Flow Chemistry

An improved, safe, and scalable isolation process for (substituted) pyridine and quinoline N-oxides in quantitative yields along with high purities using the m-CPBA−NH 3 (g) system is described. The safety was assessed by reaction calorimetry and differential scanning calorimetry studies for possible hazards during the conversion and isolation steps. Careful interpretation of the data substantiated the safety and scalability. The process flow is simplified to meet the industrial requirements of safety, cost-effectiveness, and utility minimization. The reaction was safely demonstrated at a 2.5 kg scale.

Pharmaceutical manufacturing typically uses batch processing at multiple locations.
Disadvantages of this approach include long production times and the potential for supply
chain disruptions. As a preliminary demonstration of an alternative approach, we report
here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in
a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in
the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)]
system produces sufficient quantities per day to supply hundreds to thousands of oral or
topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam,
and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this
flexible plug-and-play approach are substantial enabling advances in continuous-flow
synthesis, complex multistep sequence telescoping, reaction engineering equipment, and
real-time formulation.

Many attempts to obtain a clean stream of COF2 have been carried out in the past by means of the direct fluorination of carbon monoxide with elemental fluorine or by electrochemical fluorination. The reaction is highly exothermic, therefore difficult to control. It can easily develop into a thermal runaway with a poor selectivity. We have successfully circumvented these critical issues by using a stainless steel parallel channel microreactor (surface/volume ratio ≈ 1 × 104 m−1, residence time τ ≈ 0.1 s) for the direct fluorination of carbon monoxide. Its performance in terms of operability and selectivity is compared to that of a standard reactor assembly, namely a fluorine burner reactor coupled with a water cooled heat exchanger. While the microreactor assembly succeeded to control the exothermic reaction, in the same experimental conditions the standard assembly reactor underwent serious corrosion issues that lead to nozzle meltdown lack of selectivity and consequent plant shutdowns.

Continuous-flow chemistry has recently attracted significant interest from chemists in both academia and industry working in different disciplines and from different backgrounds. Flow methods are now being used in reaction discovery/methodology, in scale-up and production, and for rapid screening and optimization. Photochemical processes are currently an important research field in the scientific community and the recent exploitation of flow methods for these methodologies has made clear the advantages of flow chemistry and its importance in modern chemistry and technology worldwide. This review highlights the most important features of continuous-flow technology applied to photochemical processes and provides a general perspective on this rapidly evolving research field.

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

Continuous flow chemistry holds great potential for the production of biologically relevant molecules. Herein, we present an approach for the continuous synthesis of cannabidiol and tetrahydrocannabinol in a one-flow system. The designed route consists of a reaction cascade involving Friedel-Crafts alkylation, subsequent ring opening and cyclisation in up to 45% yield. The reactions were successfully performed using both hetero- and homogeneous Lewis acids in continuous flow and provide yields that are similar to comparable batch processes. Graphical abstract

The syntheses of various pyrimidinones as potentially bioactive products by means of the highly controlled continuous-flow retro-
Diels–Alder reaction of condensed pyrimidinone derivatives are presented. Noteworthy, the use of this approach allowed us to
rapidly screen a selection of conditions and quickly confirm the viability of preparing the desired pyrimidinones in short reaction
times. Yields typically higher than those published earlier using conventional batch or microwave processes were achieved.

As 3D printing technologies become more accessible, chemists are beginning to design and develop their own bespoke printable devices particularly applied to the field of flow chemistry. Designing functional flow components can often be a lengthy and laborious process requiring complex 3D modelling and multiple design iterations. In this work, we present an easy to follow design workflow for minimising the complexity of this design optimization process. The workflow follows the development of a 3D printable ‘toolkit’ of common fittings and connectors required for constructing basic flow chemistry configurations. The toolkit components consist of male threaded nuts, junction connectors and a Luer adapter. The files have themselves been made freely available and open source. The low cost associated with the toolkit may encourage educators to incorporate flow chemistry practical work into their syllabus such that students may be introduced to the principles of flow chemistry earlier on ...

Dialkyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates have been prepared in a batch mode under conventional heating as well as under continuous flow conditions in the Miniflow 200SS, Sairem's microwave-assisted batch and continuous flow equipment. Real-time monitoring of the reactions by Raman spectroscopy enabled to compare both heating modes and to determine (optimized) reaction times.

This paper reports a new continuous-flow synthesis of chiral and achiral pyridino-18-crown-6 ethers. Macrocyclizations have been performed in a packed-bed flow reactor where deprotonation of a bifunctional primary or a secondary alcohol takes place with potassium hydroxide as a heterogeneous base avoiding the use of stronger and more dangerous one, sodium hydride. Ditosylate derivatives of pyridine as precursors for the macrocyclization used in batch condition were replaced by the appropriate diiodides and optimization of the parameters provided higher yields in shorter reaction times. The setup presented here is suitable for the preparation of different ethers by Williamsontype syntheses in continuous-flow reactions.

Tetrabutylammonium decatungstate (TBADT) has emerged as an efficient and versatile photocatalyst for hydrogen atom transfer (HAT) processes that enables the cleavage of both activated and unactivated aliphatic C−H bonds. Using a recently developed oscillatory millistructured continuous-flow photoreactor, investigations of a decatungstate-catalyzed C(sp 3)−H alkylation protocol were carried out, and the results are presented here. The performance of the reactor was evaluated in correlation to several chemical and process parameters, including residence time, light intensity, catalyst loading, and substrate/reagent concentration. In comparison with previously reported batch and flow protocols, conditions were found that led to considerably higher productivity, achieving a throughput up to 36.7 mmol/h with a residence time of only 7.5 min.