An Automated Electrochemical Flow Platform to Accelerate Library Synthesis and Reaction Optimization.

Automated batch and flow reactors are well-established for high throughput experimentation in both thermal chemistry and photochemistry. However, the development of automated electrochemical platforms is hindered by cell miniaturization challenges in batch and difficulties in designing effective single-pass flow systems. In order to address these issues, we have designed and implemented a new, slug-based automated electrochemical flow platform. This platform was successfully demonstrated for electrochemical C-N cross-couplings of E3 ligase binders with diverse amines (44 examples), which were subsequently transferred to a continuous-flow mode for confirmation and isolation, showing its applicability for medicinal chemistry purposes. To further validate the versatility of the platform, Design of Experiments (DoE) optimization was performed for an unsuccessful library target. This optimization process, fully automated by the platform, resulted in a remarkable 6-fold increase in reaction yield.

Simultaneous reaction- and analytical model building using dynamic flow experiments to accelerate process development.

In modern pharmaceutical research, the demand for expeditious development of synthetic routes to active pharmaceutical ingredients (APIs) has led to a paradigm shift towards data-rich process development. Conventional methodologies encompass prolonged timelines for the development of both a reaction model and analytical models. The development of both methods are often separated into different departments and can require an iterative optimization process. Addressing this issue, we introduce an innovative dual modeling approach, combining the development of a Process Analytical Technology (PAT) strategy with reaction optimization. This integrated approach is exemplified in diverse amidation reactions and the synthesis of the API benznidazole. The platform, characterized by a high degree of automation and minimal operator involvement, achieves PAT calibration through a "standard addition" approach. Dynamic experiments are executed to screen a broad process space and gather data for fitting kinetic parameters. Employing an open-source software program facilitates rapid kinetic parameter fitting and additional in silico optimization within minutes. This highly automated workflow not only expedites the understanding and optimization of chemical processes, but also holds significant promise for time and resource savings within the pharmaceutical industry.

A robust heterogeneous chiral phosphoric acid enables multi decagram scale production of optically active N,S-ketals.

Asymmetric organocatalysis has been recognized as one of the "top 10 emerging technologies" in chemistry by IUPAC in 2019. Its potential to make chemical processes more sustainable is promising, but there are still challenges that need to be addressed. Developing new and reliable enantioselective processes for reproducing batch reactions on a large scale requires a combination of chemical and technical solutions. In this manuscript, we combine a robust immobilized chiral phosphoric acid with a new packed-bed reactor design. This combination allows scaling up of the enantioselective addition of thiols to imines from a few milligrams to a multi-decagram scale in a continuous flow process without physical or chemical degradation of the catalyst.

Preparation of Sulfonyl Chlorides by Oxidative Chlorination of Thiols and Disulfides using HNO3/HCl/O2 in a Flow Reactor.

A continuous flow metal-free protocol for the synthesis of sulfonyl chlorides from thiols and disulfides in the presence of nitric acid, hydrochloric acid and oxygen was developed. The influence of the reaction parameters was investigated under batch and flow conditions. Online 19F NMR was successfully implemented to investigate different reaction conditions within a single experiment. The sulfonyl chlorides were isolated (mostly in 70-81 % yield) after performing a simple aqueous washing procedure. In particular, the protocol was successfully operated for >6 hours to convert diphenyl disulfide to its corresponding sulfonyl chloride, achieving a throughput of 3.7 g h-1. The environmental impact of the protocol was assessed and compared to an existing continuous flow protocol using 1,3-dichloro-5,5-dimethylhydantoin (DCH) as reagent. The process mass intensity (PMI) for the newly-developed flow protocol (15) compared favorably to the DCH flow process (20).

A Slug Flow Platform with Multiple Process Analytics Facilitates Flexible Reaction Optimization.

Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low-volume optimization experiments are reported. A Buchwald-Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self-optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using <10% of the material that would be required for standard flow operation. Finally, a chemometric model is built utilizing automated data handling and three subsequent validation experiments demonstrate good agreement between the slug flow reactor and a standard (larger scale) flow reactor.

Application of an Oscillatory Plug Flow Reactor to Enable Scalable and Fast Reactions in Water Using a Biomass-Based Polymeric Additive.

The utilization of water as a sustainable reaction medium has important advantages over traditional organic solvents. Hydroxypropyl methylcellulose has emerged as a biomass-based polymeric additive that enables organic reactions in water through hydrophobic effects. However, such conditions imply slurries as reaction mixtures, where the efficacy of mass transfer and mixing decreases with increasing vessel size. In order to circumvent this limitation and establish an effectively scalable platform for performing hydroxypropyl methylcellulose-mediated aqueous transformations, we utilized oscillatory plug flow reactors that feature a smart dimensioning design principle across different scales. Using nucleophilic aromatic substitutions as valuable model reactions, rapid parameter optimization was performed first in a small-scale instrument having an internal channel volume of 5 mL. The optimal conditions were then directly transferred to a 15 mL reactor, achieving a three-fold scale-up without re-optimizing any reaction parameters. By precisely fine-tuning the oscillation parameters, the system achieved optimal homogeneous suspension of solids, preventing settling of particles and clogging of process channels. Ultimately, this resulted in a robust and scalable platform for performing multiphasic reactions under aqueous conditions.

The Rocky Road to a Digital Lab.

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.

Electrifying Friedel-Crafts Intramolecular Alkylation toward 1,1-Disubstituted Tetrahydronaphthalenes.

In this work, we successfully employed electrochemical conditions to promote a Hofer-Moest, intramolecular Friedel-Crafts alkylation sequence. The reaction proceeds under mild conditions, employing carboxylic acids as starting materials. Notably, the electrochemical process performed in batch was adapted to a continuous flow electrolysis apparatus to provide a significant improvement. This catalyst-free, electrochemical approach produces an array of tetrahydronaphthalenes that could be used for API synthesis.

A Telescoped Continuous Flow Enantioselective Process for Accessing Intermediates of 1-Aryl-1,3-diols as Chiral Building Blocks.

A telescoped continuous flow process is reported for the enantioselective synthesis of chiral precursors of 1-aryl-1,3-diols, intermediates in the synthesis of ezetimibe, dapoxetine, duloxetine, and atomoxetine. The two-step sequence consists of an asymmetric allylboration of readily available aldehydes using a polymer-supported chiral phosphoric acid catalyst to introduce asymmetry, followed by selective epoxidation of the resulting alkene. The process is highly stable for at least 7 h and represents a transition-metal free enantioselective approach to valuable 1-aryl-1,3-diols.

Metal-Free Electrochemical Reduction of Disulfides in an Undivided Cell under Mass Transfer Control.

Electroorganic synthesis is generally considered to be a green alternative to conventional redox reactions. Electrochemical reductions, however, are less advantageous in terms of sustainability, as sacrificial metal anodes are often employed. Divided cell operation avoids contact of the reduction products with the anode and allows for convenient solvent oxidation, enabling metal free greener electrochemical reductions. However, the ion exchange membranes required for divided cell operation on a commercial scale are not amenable to organic solvents, which hinders their applicability. Herein, we demonstrate that electrochemical reduction of oxidatively sensitive compounds can be carried out in an undivided cell without sacrificial metal anodes by controlling the mass transport to a small surface area electrode. The concept is showcased by an electrochemical method for the reductive cleavage of aryl disulfides. Fine tuning of the electrode surface area and current density has enabled the preparation of a wide variety of thiols without formation of any oxidation side products. This strategy is anticipated to encourage further research on greener, metal free electrochemical reductions.

Electrochemical Nickel-Catalyzed C(sp3)-C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates.

Formation of new C(sp3)-C(sp3) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp3)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates. Selective cross-coupling transformations were achieved even between C(sp3)-secondary bromides and tosylates. Key to achieve high selectivity was the combination of the tosylates with sodium bromide as the supporting electrolyte, gradually generating small amounts of the more reactive bromide by substitution and ensuring that one of the reaction partners in the nickel-catalyzed electroreductive process is maintained in excess during a large part of the process. The method has been demonstrated for a wide range of substrates (>30 compounds) in moderate to good yields. Further expanding the scope of electroorganic synthesis to C(sp3)-C(sp3) cross-coupling reactions is anticipated to facilitate the switch to green organic synthesis and encourage future innovative electrochemical transformations.

Rediscovering Cyanogen Gas for Organic Synthesis: Formation of 2-Cyanothiazole Derivatives.

The expeditious synthesis of an API building block, 2-cyanothiazole, from cyanogen gas and a readily available dithiane is reported. A previously undisclosed partially saturated intermediate is formed, which can be further functionalized and isolated by the acylation of the hydroxy group. Dehydration using trimethylsilyl chloride furnished 2-cyanothiazole, which could be further converted to the corresponding amidine. The sequence provided a 55% yield over 4 steps. We envision that this work will spark further interest in cyanogen gas as a reactive and cost-effective synthetic reagent.

Continuous-Flow Synthesis of Δ9-Tetrahydrocannabinol and Δ8-Tetrahydrocannabinol from Cannabidiol.

A challenging step in the preparation of tetrahydrocannabinol analogs is an acid-catalyzed intramolecular cyclization of the cannabidiol precursor. This step typically affords a mixture of products, which requires extensive purification to obtain any pure products. We report the development of two continuous-flow protocols for the preparation of (-)-trans-Δ9-tetrahydrocannabinol and (-)-trans-Δ8-tetrahydrocannabinol.

Harnessing a Continuous-Flow Persulfuric Acid Generator for Direct Oxidative Aldehyde Esterifications.

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.

Merger of Visible Light-Driven Chiral Organocatalysis and Continuous Flow Chemistry: An Accelerated and Scalable Access into Enantioselective α-Alkylation of Aldehydes.

The electron donor-acceptor complex-enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α-alkylated aldehydes without an external photoredox catalyst. The photosensitizer-free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales. Inspired by these limitations, a protocol was developed for the enantioselective α-alkylation of aldehydes based on the synergistic combination of visible light-driven asymmetric organocatalysis and a controlled continuous flow reaction environment. With the aim to reduce process costs, a commercially available chiral catalyst has been exploited to achieve photosensitizer-free enantioselective α-alkylations using phenacyl bromide derivates as alkylating agents. As a result of elaborate optimization and process development, the present flow strategy furnishes an accelerated and inherently scalable entry into enantioenriched α-alkylated aldehydes including a chiral key intermediate of the antirheumatic esonarimod.

Synthesis of Thiomorpholine via a Telescoped Photochemical Thiol-Ene/Cyclization Sequence in Continuous Flow.

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.

Photochemical Deracemization of a Medicinally-Relevant Benzopyran using an Oscillatory Flow Reactor.

Dynamic deracemization processes, such as crystallization-induced diastereomer transformations (CIDTs), offer the opportunity to combine racemization and resolution processes, to provide high yields of enantiomerically pure compounds. To date, few of these processes have incorporated photochemical racemization. By combining batch crystallization with a flow photoreactor for efficient irradiation, it is possible to perform such deracemization in an effective, scalable and high yielding manner. After applying design of experiment (DoE) principles and mathematical modelling, the most efficient parameter set could be identified, leading to excellent results in just 4 h reaction time: isolated yield of 82 % and assay ee of 96 %. Such photochemical racemization methods can serve to open new avenues for preparation of enantiomerically pure functional molecules on both small and industrially-relevant scales.

Autonomous Multi-Step and Multi-Objective Optimization Facilitated by Real-Time Process Analytics.

Autonomous flow reactors are becoming increasingly utilized in the synthesis of organic compounds, yet the complexity of the chemical reactions and analytical methods remains limited. The development of a modular platform which uses rapid flow NMR and FTIR measurements, combined with chemometric modeling, is presented for efficient and timely analysis of reaction outcomes. This platform is tested with a four variable single-step reaction (nucleophilic aromatic substitution), to determine the most effective optimization methodology. The self-optimization approach with minimal background knowledge proves to provide the optimal reaction parameters within the shortest operational time. The chosen approach is then applied to a seven variable two-step optimization problem (imine formation and cyclization), for the synthesis of the active pharmaceutical ingredient edaravone. Despite the exponentially increased complexity of this optimization problem, the platform achieves excellent results in a relatively small number of iterations, leading to >95% solution yield of the intermediate and up to 5.42 kg L-1 h-1 space-time yield for this pharmaceutically relevant product.

Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence Using in Situ-Generated Persulfuric Acid as Oxidant.

A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asymmetric conjugate addition-oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group reduction and concomitant lactamization. The telescoped process takes advantage of a polystyrene-supported chiral organocatalyst along with in situ-generated persulfuric acid as a robust and scalable oxidant for direct aldehyde esterification. This approach demonstrates significantly improved productivity compared with earlier methodologies while ensuring environmentally benign metal-free conditions.