SYNTHESIS
1) Selective Hydrogenation Reaction: Utilizing a Microreactor for Continuous Flow Synthesis of Nickel Nanoparticles
Introduction: In this investigation, we employed a continuous flow reactor to synthesize nickel (Ni) nanoparticles exhibiting uniform size distribution and excellent stability. Our focus centered on exploring the impact of reactant dilution and flow rate on the synthesis process.
Result: It was observed that the optimization of these parameters played a pivotal role in obtaining small-sized Ni nanoparticles. Specifically, we achieved successful synthesis using a solution of 0.00025 M NiCl2·6H2O and 0.002 M NaBH4, with a flow rate of 25 mL/h. The resulting Ni nanoparticles were effectively coated with the CTAB surfactant, as confirmed through thorough analysis using TEM and PSD techniques. Additionally, the interaction between the surfactant and nanoparticles was verified via FTIR analysis. We subjected them to high-pressure alkene hydrogenation to assess the catalytic activity of the synthesized Ni nanoparticles.
Method: Encouragingly, the Ni nanoparticles exhibited excellent performance, producing hydrogenated products with high yields. Moreover, we capitalized on Ni nanoparticles’ catalytic effect for synthesizing two natural compounds, brittonin A and dehydrobrittonin A. Remarkably, both compounds were successfully isolated in quantifiable yields. This synthesis protocol boasted several advantages, including low catalyst loading, omission of additives, broad substrate scope, straightforward product separation, and the ability to recover the catalyst up to eight times. In summary, this study effectively showcased the potential of continuous flow reactor technology in synthesizing stable and uniformly distributed nanoparticles.
Conclusion: Additionally, it highlighted the effectiveness of Ni nanoparticles as catalysts in various chemical reactions. The findings from this study hold significant implications for developing more efficient and sustainable chemical synthesis protocols.
Reference: Srivastava V. Selective hydrogenation reaction: utilizing a microreactor for continuous flow synthesis of nickel nanoparticles. Letters in Organic Chemistry [Internet]. 2024 Feb 23;21
doi: 10.2174/0115701786268828240119105533 (https://www.eurekaselect.com/article/138730)
2) Flow Chemistry for Synthesis of 2-(C-Glycosyl)acetates from Pyranoses via Tandem Wittig and Michael Reactions
C-Glycosyl compounds (C-glycosides) are a class of saccharide derivatives with improved stability over their O-linked counterparts. This paper reports the synthesis of several trans-2-(C-glycosyl)acetates via a tandem Wittig-Michael reaction from pyranoses (cyclic hemiacetals) using continuous flow processing, which gave improvements compared to reactions conducted in round-bottom flasks. Products were isolated in yields of >60% from reactions of benzyl-protected xylopyranoses, glucopyranoses, and galactopyranoses at higher temperatures and pressures, which were superior to yields from batch procedures. A two-step procedure involving the Wittig reaction followed by Michael reaction (intramolecular oxa-Michael) of the unsaturated ester obtained in the presence of DBU was developed. Reactions of protected mannopyranose gave low yields in corresponding reactions in flow due to competing C-2 epimerization.
Reference: Bennett JJ, Murphy PV. Flow Chemistry for Synthesis of 2-(C-Glycosyl)acetates from Pyranoses via Tandem Wittig and Michael Reactions. Org Process Res Dev. 2024 Feb;28(5):1848-1859. (https://pubmed.ncbi.nlm.nih.gov/38783857/)
3) Photo-induced synthesis of polymeric nanoparticles and chemiluminescent degradable materials via flow chemistry
We report the photo-induced, additive-free, continuous synthesis of polymeric particles using flow chemistry. Not only can these particles be formed under ambient conditions in a solely light-induced precipitation polymerisation, they can be prepared via continuous flow techniques to up-scale the synthetic process. We carefully assess the flow chemical parameters and analyse the resulting particles quantitatively using scanning electron microscopy (SEM). Particle formation is a direct result of the step-growth polymerisation via a photochemically induced AA + BB Diels-Alder reaction, which we herein base on the dialdehyde monomer (AA) derived from the sustainable precursor, thymol. By employing a peroxyoxalate bismaleimide (BB), we introduce particles that can be selectively degraded on-demand, self-reported by light emission through chemiluminescence.
Reference: Holloway JO, Delafresnaye L, Cameron EM, Kammerer JA, Barner-Kowollik C. Photo-induced synthesis of polymeric nanoparticles and chemiluminescent degradable materials via flow chemistry. Mater Horiz. 2024 Jul;11(13):3115-3126.
(https://pubmed.ncbi.nlm.nih.gov/38595068/)
4) 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.
Reference: Bassetti B, Hone CA, Kappe CO. Continuous-Flow Synthesis of Δ9-Tetrahydrocannabinol and Δ8-Tetrahydrocannabinol from Cannabidiol. J Org Chem. 2023;88(9):6227-6231. doi:10.1021/acs.joc.3c00300 (https://pubmed.ncbi.nlm.nih.gov/37014222/)
SCALE-UP
1) A Flow Chemistry Platform for Photochemical Macrocyclization of Peptides
The importance of macrocyclic peptides in drug discovery has spawned a variety of modern techniques to improve their synthesis. Although photocatalysis is now an indispensable tool in the synthesis of natural products and pharmaceuticals, it is rarely exploited in macrocyclization. Photochemical macrocyclization remains rare and is hampered by challenges in efficiency and scale-up. A “hybrid” reactor that incorporates aspects of plug flow and continuously stirred tank reactor systems is reported, which allows for slow addition strategies typically associated with batch processes. Via efficient light penetration, mixing, and gas manipulation, a macrocyclic aerobic oxidative coupling of thiols employing low catalyst loadings (1 mol %) was developed to access a variety of peptidic macrocycles on preparative scales. Preparation of “macromulticycles” was also demonstrated. The hybrid reactor outperformed existing technologies and permitted rare gram-scale photochemical macrocyclization.
Reference: Morin É, Neiderer W, Cruché C, Bleton O, Cave C, Collins SK. A flow chemistry platform for photochemical macrocyclization of peptides. ACS Sustainable Chemistry & Engineering [Internet]. 2024 Apr 10;12(16):6433–9.
(https://pubs.acs.org/doi/abs/10.1021/acssuschemeng.4c01441)
2) Pilot-Scale Operation and Characterization of an Organolithium-Mediated Coupling Reaction in Flow to Form a Ketone Intermediate on the Route to Nemtabrutinib
In one of the two penultimate steps in the commercial route to nemtabrutinib, a ketone intermediate is formed from 7-bromo-6-chloro-7-deazapurine and methyl 2-chloro-4-phenoxybenzoate in a series of reactions mediated by methyllithium and n-butyllithium. Flow chemistry was identified in development as a useful tool for safe and efficient scale-up for two of these reactions while minimizing the formation of unwanted impurities. Here, we present the first pilot-scale implementation of the process where a tubular flow reactor was employed to produce multiple kilograms of the ketone intermediate. Practical considerations for large-scale operations are discussed, including operation at low temperatures around −30 °C, stable and consistent control of flow rates, and planning for the prevention of and recovery from upset scenarios. Careful design and construction of equipment and procedures allowed for the successful execution of five pilot-scale batches with consistent yield and product quality to produce material needed for clinical development. Across the campaign, average isolated yield for the process was approximately 65%, with an average purity of 99.9% by weight. Also presented are the findings from a series of large-scale flow experiments, where temperature, residence time, and reaction stoichiometry were simultaneously varied to assess process robustness. In these experiments, n-butyllithium stoichiometry was found to have the greatest impact on reaction yield, as measured by product LC area percent. Additionally, the process impurities studied were each sensitive to a different combination of the varied parameters. Learnings from this pilot campaign were critical to guide future development efforts en route to a potential commercial supply of nemtabrutinib.
Reference: Robert D. Franklin, et al. Pilot-Scale Operation and Characterization of an Organolithium-Mediated Coupling Reaction in Flow to Form a Ketone Intermediate on the Route to Nemtabrutinib. Organic Process Research & Development 2024;28(5):1411-1421 (https://pubs.acs.org/doi/abs/10.1021/acs.oprd.3c00395)
3) A Scalable Solution to Constant-Potential Flow Electrochemistry
The burgeoning interest in new electrochemical methods holds promise to provide a plethora of strategic disconnections for pharmaceutical compounds that are safer, less wasteful, and more streamlined than traditional chemical strategies. The use of organic electrochemistry in the commercial production of pharmaceuticals is exceedingly rare due to the lack of a modular infrastructure. Herein we describe the use of cascading continuous stirred tank reactors with individual cell potential control applied over reaction “stages” which demonstrate a balance between high selectivity and throughput necessary for electrochemistry to be a viable strategy in the pharmaceutical space. Using the high degree of control of cell potential afforded by this reactor design, a 1 kg demonstration was achieved in 9 h with high selectivity and yield (2.6 kg/day throughput).
Reference: Griffin JD, Harper KC, Morales SV, Morrill WH, Thornton WI, Sutherland D, et al. A scalable solution to Constant-Potential flow electrochemistry. Organic Process Research & Development [Internet]. 2024;28(5):1877–85. Available from: https://doi.org/10.1021/acs.oprd.3c00432 (https://pubs.acs.org/doi/abs/10.1021/acs.oprd.3c00432)
QUALITY ANALYSIS
1) Automated quality analysis in continuous downstream processes for small-scale applications
Development of integrated, continuous biomanufacturing (ICB) processes brings along the challenge of streamlining the acquisition of data that can be used for process monitoring, product quality testing and process control. Manually performing sample acquisition, preparation, and analysis during process and product development on ICB platforms requires time and labor that diverts attention from the development itself. It also introduces variability in terms of human error in the handling of samples. To address this, a platform for automatic sampling, sample preparation and analysis for use in small-scale biopharmaceutical downstream processes was developed. The automatic quality analysis system (QAS) consisted of an ÄKTA Explorer chromatography system for sample retrieval, storage, and preparation, as well as an Agilent 1260 Infinity II analytical HPLC system for analysis. The ÄKTA Explorer system was fitted with a superloop in which samples could be stored, conditioned, and diluted before being sent to the injection loop of the Agilent system. The Python-based software Orbit, developed at the department of chemical engineering at Lund university, was used to control and create a communication framework for the systems.
To demonstrate the QAS in action, a continuous capture chromatography process utilizing periodic counter-current chromatography was set up on an ÄKTA Pure chromatography system to purify the clarified harvest from a bioreactor for monoclonal antibody production. The QAS was connected to the process to collect two types of samples: 1) the bioreactor supernatant and 2) the product pool from the capture chromatography. Once collected, the samples were conditioned and diluted in the superloop before being sent to the Agilent system, where both aggregate content and charge variant composition were determined using size-exclusion and ion-exchange chromatography, respectively. The QAS was successfully implemented during a continuous run of the capture process, enabling the acquisition of process data with consistent quality and without human intervention, clearing the path for automated process monitoring and data-based control.
Reference: Tallvod S, Espinoza D, Gomis-Fons J, Andersson N, Nilsson B. Automated quality analysis in continuous downstream processes for small-scale applications. Journal of Chromatography a/Journal of Chromatography [Internet]. 2023;1702:464085. (https://www.sciencedirect.com/science/article/pii/S0021967323003114)
2) 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.
Reference: Sagmeister P, Williams JD, Kappe CO. The Rocky Road to a Digital Lab. Chimia (Aarau). 2023;77(5):300-306. Published 2023 May 31. doi:10.2533/chimia.2023.300 (https://pubmed.ncbi.nlm.nih.gov/38047825/)
CRISTALLIZATION
1) Covalent organic framework crystallization using a continuous flow packed-bed reactor
Flow systems enable in-line synthesis and processing of organic materials in a continuous reaction pathway, which is advantageous for high-throughput and scale-up. In this work, a highly crystalline TAPB-OHPDA covalent organic framework (COF) was directly crystallized under continuous flow conditions in as little as 30 minutes. Brunauer–Emmett–Teller (BET) surface analysis reveals high surface areas greater than 1700 m2 g−1 can be afforded in 2 hours, resulting in a 36× faster processing time compared to a majority of other reported solvothermal methods. Additionally, the crystalline COF material was also washed with solvent in flow to reduce the required post-processing burden typically performed iteratively during purification and activation. The results presented herein provide foundational knowledge for COF syntheses under packed-bed flow conditions and reveal an opportunity to accelerate the formation and processing of highly crystalline COF materials.
Reference: Bhagwandin DD, Dunlap JH, Tran LD, Reidell A, Austin D, Putnam-Neeb AA, et al. Covalent organic framework crystallization using a continuous flow packed-bed reactor. CrystEngComm. 2024;26(1):27–31.(https://pubs.rsc.org/en/content/articlehtml/2023/ce/d3ce01030a)
2) Loop-Configuration for Plug Flow Crystallization Process Development
Continuous crystallization plays a pivotal role in the transition to continuous manufacturing that the pharmaceutical industry is currently undertaking. Alas, the development of a continuous crystallization process using data from continuous operation is prohibitively material-intensive. Given the state of control nature of the continuous formalism, experimental design spaces entail several experiments, in which up to ten residence times are required to assess an experimental condition at steady state. Furthermore, transferring batch kinetics determined from batch experiments to a continuous crystallizer, despite being common practice, adds undesirable uncertainty to the development endeavors due to equipment-dependent mass and heat transfer. In this work, we present a novel configuration of a tubular crystallizer, capable of characterizing a system with a few experiments, curbing the reactor footprint, and abating the development’s raw material requirements. A stream of crystallizing material, flowing inside a tubular crystallizer equipped with Kenics static mixers, was fully recirculated, implementing a looped plug flow configuration, and its evolution was monitored in-line continuously by means of in situ Process Analytical Technologies. This allows effective mimicking of long residence times (which correspond to large process volumes) in a short plug flow crystallizer while maintaining plug flow conditions and screening a process from nucleation to equilibrium. Computational fluid dynamics simulations supported the assumption of negligible back mixing and aided the comparison of the mixing with that of a cascade of continuous stirred tank reactors. The use of the novel configuration is showcased for the antisolvent crystallizations of ketoconazole, azithromycin, and glycine. Using this approach, we show reductions in raw material requirements from 50 to 98%, compared with an equivalent standard plug flow crystallizer. Naturally, the configuration can also be employed for manufacturing in a semicontinuous manner.
Reference: Aprile G, Pandit AV, Albertazzi J, Eren A, Capellades G, Thorat AA, et al. Loop-Configuration for plug flow crystallization process development. Crystal Growth & Design. 2023;23(11):8052–64 (https://pubs.acs.org/doi/abs/10.1021/acs.cgd.3c00819)
Notes
(1) Noel T, Capaldo L, Wen Z. A field guide to flow chemistry for synthetic organic chemists. Chemical Science [Internet]. 2023 Jan 1;14(16):4230–47.
