Authors:Victor Sebastian, Saif A. Khan and Amol A. Kulkarni
biological moieties needed for certain activity and the former option of chemical synthesis becomes a more reliable approach, albeit only if the synthetic recipe allows consistent product quality at all scales of production. Continuous-flowsynthesis of the
Authors:Anne-Catherine Bédard, Jeffrey Santandrea and Shawn K. Collins
The continuous-flow synthesis of a series of 11- to 26-membered macrocycles via copper-catalyzed azide-alkyne cycloaddition is reported. The approach employs homogeneous catalysis to promote formation of triazole-containing macrocycles in good to excellent yields (65–90%) at relatively high concentration (30–50 mM) using a phase separation strategy.
Flowsynthesis, especially when conducted in microreactors, has in recent years opened pathways towards synthesis methods that otherwise would be inaccessible or at least very difficult to conduct. In
Authors:Xin Li, Anbang Chen, Yangzhi Zhou, Lingling Huang, Zheng Fang, Haifeng Gan and Kai Guo
Continuous-flow synthesis of coumarin was realized in a tandem microflow system containing two microreactors in this study. Generally, better reaction yield (91%) and less side reaction were obtained in the flow system compared with conventional method. Interestingly, different reaction pathways were observed between continuous-flow system and batch methods.
Authors:Han Yueh, Anastasia Voevodin and Aaron B. Beeler
9-Hydroxymethylxanthene derivatives were optimized as a photolabile protecting group for amines in flow chemistry. 9-Methylxanthene and 2-methoxy-9-methylxanthene showed excellent deprotection yields in protic and aprotic solvents, respectively. The protecting group has good stability in acidic, basic, and thermal conditions and was successfully utilized for protection and deprotection of a variety of amines. A multistep continuous-flow synthesis of a piperazinylcarbonyl-piperidine derivative utilized the 2-methoxy-9-methylxanthene as the key protecting group utilized in an orthogonal manner.
Authors:Nathaniel B. Zuckerman, Maxim Shusteff, Philip F. Pagoria and Alexander E. Gash
The secondary high explosive 2,6-diamino-3,5-dinitropyrazine-1-oxide, or LLM-105, has been synthesized using a commercially available flow microreactor system. Investigations focused on optimizing flow nitration conditions of the cost effective 2,6-diaminopyrazine-1-oxide (DAPO) in order to test the feasibility and viability of flow nitration as a means for the continuous synthesis of LLM-105. The typical benefits of microreactor flow synthesis including safety, tight temperature control, decreased reaction time, and improved product purity all appear to be highly relevant in the synthesis of LLM-105. However, the process does not provide any gains in yield, as the typical 50—60% yields are equivalent to the batch process. A key factor in producing pure LLM-105 lies in the ability to eliminate any acid inclusions in the final crystalline material through both a controlled quench and recrystallization. The optimized flow nitration conditions, multigram scale-up results, analyses of sample purity, and quenching conditions for purity and crystal morphology are reported.
Authors:Klára Lövei, István Greiner, János Éles, Áron Szigetvári, Miklós Dékány, Sándor Lévai, Zoltán Novák and György István Túrós
In medicinal chemistry, the development of synthetic procedures for the access of new heterocyclic systems as potential scaffolds is elementary. Herein, we report our results on the formation of small drug-like heterocycles, utilizing flow chemistry. This approach enables the extension of the reaction parameter window, including high-pressure/high-temperature or hazardous chemistry. In our work, various novel condensed tricyclic benzothiazoles fused with furo- and thieno-rings were synthesized applying a multistep continuous-flow protocol. The process includes two ring closure steps and a nitro group reduction step. Batch and telescoped continuous-flow syntheses were also designed and performed.
Authors:Dominique Roberge, Christian Noti, Eberhard Irle, Markus Eyholzer, Bruno Rittiner, Gerhard Penn, Gottfried Sedelmeier and Berthold Schenkel
After a short section of safety aspects related to 2-nitroethanol, the paper describes a powerful methodology for developing flow processes based on a proof of concept (1), an optimization and modeling analysis (2), and a long run study in a mini-plant (3). The proof of concept is the initial stage where the solubilities and concentrations are fixed, taking into account the rough kinetics with a mass transfer understanding. It is followed by a complete kinetic analysis including activation energy to model the reaction under various conditions to optimize different targets (yield not being the only driver!). The last section shows the operation of a mini-plant including a microreactor and work-up unit operations. The approach is extremely powerful as it enables the study at laboratory scale of all the features that are usually associated with a pilot plant namely: stability over time on stream, solvent recirculation, model prediction, and robustness.
Authors:Sarah E. Smith, Zachary J. Huba, Fahad Almalki, J. R. Regalbuto, John Monnier and Everett E. Carpenter
Magnetic nanomaterials have many applications in the fields of catalysis, medicine, and environmental studies. An emerging synthetic method capable of large-scale production of nanomaterials is a continuous-flow microreactor. However, translating known conventional benchtop reactions to a continuous-flow system can be difficult; reaction parameters such as reaction time and viscosity of the solution are significant limitations in flow-based systems. In this study, nanocrystalline Cu—Ni and Cu—Co core—shell materials were successfully synthesized using a capillary microreactor in a one-step process. Ethanol was used as solvent, allowing for faster reaction times and reduced reaction solution viscosity, compared to similar bench top synthetic protocols. Both nanocomposites were tested for activity in Fischer—Tropsch and showed activity above 220 °C. This study shows that a continuous-flow capillary microreactor has the capabilities to make complex metallic nanomaterials at short reaction times with proper selection of reaction solvent systems.
Authors:Yun Zhao, Ajay Singh, Seungwook Jang, Anjie Wang and Dong-Pyo Kim
Plain and N-doped carbonaceous particles are synthesized from biomass resources such as glucose via continuous hydrothermal carbonization (HTC) process at 200 °C and 250 psi for the first time using a microfluidic system in a fast and continuous manner. The continuous HTC is controlled by reaction time (3.7–30 min) and concentration (0–10 wt.%) of ethylenediamine as a nitrogen additive to produce a series of the plain carbonaceous and N-doped carbonaceous particles with size range from 0.8 to 1.2 um. The as-synthesized and the pyrolyzed particles are characterized by various analytical instruments to understand their chemical structures with elemental compositions, morphology of particles, and thermal defunctionalization.