calophyllum inophyllum) (MC) with a PS:MC mole ratio of 80:20 (mol/mol). Subsequently, the acylglycerol concentration and physical properties of the product were analyzed. The results showed that the material flow rate had a significant effect on MDAG and the physical properties of the product. The highest MDAG was obtained at a flow rate of 6 mL/min with content of 58.56±0.91%, and Slip Melting Point (SMP) of 41.44±0.08 °C and 42.9±0.03 °C. The hardness, emulsion capacity, and stability values were 10.88±0.22 N, 85.2±6.93%, and 88.7±5.00%, respectively. The acylglycerol concentration and physical properties of the product did not significantly fluctuate throughout the process, indicating that the process had achieved a steady state condition.
... The microreactor technology also allows for a lower energy consumption, a modular, compact and flexible construction, and an improvement of product quality thanks to the possibility of realtime analysis and quick variation of operating variables, which makes it suitable in both research & process development and industrial applications [17][18][19][20]. Moreover, it enables reactions to occur in solvents under supercritical conditions or in volatile solvents at temperatures above the boiling point, keeping them in liquid state at high pressure, thus facilitating their final removal [21]. ...
Continuous flow synthesis in microreactors has been integrated into chemical-pharmaceutical industry in recent years as an alternative to the batch process due to its advantages, especially process intensification, which can reduce the time for a new drug to be placed on the market on a large scale. This work aimed to transpose the synthesis of Lobeglitazone, a drug employed in the treatment of diabetes mellitus type 2, from batch to flow process in a microreactor as well as to determine the reaction kinetics of each step. The synthesis was carried out in five-steps, being synthesized intermediates 4-chloro-6-(4-methoxyphenoxy)pyrimidine (I1), 2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino}ethanol (I2), 4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino}ethoxy)benzaldehyde (I3), 5-[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino}ethoxy)benzylidene]thiazolidine-2,4-dione (I4) and Lobeglitazone. Intermediates I1 and I4 were synthesized in flow, while I4 was synthesized either in a continuous flow multistep synthesis or in a one-pot batch process. The flow syntheses of I1, I2 and I4 showed 28.0 %, 61.8 % and 32.0 % yields at 25, 160 and 120 °C, respectively, while the yield of I3 in batch process was 73.3 % at 60 °C. In one-pot batch process and continuous flow multistep synthesis, I2 was obtained with 13 and 16 % yields, respectively. These preliminary results constitute a starting point for the synthesis of this drug in flow on an industrial scale, with the aim of improving reaction performance using this new technology.
... Due to these characteristics, flow chemistry is inspiring the development of green [103][104][105] and modern methods [106][107][108][109][110][111][112][113][114][115], and many applications in biocatalysis, photochemistry and electrochemistry have been described so far [116][117][118]. However, involving chalcogens, especially selenium, in this chemistry is quite recent. ...
Organoselenium compounds have been successfully applied in biological, medicinal and material sciences, as well as a powerful tool for modern organic synthesis, attracting the attention of the scientific community. This great success is mainly due to the breaking of paradigm demonstrated by innumerous works, that the selenium compounds were toxic and would have a potential impact on the environment. In this update review, we highlight the relevance of these compounds in several fields of research as well as the possibility to synthesize them through more environmentally sustainable methodologies, involving catalytic processes, flow chemistry, electrosynthesis, as well as by the use of alternative energy sources, including mechanochemical, photochemistry, sonochemical and microwave irradiation.
... 23 The inherent technical benefits of continuous flow equipment facilitate on-demand generation and simultaneous consumption of toxic or highly reactive reagents, which would otherwise be impossible under conventional batch conditions. 26 These features open up novel reaction pathways within traditionally forbidden chemical spaces, 27 and imply not only higher reaction rates and improved selectivity, 28 but also safer and greener chemistries. 29 Importantly, continuous flow reaction technologies ensure inherent scalability without re-optimization of critical reaction parameters, 30 and allow multistep reactions to be combined into telescoped one-flow sequences without isolation of any intermediates. ...
Catalytic enantioselective transformations provide well-established and direct access to stereogenic synthons that are broadly distributed among active pharmaceutical ingredients (APIs). These reactions have been demonstrated to benefit considerably from the merits of continuous processing and microreactor technology. Over the past few years, continuous flow enantioselective catalysis has been grown into a mature field and has found diverse applications in asymmetric synthesis of pharmaceutically active substances. The present review therefore surveys flow chemistry-based approaches for the synthesis of chiral APIs and their advanced stereogenic intermediates, covering the utilization of biocatalysis, organometallic catalysis as well as metal-free organocatalysis to introduce asymmetry in continuously operated systems. Single-step processes, interrupted multistep flow syntheses, combined batch/flow processes as well as uninterrupted one-flow syntheses are discussed herein.
... The application of heterogeneous catalysts in continuous flow systems have received an upsurge of interest, which is due to numerous benefits, such as facile catalyst handling, recycling and reuse, as well as simple product isolation [43][44][45][46][47][48][49]. Additionally, in loaded catalyst columns, continuous substrate streams interact with a superstoichiometric amount of catalyst species, which enhances the reaction rates considerably [50,51], while the improved control over temperature and residence time ensures a high selectivity and low waste generation [52][53][54][55]. We therefore intended to study the reactions not only under the traditional batch conditions but, also, within a continuous flow packed-bed reactor environment. ...
Bismuth subnitrate is reported herein as a simple and efficient catalyst for the atomeconomical synthesis of methyl ketones via Markovnikov-type alkyne hydration. Besides an effective batch process under reasonably mild conditions, a chemically intensified continuous flow protocol was also developed in a packed-bed system. The applicability of the methodologies was demonstrated through hydration of a diverse set of terminal acetylenes. By simply switching the reaction medium from methanol to methanol-d4, valuable trideuteromethyl ketones were also prepared. Due to the ready availability and nontoxicity of the heterogeneous catalyst, which eliminated the need for any special additives and/or harmful reagents, the presented processes display significant advances in terms of practicality and sustainability.
... More interestingly, the typically unstable species generated in the conventional reactors could be well controlled in microreactors due to their unique operating continuous laminar flow mode. Therefore, highly selective reactions with unstable and challenging species could be readily achieved [40]. ...
As one of the most important biogeochemical cycles, the carbon dioxide (CO2) cycle between atmosphere and biosphere has a profound impact on the life on earth. Therefore, the search for sustainable solutions to normalize the currently unbalanced carbon dioxide cycle is the central research topic of many scientific disciplines. The green and sustainable electrocatalysis offers a very promising answer to currently unbalanced carbon dioxide cycle. In this review, recent advances in electrocatalysis enabled CO2 cycle including the electrochemical carboxylation of CO2 and decarboxylative functionalization of carboxylic acids are highlighted.
... Le temps de résidence est une variable introduite pour décrire le temps passé par une particule fluide dans un système (ce concept est très utilisé en génie chimique pour l'étude des réacteurs [27,69,104]). Elle est dans ce cas initialiséeà nulleà l'entrée du système. ...
Cette thèse de doctorat est consacrée à la modélisation des écoulements turbulents réactifs dans des cas où les niveaux de température peuvent conduire à l'auto-allumage du mélange. La stratégie de modélisation proposée consiste à traiter séparément les différents mécanismes physiques les plus importants : mélange des espèces chimiques, propagation de fronts de flammes et auto-inflammation. Ainsi, des méthodes simples, dérivées de modèles connus en combustion turbulente non-prémélangée et prémélangée (méthodes de tabulation, PDF présumée) sont utilisées pour représenter les mécanismes de mélange des espèces et de propagation des fronts. Des développements spécifiques sont apportés pour que ces modèles soient toujours valides en présence d'auto-allumage. Les paramètres de modélisation introduits sont clairement identifiés et la sensibilité des résultats numériques à leurs valeurs est étudiée en détail. Le développement le plus important de ce travail concerne la méthode basée sur l'utilisation d'un temps de résidence pour modéliser l'auto-allumage du mélange. Comme la comparaison directe du temps de résidence au délai d'auto-allumage n'a plus de signification physique dès lors que la composition et la température évoluent avant l'auto-inflammation, un temps de résidence normalisé est introduit. Cette quantité peut aussi être présentée comme l'âge relatif des particules qui vieillissent différemment selon les caractéristiques du mélange local. L'équation bilan correspondante est dérivée soit de celle pour le temps de résidence soit par analogie avec l'équation G décrivant la propagation d'un front de flamme. Dans ce dernier cas, le temps de résidence est considéré comme une fonction "level-set" adaptée au suivi de fronts d'auto-inflammation. L'utilisation de ce temps normalisé permet aussi de traiter la difficulté liée aux conditions limites de temps de résidence. Le modèle proposé est d'abord utilisé pour simuler une flamme turbulente non-prémélangée de type JHC (Jet-in-Hot-Coflow) en RANS avec le logiciel de calcul numérique Code-Saturne (Bas Mach). Les résultats numériques sont validés pour deux conditions expérimentales différentes. Le modèle est ensuite validé par des calculs DNS de couche de mélange 1D soumise à l'auto-inflammation. Enfin, des simulations numériques préliminaires d'une configuration expérimentale récente disponible au laboratoire (Constant Volume Vessel) sont réalisées pour évaluer la faisabilité de l'extension du modèle en LES compressible avec OpenFOAM.
... 2,9−11 Microreactors, i.e., devices with interconnected microchannels that handle low amounts of reactants in a determined time, present some advantages over conventional batch reactors, such as low mixing time due to the reduced diffusion path; 12 high conversion and selectivity; high heat transfer coefficients with reported values up to 60 000 W/m 2 K, due to the large surface area to volume ratio, while conventional batch reactors experience heat transfer coefficients of about 100 W/ m 2 K; 13 increased safety; a substantial increment of reaction rates; a smaller time to achieve industrial scale (microfluidic devices can be used in research and development of products and processes and also in industrial scale production); easier and safety scale-up procedures that can be accomplished by device parallelization or hydraulic diameter enlargement; 14,15 less energy consumption; the use of modular and compact plants allowing flexible operation; multipurpose production as batch reactors; improved product quality due to in-line analyses; and faster response in operating variable alteration. 16,17 Continuous microreactors allow reactions to be performed under steady state conditions with high reproducibility. Accordingly, microdevices can be used also for kinetic parameter determination with advantages of a lower consumption of reactants, on the order of milligrams per run, and short runs, usually taking a few minutes. ...
Microfluidics and 3D printing will allow a faster research and development in pharmaceutical and medical areas, supporting new solutions for active pharmaceutical production and clinical tests without the necessity of in vivo animal models. The present review aims to show the role of these two technologies in the resolution of current pharmaceutical issues (e.g., efficient continuous production of active pharmaceutical ingredients, high costs for medicine development and lack of pre-clinical systems capable to predict accurate human responses to new medicine drugs) and in the development of biomedical and tissue engineering. The present paper was divided in the following sections: microfluidics and active pharmaceutical ingredients synthesis; organs-on-a-chip and multi-organs microdevices; 3D printing/bioprinting; and hydrogels and bioinks. Finally, conclusions and future perspectives were exposed.
