Journal of Flow Chemistry最新文献

{"title":"Rapid and practical synthesis of N-protected amino ketones in continuous flow via pre-deprotonation protocol","authors":"Weixia Lin, Zilong Lin, Chaoming Liang, Maolin Sun, Ruihua Cheng, Jinxing Ye","doi":"10.1007/s41981-024-00336-x","DOIUrl":"https://doi.org/10.1007/s41981-024-00336-x","url":null,"abstract":"<p>The nucleophilic reaction of Weinreb amides with Grignard or organic lithium reagents is widely used in the synthesis of amino ketones because of the formation of stable metal chelate tetrahedral intermediates. However, their large-scale synthesis in batch seriously suffers from the use of excess of nucleophiles due to carbamate group of <i>N</i>-protected amino Weinreb amides and the harsh reaction conditions required by Grignard or organic lithium reagents. In this case, <i>N</i>-protected amino ketones were rapidly synthesized by a practical and efficient continuous flow method under mild conditions. By precisely introducing a simple alkyl Grignard base to deprotonate the carbamate group, the functionalized <i>N</i>-protected amino ketones can be efficiently obtained within 128 s with only a slightly excess of stoichiometric amount of nucleophile, with the yield up to 96%. In addition, the scope of this method was demonstrated over 35 substrates with 3 protective groups signifying the excellent substrate and protecting group tolerances. A scale-up preparation affords a throughput of 7.9 g h^-1, indicating potential large-scale application. This work lays the foundation for the large-scale automated synthesis of a variety of <i>N</i>-protected amino ketones.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"119 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expedited access to β-lactams via a telescoped three-component Staudinger reaction in flow","authors":"Federica Minuto, Andrea Basso, Marcus Baumann","doi":"10.1007/s41981-024-00333-0","DOIUrl":"https://doi.org/10.1007/s41981-024-00333-0","url":null,"abstract":"<p>The Staudinger reaction is widely used for the generation of β-lactams <i>via</i> the thermal cycloaddition of imines with ketenes. Traditionally, it cannot be performed as a multicomponent reaction between aldehydes, amines and ketenes, thus limiting its versatility. Recently we reported for the first time a three-component Staudinger reaction in batch, exploiting a photochemical Wolff rearrangement of diazoketones and an in situ generation of the imine. Here we report an expedited continuous flow approach that generates the crucial ketene intermediate prior to its telescoped reaction with an imine component at ambient temperatures. The imine is prepared by an in situ dehydration between amines and aldehydes in a packed bed reactor containing basic alumina as drying agent. The resulting telescoped flow approach features a fast dehydration reaction (t_Res ca. 3 min) as well as an efficient Wolff rearrangement using LEDs (420 nm) to afford the desired β-lactam products in less than 30 min which compares favorably with reaction times of several days in batch mode. Flow processing thereby affords a safe and streamlined entry to these important targets and allows their effective generation on gram scale. Moreover, this approach exploits several homogeneous and heterogeneous transformations under mild conditions that generate water and nitrogen gas as the only by-products.</p><h3 data-test=\"abstract-sub-heading\">Graphical abstract</h3>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"2 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient “One-Column” grignard generation and reaction in continuous flow","authors":"Maolin Sun, Hong Li, Hualiang Chen, Rixin Shao, Fanghua Chen, Xiangmin Sang, Weixia Lin, Yueyue Ma, Ruihua Cheng, Jinxing Ye","doi":"10.1007/s41981-024-00332-1","DOIUrl":"https://doi.org/10.1007/s41981-024-00332-1","url":null,"abstract":"<p>A straightforward “one-column” continuous flow method of Grignard generation and reaction was successfully developed. The diverse mixtures of aryl- or alkyl- halides and electrophiles were flowed through an activited magnesium packed-bed column, delivering a series of ketones, secondary alcohols, tertiary alcohols, esters, amides, and sulfinamides immediately in moderate to good yields. By combining Grignard generation and reaction into one step and avoiding the separate preparation and storage of Grignard reagents, this practical and efficient protocol dramatically enhanced the safety of operation and provided a convenient access for Grignard reactions, compared with traditional batch process. The continuous flow synthesis of Grignard generation and reaction is carried out in a magnesium packed-bed column successfully.The target product is provided in moderate to good yields within 6.0 min. This protocol with preferable controllability, good selectivity, and safety extremely simplified operational procedure.</p>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"7 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two deep learning methods in comparison to characterize droplet sizes in emulsification flow processes","authors":"Inga Burke, Thajeevan Dhayaparan, Ahmed S. Youssef, Katharina Schmidt, Norbert Kockmann","doi":"10.1007/s41981-024-00330-3","DOIUrl":"https://doi.org/10.1007/s41981-024-00330-3","url":null,"abstract":"<p>For reliable supervision in multiphase processes, the droplet size represents a critical quality attribute and needs to be monitored. A promising approach is the use of smart image flow sensors since optical measurement is the most commonly used technique for droplet size distribution determination. For this, two different AI-based object detection methods, Mask RCNN and YOLOv4, are compared regarding their accuracy and their applicability to an emulsification flow process. Iterative optimization steps, including data diversification and adaption of training parameters, enable the models to achieve robust detection performance across varying image qualities and compositions. YOLOv4 shows better detection performances and more accurate results which leads to a wider application window than Mask RCNN in determining droplet sizes in emulsification processes. The final droplet detection model YOLOv4 with Hough Circle (HC) for feature extraction determines reliable droplet sizes across diverse datasets of liquid-liquid flow systems (disperse phase content 1–15 vol.-%, droplet size range 5–150 μm). Evaluating the adjustment of Confidence Scores (CS) ensures statistical representation of even smaller droplets. The droplet detection performance of the final YOLOv4 model is compared with a manual image processing method to validate the model in general as well as its accuracy and reliability. Since YOLOv4 in combination with Hough Circle (HC) shows an accurate and robust detection and size determination, it is applicable for online monitoring and characterization of various liquid-liquid flow processes.</p><h3 data-test=\"abstract-sub-heading\">Graphical abstract</h3>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"20 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141862809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced emulsification process between viscous liquids in an ultrasonic capillary microreactor: mechanism analysis and application in nano-emulsion preparation","authors":"Sawita Tanwinit,&nbsp;Shuainan Zhao,&nbsp;Chaoqun Yao,&nbsp;Guangwen Chen","doi":"10.1007/s41981-024-00331-2","DOIUrl":"10.1007/s41981-024-00331-2","url":null,"abstract":"<div><p>Experimental investigations into acoustic cavitation and ultrasound-assited emulsification process between highly viscous liquids were systematically conducted in a laboratory-built ultrasonic microreactor. Under ultrasound irradiation, four cavitation modes were observed simultaneously in soybean oil, including volume, shape, transient collapse and cavitation clouds. Influenced by the intense oscillation of cavitation bubbles, emulsification between viscous liquids was initiated through a dispersion and migration mode. The effects of varying parameters, such as input power, residence time, channel size, HLB value, surfactant concentration and volume ratio between aqueous and oil phase, on the size and polydispersity of prepared emulsion were investigated using water-soybean oil two-phase system as a model. The emulsion size was reduced to 75.60 nm through optimization of experimental parameters. Based on these findings, the ultrasonic microreactor was successfully employed in the preparation of Vitamin E-enriched nano-emulsions. A fine emulsion with low average size (47.69 nm) and good storage stability (60 days) was prepared within 2 min, further indicating the potential application of ultrasonic microreactor in the beverage and pharmaceutical industries.</p></div>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"14 3","pages":"569 - 584"},"PeriodicalIF":2.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141741485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel insights into acetylation kinetics in a continuous Flow milli-reactor for chemo-enzymatic separation of silybin A/B","authors":"Michele Emanuele Fortunato,&nbsp;Rita Pagano,&nbsp;Valeria Romanucci,&nbsp;Chiara Licenziato,&nbsp;Armando Zarrelli,&nbsp;Martino Di Serio,&nbsp;Giovanni Di Fabio,&nbsp;Vincenzo Russo","doi":"10.1007/s41981-024-00329-w","DOIUrl":"10.1007/s41981-024-00329-w","url":null,"abstract":"<div><p>The separation of silybin A (<b>SilA</b>) and B (<b>SilB</b>) diastereomers in optically pure compounds is challenging due to their very similar physical and chemical properties. However, such separation is crucial for evaluating the biological activity of the diasteroisomers <b>SilA</b> and <b>SilB</b>, which show very different performance in pharmacological applications like treating prostate cancer, liver diseases, and Alzheimer’s disease. The most common isolation method is based on high-performance liquid chromatography, but it is slow and has a yield in pure <b>SilB</b> of hundreds of milligrams per day. An alternative chemo-enzymatic separation method, utilizing an immobilized lipase CALB catalyst to stereoselectively acetylate silybin B (<b>1b</b>), offers advantages in terms of higher productivity, selectivity, and scalability, particularly when applied in flow reactors. This study delves into the kinetics of <b>Sil</b> acetylation catalyzed by Novozym 435 in a continuous flow milli-reactor, investigated at various temperatures, volumetric flow rates, and Sil initial concentrations. It is noteworthy that, at the current state of the art, there is a lack of kinetic studies on this reaction, emphasizing the novelty and significance of this work. The kinetic and fluid dynamic parameters were estimated using a non-linear regression analysis of experimental data. The examined reaction showed a null apparent activation energy, explaining the temperature insensitivity of the final acetylated silybin B (<b>1b</b>) concentration. Furthermore, the decrease in steady-state concentrations of the acetylated products with increasing volumetric flow rates indicated that the reaction was occurring in a kinetic regime. Interestingly, a maximum starting Sil concentration was identified, above which there was no favorable impact on conversion.</p></div>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"14 3","pages":"585 - 595"},"PeriodicalIF":2.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s41981-024-00329-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141741486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functionalization of unsaturated carbon–carbon bonds by continuous-flow ozonolysis","authors":"Caio M. Pacheco,&nbsp;Fernanda A. Lima,&nbsp;Mauro R. B. P. Gomez,&nbsp;Lucas B. Barbosa,&nbsp;Raquel A. C. Leão,&nbsp;Rodrigo O. M. A. de Souza","doi":"10.1007/s41981-024-00328-x","DOIUrl":"10.1007/s41981-024-00328-x","url":null,"abstract":"<div><p>In the continuous struggle for improvements in laboratory processes, flow synthesis has been widely used for being safer, more reproducible, as for improving yields and scalability. Therefore, flow ozonolysis has become a turning point as flow reactors provides a much safer work environment and reactions can now be produced at industrial scales. In this review we would discuss several reactors used in flow ozonolysis and its importance for the safety of the ozonolysis process.</p></div>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"14 3","pages":"491 - 513"},"PeriodicalIF":2.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141719420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Continuous preparation and reaction of nonaflyl azide (NfN3) for the synthesis of organic azides and 1,2,3-triazoles","authors":"Sebastian P. Green,&nbsp;Hannah C. Broderick,&nbsp;Katherine M. P. Wheelhouse,&nbsp;Jason P. Hallett,&nbsp;Philip W. Miller,&nbsp;James A. Bull","doi":"10.1007/s41981-024-00327-y","DOIUrl":"10.1007/s41981-024-00327-y","url":null,"abstract":"<div><p>Organic azides are widely used in organic synthesis. Continuous flow processing can be used to bypass their isolation, and can therefore be useful in mitigating the hazards associated with these potentially toxic and explosive reagents. Nonaflyl azide has been reported as an effective, bench-stable, and relatively safe diazo transfer reagent that can be useful in the preparation of azides from amines and so avoid the use of alkyl halides. Here we demonstrate the synthesis and purification of nonaflyl azide in continuous flow with isolation of the neat, pure reagent by membrane filtration. The neat reagent was used in the preparation of organic azides from primary amines, and then applied to the synthesis of triazoles. A variety of triazoles, including the antiseizure drug Rufinamide, were prepared from primary amines and alkynes via the CuAAC click reaction in a semi-batch parallel array without isolation of alkyl azide intermediates. A telescoped two-stage continuous flow process was also designed and demonstrated to form triazoles via the same CuAAC reaction, which avoids the handling of the intermediate reactive azides.</p></div>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"14 3","pages":"559 - 568"},"PeriodicalIF":2.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s41981-024-00327-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141546631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance of different microfluidic devices in continuous liquid-liquid separation","authors":"Bastian Oldach,&nbsp;Ya-Yu Chiang,&nbsp;Leon Ben-Achour,&nbsp;Tai-Jhen Chen,&nbsp;Norbert Kockmann","doi":"10.1007/s41981-024-00326-z","DOIUrl":"10.1007/s41981-024-00326-z","url":null,"abstract":"<div><p>Droplet-based microfluidics exhibit numerous benefits leading to relevant innovations and many applications in various fields. The precise handling of droplets in capillaries, including droplet formation, manipulation, and separation, is essential for successful operation. Only a few reports are known concerning the separation of segmented flows, particularly the continuous separation of droplets, which is of high interest regarding the control of biochemical and chemical reactions or other applications where the contact time of the involved phases is crucial. Here, the separation must be flexible and adjusted to different flow parameters, such as the surface tension, the volumetric flow rates, and their ratios. This contribution presents two novel open-source approaches based on additive manufacturing and mechanical deforming for continuous liquid–liquid separation under various flow conditions. The Laplace pressure is the driving force for the separation, which is adjusted to the flow conditions by adapting the distance of pinning points provided by the design of the devices. Details of the device design and experimental setup are shown along with limitations to promote further development and to increase availability for researchers. With the right parameters, sophisticated separations can be realized by inexpensive laboratory equipment and simple control of them. It was found that the distance between the pinning points needs to enlarged for increasing volumetric flow rates and reduced for higher viscosities of the continuous phase respectively higher amounts of the dispersed phase. The open source approach of this article expands the exploration space in addition to commercially available phase separators only available to a selected group of people.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"14 3","pages":"547 - 557"},"PeriodicalIF":2.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s41981-024-00326-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141350167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Continuous flow process optimization aided by machine learning for a pharmaceutical intermediate","authors":"Jinlin Zhu,&nbsp;Chenyang Zhao,&nbsp;Li Sheng,&nbsp;Dadong Shen,&nbsp;Gang Fan,&nbsp;Xufeng Wu,&nbsp;Lushan Yu,&nbsp;Kui Du","doi":"10.1007/s41981-024-00318-z","DOIUrl":"10.1007/s41981-024-00318-z","url":null,"abstract":"<div><p>In this paper, we demonstrate the use of machine learning to optimize the continuous flow process of a crucial intermediate in the production of Nemonoxacin. Our focus is to achieve the good yield and enantioselectivity in the construction of chiral methyl group utilize the initial 29 experimental datasets and consider six important variables. Employing Single-Objective Bayesian optimization (SOBO), we achieved an impressive predicted yield of up to 89.7%, which is consistent with the experimental results, with a yield of 89.5%. Additionally, A Multi-Objective Bayesian Optimization (MOBO) algorithm, namely qNEHVI, to strike a balance between yield and enantioselectivity in the continuous flow system is applied. The algorithm’s prediction, with a yield of 81.8% and enantioselectivity of 97.85%, was experimentally validated, yielding 83.8% and 97.2%, respectively. This study effectively demonstrates that Bayesian optimization is a powerful tool for optimizing the continuous process in the production of active pharmaceutical ingredients (APIs).</p></div>","PeriodicalId":630,"journal":{"name":"Journal of Flow Chemistry","volume":"14 3","pages":"539 - 546"},"PeriodicalIF":2.0,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140934607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}