Journal of Flow Chemistry最新文献

In recent years, resveratrol and its analogues have gained significant attention due to their potential bioactivity in disease prevention and therapy. Consequently, there is a growing interest in producing these compounds in larger quantities, which increases the importance of chemical synthesis methods. The Wittig reaction is commonly used for the synthesis of these stilbene analogues and can be carried out in a two-phase system using phase-transfer catalysis (PTC). This approach helps to avoid the use of harsh and hazardous bases. In addition, hazardous solvents such as dichloromethane (DCM) are replaced by natural deep eutectic solvents (NADESs), which increases the safety and sustainability of the synthesis. Further improvements in the productivity of the process can be achieved through flow chemistry, which offers safer and less time-consuming production compared to batch processes. In this study, resveratrol analogues were synthetized using two approaches. In the first approach, the reaction was carried out in DCM, and in the second, DCM was replaced by synthetized hydrophobic NADESs to make the process more environmentally friendly. The preliminary results, obtained in a batch reactor, indicated that DCM could be replaced with NADES as a solvent for resveratrol analogues synthesis. To intensify the process, an integrated Wittig-PTC reaction and product separation were performed in a millireactor and two different microseparators (liquid-liquid membrane microseparator Zaiput SEP-10 and 3D printed membrane-free liquid–liquid microseparator) connected in series. In order to enhance conversion and productivity, different process parameters (temperature, residence time, millireactor diameter, and pressure) were tested. After determining the best process conditions, the product-rich DCM/NADES phase was separated using a microseparator. The best conditions for reaction performed in a millireactor using DCM as solvent were a temperature of 40–45 °C, a residence time of 20 min, a millireactor diameter of 1.016 mm, and a pressure of 8 bar where a selectivity of 28.12%, calculated on the trans-isomer, was achieved. By combining the millireactor and the Zaiput microseparator, a complete product-rich DCM phase was separated from the aqueous phase. When DCM was replaced by NADES, a temperature of 40–45 °C and a residence time of 10 min were selected as optimal, resulting in a selectivity of 27.30%. When the millireactor was combined with a 3D printed membrane-free liquid–liquid microseparator, the product-rich NADES phase was separated from the aqueous phase with minor loses.

A continuous flow process for the N-methylation of demethylbromonarwedine employing Eschweiler-Clarke conditions is reported for the synthesis of methylbromonarwedine, an intermediate of the anti-Alzheimer’s drug (−)-galanthamine. By intensifying this reaction by performing the N-methylation at elevated temperature and pressure, the reaction time was drastically reduced from 3 h in batch to only 40 s. The robustness of this process was demonstrated by operating it for 4.5 h, resulting in a product throughput of 20 g/h. Methylbromonarwedine was obtained not only in high yield (83%) but also with an excellent product content of 90%, which is a crucial factor in this route toward (−)-galanthamine.

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Carbon monoxide (CO) is a very useful and reactive gas in organic chemistry, but it is highly toxic. Therefore, in situ generation remains highly desirable to avoid direct manipulation. Generating CO from CO₂ represents a double interest: in situ CO generation from a cheap and abundant source and accessible applications for radiolabeling with carbon 11, which comes out of the cyclotron as [11C]CO₂. In this context, we developed an efficient process for incorporating a carbon atom from carbon dioxide (CO₂) in an amide compound in less than 5 min thanks to flow chemistry. Indeed, we successfully transformed CO₂ into CO in a column reactor filled with a disilane reductant and cesium fluoride (CsF) catalyst, connected to a microreactor where the CO could be incorporated into an amide through palladium-catalyzed aminocarbonylation. Validation with [13C]CO₂ demonstrated the process's applicability to other carbon isotope. This entirely flow-based process was completed within 3 min, and therefore offers a rapid, efficient, and safe approach for PET radiotracer synthesis with carbon-11, aligning with green chemistry principles.

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1-Chloro-3-methyl-2-butene is an important synthetic precursor or alkylating agent in the preparation of various bioactive chemicals and essential nutrients for human beings. A flow surface-mediated HCl in situ generation and subsequent hydrochlorination of isoprene were realized in the PTFE tubing reactor and the packed-bed reactor separately. Up to 86% isolated yield of 1-chloro-3-methyl-2-butene was achieved in the packed-bed reactor by performing the flow hydrochlorination at -15 °C within a 15 min residence time in the presence of 0.5 equiv. SOCl₂. The in-line recycling and regenerating of solid proton donor Al₂O₃ were accomplished via simple washing with DCM and MeOH in sequence, the activity of Al₂O₃ filled in the packed-bed reactor maintain consistent on the isolated yield of 1-chloro-3-methyl-2-butene after ten times consecutive reutilization. The flow platform consisting of two parallel packed-bed reactors were assembled for the continuous synthesis of desired 1-chloro-3-methyl-2-butene without interruption through delicate coordinating opening direction of a series of three-way valves. Long-term stability and reliability were demonstrated by continuous running the designed cyclic rotation system for 10 h, the targeted hydrochlorination product was furnished in 91–93% yield.

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Continuous-flow synthesis of prenyl chloride was enabled by cross-sequential utilization strategy using two parallel packed-bed reactors and precise alternating a series of three-way valves opening direction.

The exact measurement of the temperature in laboratory continuous flow processes is of high importance for many investigations e.g. of heat transfer or reaction kinetics. In particular, miniaturization poses high challenges on temperature measurement due to increased heat transfer. Despite the high relevance of this topic, there are only few publications dealing with accurate inline temperature measurement in flow chemistry and no studies examining the influence of the installation of the temperature sensor on the actual measured temperature. This work deals with inline temperature measurement using a conventional Pt100 sensor with 1.6 mm outer diameter and 20 mm measuring length in a T-piece in a continuous flow reactor on the micro-scale. The issue of heat loss in the T-piece is illustrated in a computational fluid dynamics CFD simulation. The T-piece temperature and the corresponding temperature measured by the Pt100 sensor in an insulated and not insulated T-piece are simulated and compared with experimental data. Moreover, different insert positions and orientations of the Pt100 sensor are simulated and discussed. The extensive CFD simulations demonstrate that using the side-on position of the Pt100 within an insulated T-piece leads to the most precise temperature measurements. Furthermore, the study shows that tilting of the Pt100 inside the T-piece has almost no influence on the temperature measurement as long as the measuring section of the Pt100 is fully inserted. Based on these results, a best practice approach for inline temperature measurement in micro-scale continuous flow reactors is presented for minimal measurement error.

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To evaluate the feasibility of transforming batch manufacturing processes in the fine chemicals and pharmaceutical industries to continuous synthesis, Capex, Opex and the total cost of manufacturing are estimated for production facilities for the hydrogenation of a nitro compound to its final amino counterpart. Two cases are evaluated: First, a high annual production dedicated plant, designed on the basis of processing 100,000 kg of the principal raw material per year, where raw materials cost, catalyst cost, and catalyst activity maintenance are varied over a broad range for typical industrial cases. Second, a “short campaign” model for a small volume production trial setup designed for the manufacture of only 100 kg of the final product, as a way to evaluate relevant industrial scenarios of scale-up and process development. A comparison is made between slurry batch, catalyst basket batch reactor and fixed bed continuous reactor manufacturing facilities. The hydrogenation of 2,4-dinitrotoluene was chosen as a probe reaction for the development of the manufacturing processes, with costs of the key raw material varying between $5 and $100 per kilogram, costs of catalyst varying between $100 and $1,500 per kilogram, and catalyst activity maintenances varying between 1,000 and 2,000,000 total turnovers before a change in catalyst load is necessary. For low catalyst activity maintenance, the total manufacturing costs for the fixed bed reactor process were always found to be higher than those of the two other alternatives. As catalyst activity maintenance increases, the manufacturing costs for the continuous alternative rapidly fall, reaching savings between 37 and 75% compared to the base batch reactor case, depending on the combination of costs of the key raw material and catalyst used.

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A solvent extraction system for extracting glyoxylic acid from aqueous solutions by using trioctylamine in n-octanol in a microchannel is developed, operating in the slug flow regime. The extraction system is composed of two preheating capillary loops, a T-junction micromixer, and a capillary microchannel. The influences of the volume ratio of the organic phase to the aqueous phase (O/A ratio), temperature, concentration of trioctylamine, total flow rate, and residence time on extraction and mass transfer are systematically investigated. A relationship between the total volumetric mass transfer coefficient and the capillary number, Reynolds number, capillary diameter and length is proposed. This study holds significant implications for the efficient extraction of glyoxylic acid in microchannels.

Impact in Continuous flow Heated Mechanochemistry (ICHEM) was used for the production of solketal at 60 °C using glycerol and acetone in the presence of homogeneous FeCl₃.6H₂O (1 mol%). In our optimized conditions, the target compound was obtained in 96% yield (conversion of 97% and selectivity of 99%) with a productivity of 276 g day^–1 with a 80 mL continuous flow reactor. This new technology combines beads mechanochemistry and continuous flow and offers: (i) a better mixing of the two unsoluble parts (glycerol and acetone) by reducing the viscosity of the feed stream and (ii) an alternative of the single-screw and double-screw extruders which are unefficient with a liquid reaction media.

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Nanotechnology has emerged as a groundbreaking field with profound implications for drug delivery systems, offering precise targeting, controlled release, and enhanced therapeutic efficacy. Continuous flow process is a compelling approach in the production of nanoparticles, providing numerous advantages over traditional batch methods. By maintaining uniform conditions and precise control over reaction parameters, continuous flow systems enable enhanced reproducibility, scalability, and efficiency in nanoparticle synthesis. In this context, microfluidic hydrodynamic focusing (MHF) is a promising method for continuous flow lipid nanoparticle synthesis. Herein, we report a study for the development of a single-step continuous flow process to generate nanoparticles using a PLA chip device inspired by microfluidic techniques. A lipid peptoid synthesized via Ugi reaction was chosen from an ongoing study to evaluate the most appropriate conditions for the continuous flow process. It was possible to produce nanoparticles with small size and the optimized parameters generated nanoparticles with sizes ≤ 200 nm, making them good candidates for drug delivery system.

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