this sense, continuous-flow techniques do not only mark a technological advance and yet merely a different approach from a chemical engineering point of view. Much more, flow technology is an enabler for the development of novel (or rediscovered
Authors:Sofie Seghers, Frederik E.A. Van Waes, Ana Cukalovic, Jean-Christophe M. Monbaliu, Jeroen De Visscher, Joris W. Thybaut, Thomas S.A. Heugebaert and Christian V. Stevens
Despite extensive research into peptide synthesis, coupling of amino acids with weakly nucleophilic heterocyclic amines remains a challenge. The need for microwave technology to promote this coupling interferes with the scalability of the process. By applying the microwave-to-flow paradigm, a library of (α-aminoacyl)amino-substituted heterocycles was continuously produced at near quantitative conversions and the reaction was scaled up successfully. Various N-Cbz-protected amino acids were activated using BtH/SOCl2 under continuous-flow conditions with excellent yields. Their coupling with heterocyclic amines was accomplished in MeCN—NMP on a preparative scale. However, performing both steps in-line resulted in an inconvenient work-up. Therefore, a two-step approach was taken, isolating the intermediate Bt-activated amino acid via simple filtration. This allows for a solvent switch to DMSO for the coupling reaction which led to excellent conversions for a broad range of substrates.
Authors:Raquel A. C. Leão, Raquel de O. Lopes, Marco A. de M. Bezerra, Mauro N. Muniz, Bruna B. Casanova, Simone C. B. Gnoatto, Grace Gosmann, Laszlo Kocsis, Rodrigo O.M.A. de Souza and Leandro S. de M. Miranda
The use of continuous-flow chemistry has shown to be an important tool in improving API manufacture. In the present paper, we report the use of continuous-flow reactors in the synthesis of the bicyclic side chain of antiretroviral Darunavir.
Authors:Daniel Blanco-Ania and Floris P. J. T. Rutjes
be used for virtually any chemical reaction and are therefore cost efficient to operate. Nevertheless, since two decades or so, continuous-flow chemistry has become more widespread in academic synthetic chemistry groups that recognized the benefits of
Authors:Meaghan M. Sebeika, Nicholas G. Gedeon, Sara Sadler, Nicholas L. Kern, Devan J. Wilkins, David E. Bell and Graham B. Jones
Interest in the field of antibody—drug conjugates (ADCs) has grown exponentially over the past decade. As the product pipeline grows, there is increasing need for robust chemistries which allow selective and efficient functionalization of the antibody cores for introduction of appropriate linkers and spacer groups. Under conventional bioconjugation conditions, product heterogeneity often results, and the drug-to-antibody ratios (DAR) are inconsistent. Based on our experience in protein derivatization, we have investigated the potential for continuous-flow microreactor technology to expedite and facilitate such processes. We demonstrate its potential using reagent proteins and the chimeric monoclonal antibody infliximab (Remicade™).
Authors:Viktor Misuk, Andreas Mai, Yuning Zhao, Julian Heinrich, Daniel Rauber, Konstantinos Giannopoulos and Holger Löwe
Fast mixing is essential for many microfluidic applications, especially for flow at low Reynolds numbers. A capillary tube-in-tube coaxial flow setup in combination with a glass microreactor was used to produce immiscible multiphase segments. These double emulsion segments are composed of an organic solvent as the shell (outer) phase and a completely fluorinated liquid (Fluorinert® FC-40) as the core (inner) phase. Due to the higher density of the core droplets, they are responsive to changing their position to the force of gravity (g-force). By gently shaking or jiggling the reactor, the core drop flows very fast in the direction of the g-field without leaving the shell organic phase segment. Furthermore, by shaking or jiggling the reactor, the inner droplet moves along the phase boundary of the shell segment and continuous phase. Computational fluid dynamics (CFD) calculations show an enhancement of the internal circulations, i.e., causing an exceptional mixing inside of the shell segment. For reactions which are limited by mass transfer, where the conversion significantly increases with improved mixing, these recirculation zones are decisive because they also accelerate the mixing process. With a common phase-transfer catalytic (PTC) etherification of phenol with dimethyl sulphate, a remarkable increase of yield (85% gas chromatography [GC]) could be achieved by applying active mixing within a segment in continuous flow.
efficient flow of information.
Continuousflow could be an ideal platform for complete integration of the early stages of drug discovery. There have been significant advances in both chemical synthesis in flow and biological screening in flow and the
Authors:Frederik E. A. Van Waes, Sofie Seghers, Wim Dermaut, Bart Cappuyns and Christian V. Stevens
An efficient continuous-flow procedure for the synthesis of tribromomethylsulfones and tribromomethanesulfonates has been developed starting from the corresponding methylsulfones or methanesulfonates and potassium hypobromite using a biphasic reaction. Two different continuous-flow systems were used and compared for the bromination reaction. Different derivatives were synthesized in excellent isolated yields in very short reaction times using a small excess of potassium hypobromite. Hypobromite can be synthesized continuously leading to the continuous production of the brominated derivates. With the optimized flow conditions, a throughput of up to 53 g/day was obtained. The bromination reaction in flow has significant advantages compared to the corresponding batch process.
Authors:Dustin M. Clifford, Ahmed A. El-Gendy, Amos J. Lu, Dmitry Pestov and Everett E. Carpenter
Cobalt nanoparticles were synthesized using continuous-flow (CF) chemistry in a stainless steel microreactor for the first time at high output based on the ethanol hydrazine alkaline system (EHAS) producing a yield as high as 1 g per hour [1, 2]. Continuous-flow (CF) synthetic chemistry provides uninterrupted product formation allowing for advantages including decreased preparation time, improved product quality, and greater efficiency. This successful synthetic framework in continuous-flow of magnetic Co nanoparticles indicates feasibility for scaled-up production. The average particle size by transmission electron microscopy (TEM) of the as-synthesized cobalt was 30±10 nm, average crystallite size by Scherrer analysis (fcc phase) was 15±2 nm, and the estimated magnetic core size was 6±1 nm. Elemental surface analysis (X-ray photoelectron spectroscopy [XPS]) indicates a thin CoO surface layer. As-synthesized cobalt nanoparticles possessed a saturation magnetization (Ms) of 125±1 emu/g and coercivity (Hc) of 120±5 Oe. The actual Ms is expected to be greater since the as-synthesized cobalt mass was not weight-corrected (nonmagnetic mass: reaction by-products, solvent, etc.). Our novel high-output, continuous-flow production (>1 g/hr) of highly magnetic cobalt nanoparticles opens an avenue toward industrial-scale production of several other single element magnetic nanomaterials.
Authors:Sebastiaan A. van den Berg, Raoul A.M. Frijns, Tom Wennekes and Han Zuilhof
Alcohol protection and deprotection reactions, catalyzed by solid-supported sulfonic acid, have been investigated under continuous-flow conditions. Primary, secondary, benzylic and phenolic alcohols can be protected under these conditions by tetrahydropyranyl and several silyl ether moieties, generating synthetically useful amounts of material in short time. Furthermore, the described setup can be used to deprotect protected alcohols and be used in selective protection reactions. Because the solid-supported acid catalyst is continually reused in a packed-bed approach, workup is greatly simplified and in most cases only solvent removal is necessary, while reaching high turn-over numbers.