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Robust calorimetric data for highly exothermic organolithium reactions are obtained within a modular 3D printed continuous flow calorimeter.

To automate and democratize model-based experimental design for flow chemistry applications, we report the development of open-source software, Optipus. Reaction models are built in an iterative and automated fashion, for rapid reaction development.

We develop a continuous flow protocol for the synthesis of sulfonyl chlorides from disulfides and thiols, using 1,3-dichloro-5,5-dimethylhydantoin (DCH) as a dual-function reagent for oxidative chlorination.

An automated continuous flow and real-time analytics platform facilitates the generation of quantitative data to understand the sensitivity of the reaction performance in the presence of different functional groups and heterocycles.

A continuous synthesis line was developed integrating different common reaction steps namely nitration, substitution and hydrogenation. Mesalazine as model drug substance was produced from 2-chlorobenzoic acid in continuous flow mode. A multi-instrument PAT strategy was implemented to equip the full line with in-line monitoring capability for critical quality attributes (CQAs) at several points. While most applications of PAT in research and manufacturing of the drug substance are limited to in-process control of quality, in this study real-time process information was generated to support automated process control actions. Process models were developed for all steps of the synthesis route either mechanistic based on reaction kinetics, data driven based on process data or depicting the residence time distribution (RTD). These models facilitated the development and implementation of an automation concept. Feedback loops were established using model predictive controllers for each unit operation, with the objective to maximize yield and minimize side products. The results indicate the high potential of an advanced control concept based on process models and real-time process data.

A novel type of catalytic static mixers with rectangular cross-section coated with Pd/Al2O3 has been developed. The catalytic mixers, produced by additive manufacturing and coated with the metal catalyst, have shown excellent catalytic performance for continuous flow hydrogenation of nitroaromatics. The heterogeneous catalyst is highly stable. No loss of catalytic performance was observed after long periods of activity and ICP-MS measurements determined that essentially no Pd or Al leaches from the reactor. The rectangular cross-section reactor is readily scalable. The process developed has been showcased for the synthesis of the key intermediate of the medicine tizanidine.

Artificial neural networks (ANNs) facilitate rapid quantification of process spectra from inline process analytical technologies. Data fusion also enables combination of multiple data sources, resulting in better quality concentration measurements.

Persulfuric acid is a well-known oxidant in various industrial-scale purification procedures. However, due to its tendency toward explosive decomposition, its usefulness in organic synthesis remained largely underexplored. Herein, a continuous in situ persulfuric acid generator was developed and applied for oxidative esterification of aldehydes under flow conditions. Sulfuric acid served as a readily available and benign precursor to form persulfuric acid in situ. By taking advantage of the continuous-flow generator concept, safety hazards were significantly reduced, whilst a robust and effective approach was ensured for direct transformations of aldehydes to valuable esters. The process proved useful for the transformation of diverse aliphatic as well as aromatic aldehydes, while its preparative capability was verified by the multigram-scale synthesis of a pharmaceutically relevant key intermediate. The present flow protocol demonstrates the safe, sustainable, and scalable application of persulfuric acid in a manner that would not be amenable to conventional batch processing.

A scalable continuous flow setup for the preparation of the opioid medication oxycodone is presented. The process is based on a two-step synthetic sequence consisting of C14 hydroxylation of thebaine with performic acid, followed by catalytic hydrogenation of the ensuing 14-hydroxycodeinone intermediate. Safe and efficient oxidation with performic acid has been achieved by generating the reagent in situ in the presence of the starting material using a micromixer. Catalytic hydrogenation has been carried out in a scalable shell-and-tube reactor equipped with palladium-electroplated catalytic static mixers. Acquisition of real-time process data has been enabled by integrating online UHPLC analysis at the reactor output. The continuous process features safe operation, high atom economy, simple workup and production of 7 g/h of high purity oxycodone in a small footprint setup.

An electrochemical procedure for the α-arylation of ketones has been developed. The method is based on the generation and one-pot anodic oxidation of silyl enol ethers in the presence of the arene. This strategy avoids isolation of the silyl enol intermediate and the utilization of external supporting electrolytes. Intermolecular arylations, which had not been reported so far, are possible when electron-rich arenes are utilized as coupling partners. The method has been demonstrated for a wide variety of aryl ketones and activated arenes, with moderate to good yields (up to 69%) obtained. Mechanistic insights and a theoretical rationale that explains the ketone α-arylation versus dimerization selectivity are also presented.

This study provides a comparative life cycle assessment (LCA) of four different polyurethane dispersion production processes from cradle-to-gate. The environmental performances of the NMP process, the acetone process, the melt process, and a conceptualized continuous flow process were evaluated and compared following the CML 2001 methodology. The LCA revealed that the conceptualized flow process exhibits the lowest environmental impact in all investigated impact categories. Depending on the impact category, the melt process or the acetone process rank second. The NMP process was observed to have the highest impact in all categories. Consequently, the flow process has the lowest carbon footprint (1.13 kg CO2-eq), according to the global warming potential (100 years), followed by the melt (1.45 kg CO2-eq), the acetone (1.95 kg CO2-eq) and the NMP process (3.11 kg CO2-eq).

Selective anodic oxidation of alcohols in the presence of other functional groups can be accomplished by using nitroxyl radical mediators. However, the electrochemical chemoselective oxidation of secondary alcohols in the presence of primary alcohols is an unsolved issue. Herein, we report an electrochemical procedure for the selective oxidation of secondary alcohols by using an inexpensive chloride salt that acts as a redox mediator and supporting electrolyte. The method is based on the controlled anodic generation of active chlorine species, which selectively oxidize secondary alcohols to the corresponding ketones when primary hydroxy groups are present. The method has been demonstrated for a variety of substrates. The corresponding ketones were obtained in good to excellent yields. Moreover, the chloride salt can be easily recovered by a simple extraction procedure for reuse, rendering the method highly sustainable.

Continuous flow processing presents a solution for the safe and effective formation of 1,5-tetrazoles due to the small reactive inventory and absence of a reactor headspace. This has been exemplifi...

The oxidation of aldehydes is one of the most prevalent methods for the synthesis of a diverse range of carboxylic acids. We herein present a performic acid generator and its application for aldehy...

The pharmaceutical industry has begun incorporating continuous manufacturing technology in synthetic routes toward active pharmaceutical ingredients (APIs). The development of smart manufacturing routes can be accelerated by utilizing digitalization, process analytical technology (PAT), and data-rich experimentation from an early stage. Here, we present the key aspects of implementing automated flow chemistry reactor platforms with real-time process analytics. Based on our experiences in this field, we aim to highlight the potential of these platforms to conduct self-optimization, automated reaction model building, dynamic experiments and to implement advanced process control strategies

The development of a continuous-flow sequence for the synthesis of an important drug candidate precursor is reported. Abediterol is a β2-adrenoceptor agonist that has undergone phase IIa clinical t...

The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidation has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids. In addition, simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of saturated androgens.

In a rapidly changing environment, such as the current COVID-19 pandemic, continuous flow reactors bear the potential to increase the production of urgently needed active pharmaceutical ingredients (APIs) on demand In the synthesis of remdesivir, the organometallic C-glycosylation step was identified as a limitation for the large-scale production, requiring long addition periods and cryogenic temperatures Previous studies have focused on a Grignard-based protocol, but a flash chemistry approach, using organolithium reagents, has facilitated significant improvements After gaining further understanding of the C-glycosylation, this step was successfully transferred to a five-stream continuous flow process, achieving 60% yield at a moderate temperature (−30 °C) in a total residence time of just 8 s Stable processing was demonstrated for 2 h, providing an exceptionally high space−time yield of 10 4 kg L−1 h−1, in a scalable flow reactor system © XXXX American Chemical Society

N-Chloroamines have recently seen interest as substrates for atom-transfer radical addition (ATRA) reactions with olefins, to form β-chloroamine products, with complete atom incorporation. We report the development of a fully continuous method for N-chloroamine formation and photochemical reaction, utilizing membrane separation to purify the reactive intermediate species. Through detailed reaction optimization, supported by computational studies, we have determined that this type of reaction can be activated by direct substrate irradiation or via a range of triplet sensitizers at different wavelengths (up to 540 nm), allowing access to more favorable and sustainable reaction conditions. A number of substrates were reacted under sensitized or unsensitized conditions and the longer-term stability of the process was demonstrated in a 4.5 h experiment, achieving 94% yield and a throughput of 21.2 g h−1. This study serves to bring N-chloroamines to the fore as ATRA substrates, for implementation in efficient and sustainable synthetic routes.

Ozonolysis reactions are generally high-yielding, highly selective, and sustainable processes, especially when performed in green solvents. However, ozonolysis is underutilized in organic synthesis and chemical manufacture due to the safety concerns associated with handling ozone (O3) gas and the highly reactive ozonide intermediate. In this article, the development of ozonolysis reactions within a dedicated microreactor platform suitable for gas–liquid transformations is described. The optimization of the reaction conditions for the ozonolysis of cyclohexene to hexanedial, and thioanisole to methyl phenyl sulfoxide is presented. Cyclohexene is transformed to hexanedial in 94% yield at 0 °C within 1.7 seconds. In a similar fashion, the ozonolysis of thioanisole was achieved in 99% yield at 0 °C within

Metal oxides represent an abundant and non-toxic class of photocatalysts for organic transformations. However, their use in larger scale processes is complicated by incompatibilities with continuous flow processing – a proven scale-up route for photochemistry. We detail the development of an efficient atom transfer radical addition protocol using a sustainable solvent system (acetone : PEG 400) and a low loading (2 mol%) of Bi2O3, which can be handled in an oscillatory flow reactor. Optimization of the reaction and oscillatory parameters led to high throughput (36 g in 4 h, 89% yield, 599 g L−1 h−1), with a process mass intensity (PMI) of just 8.5. The process also facilitates high recyclability (3 cycles with no loss of yield), and was demonstrated to be applicable to a range of other substrates on multigram scale, in moderate to excellent yields.

Despite the fact that continuous flow processing exhibits well-established technical advances, aqueous micellar chemistry, a field that has proven extremely useful in shifting organic synthesis to sustainable water-based media, has mostly been explored under conventional batch-based conditions. This is particularly because of the fact that the reliable handling of slurries and suspensions in flow has been considered as a significant technical challenge. Herein, we demonstrate that the strategic application of an oscillatory plug flow reactor enables heterogeneous catalytic reductive aminations in aqueous micellar media enhancing mass transport and facilitating process simplicity, stability and scalability. The micellar flow process enabled a broad range of substrates, including amino acid derivatives, to be successfully transformed under reasonably mild conditions utilizing only very low amounts of Pd/C as a readily available heterogeneous catalyst. The preparative capabilities of the process along with the recyclability of the heterogenous catalyst and the aqueous reaction media were also demonstrated.

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 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 and metal-free organocatalysis to introduce asymmetry in continuously operated systems. Single-step processes, interrupted multistep flow syntheses, combined batch/flow processes and uninterrupted one-flow syntheses are discussed herein., This review surveys continuous flow approaches for the synthesis of chiral APIs and their advanced stereogenic intermediates, covering the utilization of biocatalysis, organometallic catalysis and metal-free organocatalysis to introduce asymmetry.

A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol-ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions using a low amount (0.1-0.5 mol %) of 9-fluorenone as the photocatalyst, leading to the corresponding half-mustard intermediate in quantitative yield. Thiomorpholine was subsequently obtained by base-mediated cyclization. The robustness of the process was demonstrated by performing the reaction for 7 h (40 min overall residence time), isolating the desired thiomorpholine via distillation.

A continuous flow procedure for the synthesis of aziridines from alkenes based on the in situ generation and utilization of bromodimethylsulfonium bromide (BDMS) is presented. In this process, BDMS was generated from hydrogen bromide and dimethylsulfoxide in the presence of the olefin, ensuing the corresponding 1,2-bromodimethylsulfonium bromide addition product. The solution containing this intermediate was mixed with a primary amine in flow, resulting in a rapid aziridination in a fast 3-step telescoped process. Notably, the exothermic formation of BDMS could be readily controlled in flow mode at room temperature, rendering a safe and reliable process. The complete sequence only required 7 min of total residence time, and provided a variety of 2-aryl aziridines in synthetically useful yields.

The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro...

The use of gases as reagents in organic synthesis can be very challenging, particularly at a laboratory scale. This Concept takes into account recent studies to make the case that gases can indeed be efficiently and safely formed from relatively inexpensive commercially available reagents for use in a wide range of organic transformations. In particular, we argue that the exploitation of continuous flow membrane reactors enables the effective separation of the chemistry necessary for gas formation from the chemistry for gas consumption, with these two stages often containing incompatible chemistry. The approach outlined eliminates the need to store and transport excessive amounts of potentially toxic, reactive or explosive gases. The on‐demand generation, separation and reaction of a number of gases, including carbon monoxide, diazomethane, trifluoromethyl diazomethane, hydrogen cyanide, ammonia and formaldehyde, is discussed., Go with the flow: Gas–liquid transformations are very important for organic synthesis. However, gases can be very challenging to use at laboratory scale. Continuous flow membrane reactors enable the safe on‐demand laboratory‐scale generation, separation, and reaction of gases without the need for distillation or gas cylinders.

The most challenging step in the preparation of many opioid antagonists is the selective N-demethylation of a 14-hydroxymorphinan precursor. This process is carried out on a large scale using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild reagent- and catalyst-free procedure for the N-demethylation step based on the anodic oxidation of the tertiary amine. The ensuing intermediates can be readily hydrolyzed to the target nor-opioids in very good yields.

Oscillatory flow reactors (OFRs) superimpose an oscillatory flow to the net movement through a flow reactor. OFRs have been engineered to enable improved mixing, excellent heat- and mass transfer and good plug flow character under a broad range of operating conditions. Such features render these reactors appealing, since they are suitable for reactions that require long residence times, improved mass transfer (such as in biphasic liquid-liquid systems) or to homogeneously suspend solid particles. Various OFR configurations, offering specific features, have been developed over the past two decades, with significant progress still being made. This review outlines the principles and recent advances in OFR technology and overviews the synthetic applications of OFRs for liquid-liquid and solid-liquid biphasic systems.

Although continuous flow technology can facilitate the scale-up of photochemical processes it is not yet routinely implemented on production scale in the fine chemical industries. This can be attri...

N‐Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable organophotocatalytic procedure that accomplishes the N‐demethylation step using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst. Optimization of the reaction conditions under continuous flow conditions using visible‐light irradiation led to an efficient, reliable, and scalable process, producing noroxycodone hydrochloride in high isolated yield and purity after a simple workup., A green and scalable organophotocatalytic procedure that accomplishes the N‐demethylation of oxycodone using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst is presented. Optimization of the reaction conditions under continuous flow conditions using visible‐light irradiation led to an efficient, reliable, and scalable process (see scheme).