Berthold Schenkel

Flow Chemistry Syntheses of Styrenes, Unsymmetrical Stilbenes and Branched Aldehydes

Two tandem flow chemistry processes have been developed. A single palladium‐catalysed Heck reaction with ethylene gas provides an efficient synthesis for functionalised styrenes. Through further elaboration the catalyst becomes multi‐functional and performs a second Heck reaction providing a single continuous process for the synthesis of unsymmetrical stilbenes. In addition, the continuous, rhodium‐catalysed, hydroformylation of styrene derivatives with syngas affords branched aldehydes with good selectivity. Incorporation of an in‐line aqueous wash and liquid–liquid separation allowed for the ethylene Heck reaction to be telescoped into the hydroformylation step such that a single flow synthesis of branched aldehydes directly from aryl iodides was achieved. The tube‐in‐tube semi‐permeable membrane‐based gas reactor and liquid–liquid separator both play an essential role in enabling these telescoped flow processes.

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross-Couplings in Flow

Abstract We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp2)–C(sp3) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2)–C(sp3) coupling method using boronic esters and cyano heteroarenes under flow conditions.

Toolbox study for application of hydrogen peroxide as a versatile, safe and industrially-relevant green oxidant in continuous flow mode

Hydrogen peroxide embodies an ideal oxidant in terms of atom-economy, availability and green metrics. However, its use has been limited because of risks associated with disproportionation and the exothermic potential of oxidizing reaction mixtures. This study aims to showcase the versatility of hydrogen peroxide in a range of oxidations, while ensuring that such processes operate practically and with a defined and minimized risk. To offset the hazards of using peroxides, continuous-flow equipment was utilized to limit the volume of unquenched peroxides and to maintain process control. A methodological approach was established relying on kinetic and calorimetric understanding. Finally, scalability was highlighted in an organocatalysed heterocyclic N-oxidation using a cascade of stirred tank reactors with nitrogen flushing.

Control of Hazardous Processes in Flow: Synthesis of 2-Nitroethanol

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.

Dichloromethyllithium: Synthesis and Application in Continuous Flow Mode

A simple and robust procedure for the synthesis and use of thermally unstable dichloromethyllithium in continuous flow mode is described. By utilizing residence times in the range of milliseconds for the generation and electrophilic quench of dichloromethyllithium, the straightforward synthesis of dichlorocarbinols and benzylic pinacol esters was realized at reaction temperatures of -30 °C, whereas typical temperatures in traditional batch mode are below -78 °C. The excellent purity profile obtained from the flow process allows us to directly telescope the exiting flow stream into semibatch quenches for further modifications. All transformations gave the desired products in remarkable purity and yield on gram scale with no need for chromatography.

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.

Design of chromatographic separations on reversed phase

The accurate determination of adsorption isotherms is of key importance in the design and optimization of preparative chromatographic bulk separations and purifications. Issues to be considered involve other things: limited amount of test material, particularly in the case of the development of drugs; multicomponent mixture with widely different concentration levels of the main product and of the impurities. In this work, a rational procedure for the characterization of adsorption equilibria in reversed phase chromatography is proposed. This is applied to two different model separations, both involving an ascomycin derivative of industrial interest. The procedure is based on the peak fitting method and the use of a lumped pore diffusion model to simulate column dynamics. The accuracy of the obtained results is assessed thoroughly.

Modeling of the Chromatographic Solvent Gradient Reversed Phase Purification of a Multicomponent Polypeptide Mixture

Abstract A model for Calcitonin purification from an industrial peptide mixture using polymer‐based reversed phase columns was developed. Regressed competitive bi‐Langmuir isotherm parameters for pure calcitonin are strong functions of the eluent composition and were correlated to the overall Henry coefficient only. It is shown that, by keeping constant these correlations, the adsorption behavior of impurities can be predicted simply by estimating their Henry coefficient from the raw mixture. The same can be repeated with very good results when changing the stationary phase or the organic solvent in the eluent. In both cases, only the Henry coefficient must be re‐estimated from pulse injections.

Catalytic hydrogenation of N -4-nitrophenyl nicotinamide in a micro-packed bed reactor

Recent advancements in micro-flow technologies and a drive toward more efficient, greener and safer processes have led to a renaissance in flow-chemistry for pharmaceutical production. In this work, we demonstrate the use of a stabilized Pd nanoparticle-organic-silica catalyst to selectively catalyze the hydrogenation of N-4-nitrophenyl nicotinamide, a functionalized active pharmaceutical ingredient (API) surrogate. Extensive catalyst and reactor characterization is provided to establish an in-depth understanding of the unique multiphase dynamics within the micro-packed bed reactor, including the identification of a large liquid holdup (74–84%), rapid multiphase mass transfer (kma > 1 s−1), and liquid residence time distributions. A kinetic analysis has revealed that the surface catalyzed hydrogenation progresses through a condensation mechanism whereby an azo dimer intermediate is formed and rapidly consumed. Finally, a parametric study was performed at various pressures, temperatures, residence times and flow regimes to achieve quantitative chemoselective conversion of the nitroarene to the corresponding primary amine.

The scale-up of continuous biphasic liquid/liquid reactions under super-heating conditions: methodology and reactor design

Biphasic liquid/liquid reactions are commonplace, however their scale-up under super-heating conditions is not. Even more challenging efforts have to be expected in the case of a large scale continuous production process, which also includes the development at a lab scale, the selection and design of the continuous reaction equipment. However, by running chemistry above the boiling point of the solvent, the solvent selection can be widened to include green solvents and continuous processing guarantees a limited and safe footprint. Herein is reported a systematic methodology for the development and scale-up of a biphasic reaction under super-heating conditions, as well as the design of a continuous reactor column suitable for handling such conditions. Taking the alkylation of benzylamine with 1,5-dibromopentane as a model reaction, kinetic determination and fluid dynamic characterization of the biphasic media have been instrumental for a successful scale-up concept which was proven in a custom-made hastelloy reactor column.