Flash Chemistry Approach to Organometallic C-Glycosylation for the Synthesis of RemdesivirClick to copy article linkArticle link copied!
- Timo von KeutzTimo von KeutzCenter for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, AustriaMore by Timo von Keutz
- Jason D. Williams*Jason D. Williams*Email: [email protected]Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, AustriaMore by Jason D. Williams
- C. Oliver Kappe*C. Oliver Kappe*Email: [email protected]Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, AustriaMore by C. Oliver Kappe
Abstract
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.
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License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
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License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
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Introduction
Scheme 1
aScheme showing the C-glycosylation of pyrrolotriazinamine 1/1a with lactone 2 to furnish key intermediate 3 as part of the synthesis of remdesivir (4). The different literature approaches using Grignard or organolithium chemistry are highlighted.
bReproduction of published organolithium procedure, (11) focusing on the intermediates formed and any potential obstacles to developing a continuous flow process.
Results and Discussion
Investigation of the C-Glycosylation Process
Initial Continuous Flow Process

entry | temp. [°C] | protonated heterocycle 1-H [%]a | desired product 3 [%]a |
---|---|---|---|
1 | –40 | 21 | 54 |
2b | –40 | 24 | 56 |
3c | –40 | 19 | 31 |
4d | –40 | 18 | 56 |
5e | –40 | 20 | 54 |
6 | –50 | 21 | 56 |
7 | –30 | 19 | 54 |
8 | –20 | 24 | 50 |
Experiments were performed in Ehrfeld FlowPlate using the following flow rates: 1 (4.11 mL/min, 1.0 equiv), BCDSE (0.452 mL/min 1.1 equiv), LDA (0.411 mL/min, 1.0 equiv), n-BuLi (0.848 mL/min 3.3 equiv), and 2 (0.822 mL/min, 2.0 equiv). HPLC yield versus biphenyl as an internal standard.
Flow rates ×1.5 compared to entry 1.
Flow rates ×0.5 compared to entry 1.
Additional capillary reactor (4 mL, −40 °C) after FlowPlate.
Additional capillary reactor (4 mL, 20 °C) after FlowPlate.
Further Optimization in Flow
Figure 1
Figure 1. Internal quenching of heteroaryllithium and its prevention by varying LDA stoichiometry (a) Proposed mechanism of internal quenching to 1-H arising from the rapid Li–Br exchange, which competes with deprotonation. (b) Results of experiments with varying LDA stoichiometry in an attempt to separate the deprotonation and lithium–halogen exchange steps.
Figure 2
Figure 2. Side reaction of heteroaryllithium with silyl chloride (a) Observed side products arising from the reaction of heteroaryllithium with BCDSE. Structures are proposed based on LCMS analysis. (b) Results of experiments with varying BCDSE stoichiometry to minimize the formation of side products 6–8. Yields of 3 and 1-H are calibrated versus an internal standard, while the yield of 6 + 7 + 8 is based only on area%.
Demonstration of Process Stability
Figure 3
Figure 3. Schematic layout of the flow setup with optimized reaction conditions and long-run stability (a) Schematic layout of Ehrfeld FlowPlate (TG mixer), showing the optimized reaction conditions used for the long run. (b) Reaction performance over time during long-run operation. The yield was determined by HPLC analysis versus an internal standard.
Conclusions
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.1c00024.
Further details of reaction setup, experimental results, and characterization data (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgments
The authors would like to thank Dr. René Lebl for additional analytical work.
API | active pharmaceutical ingredient |
BCDSE | 1,2-bis(chlorodimethylsilyl)ethane |
TBACl | tetrabutylammonium chloride |
TMS | trimethylsilyl |
References
This article references 21 other publications.
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As academic synthetic chemists, we examine how best to contribute to this ongoing effort. The current pandemic draws comparisons to past global health crises where synthetic chemists have made significant translational contributions through fundamental research. In the context of manufg. compds. like remdesivir, several research areas are outlined herein which require further development and creativity from chemists in order to drive advances in antiviral research during this time of need. As a community, driving future innovations in synthetic chem. will be imperative if we are to tackle global health threats such as COVID-19. The SARS-CoV-2 pandemic has prompted scientists from many disciplines to work collaboratively toward an effective response. As academic synthetic chemists, we examine how best to contribute to this ongoing effort.(b) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-Flow Technology - A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients. Angew. Chem., Int. Ed. 2015, 54, 6688– 6728, DOI: 10.1002/anie.201409318Google Scholar6bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosVGnt7k%253D&md5=49251387f0f3378dff4e710afe9fbca8Continuous-Flow Technology-A Tool for the Safe Manufacturing of Active Pharmaceutical IngredientsGutmann, Bernhard; Cantillo, David; Kappe, C. OliverAngewandte Chemie, International Edition (2015), 54 (23), 6688-6728CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in org. synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor vols., the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technol. offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow org. synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the prepn. of pharmaceuticals.(c) Baumann, M.; Baxendale, I. R. The Synthesis of Active Pharmaceutical Ingredients (APIs) Using Continuous Flow Chemistry. Beilstein. J. Org. Chem. 2015, 11, 1194– 1219, DOI: 10.3762/bjoc.11.134Google Scholar6chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht12qur7N&md5=cc70c6db28d1139d8b20791e4f58d99cThe synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistryBaumann, Marcus; Baxendale, Ian R.Beilstein Journal of Organic Chemistry (2015), 11 (), 1194-1219CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A review. This review article aims to illustrate the holistic systems approach and diverse applications of flow chem. to the prepn. of pharmaceutically active mols., demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line anal. and purifn. to final formulation and tableting. Although this review will primarily conc. on large scale continuous processing, addnl. selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technol. and transformational nature that flow chem. can leverage to an overall process.(d) McWilliams, J. C.; Allian, A. D.; Opalka, S. M.; May, S. A.; Journet, M.; Braden, T. M. The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations. Org. Process Res. Dev. 2018, 22, 1143– 1166, DOI: 10.1021/acs.oprd.8b00160Google Scholar6dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVOjsL%252FP&md5=22f54c6115477d8d83a74c4e7cc737c0The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing OrganizationsMcWilliams, J. Christopher; Allian, Ayman D.; Opalka, Suzanne M.; May, Scott A.; Journet, Michel; Braden, Timothy M.Organic Process Research & Development (2018), 22 (9), 1143-1166CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufg. Organizations (CMOs). The survey includes staffing (personnel), chem., reaction platforms, postreaction processing, anal., regulatory, and factors that influence the adoption of continuous manufg. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufg. executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chem., while postprocessing and anal. remain in the very early stages of development and implementation.(e) Porta, R.; Benaglia, M.; Puglisi, A. Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products. Org. Process Res. 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Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradn., supported reagents or catalysts, photochem., inductive heating, electrochem., new solvent systems, 3D printing, or microreactor technol. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufg. of org. intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with min. risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of org. mols. which found application as APIs, esp. highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufg. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.(f) Lee, S. L.; O’Connor, T. F.; Yang, X.; Cruz, C. N.; Chatterjee, S.; Madurawe, R. D.; Moore, C. M. V.; Yu, L. X.; Woodcock, J. Modernizing Pharmaceutical Manufacturing: From Batch to Continuous Production. J. Pharm. 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- 8(a) Warren, T. K.; Jordan, R.; Lo, M. K.; Ray, A. S.; Mackman, R. L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H. C. Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys. Nature 2016, 531, 381– 385, DOI: 10.1038/nature17180Google Scholar8ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjvVGnu70%253D&md5=ab121d827ac0a40cc1fed3dd1df905b6Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeysWarren, Travis K.; Jordan, Robert; Lo, Michael K.; Ray, Adrian S.; Mackman, Richard L.; Soloveva, Veronica; Siegel, Dustin; Perron, Michel; Bannister, Roy; Hui, Hon C.; Larson, Nate; Strickley, Robert; Wells, Jay; Stuthman, Kelly S.; Van Tongeren, Sean A.; Garza, Nicole L.; Donnelly, Ginger; Shurtleff, Amy C.; Retterer, Cary J.; Gharaibeh, Dima; Zamani, Rouzbeh; Kenny, Tara; Eaton, Brett P.; Grimes, Elizabeth; Welch, Lisa S.; Gomba, Laura; Wilhelmsen, Catherine L.; Nichols, Donald K.; Nuss, Jonathan E.; Nagle, Elyse R.; Kugelman, Jeffrey R.; Palacios, Gustavo; Doerffler, Edward; Neville, Sean; Carra, Ernest; Clarke, Michael O.; Zhang, Lijun; Lew, Willard; Ross, Bruce; Wang, Queenie; Chun, Kwon; Wolfe, Lydia; Babusis, Darius; Park, Yeojin; Stray, Kirsten M.; Trancheva, Iva; Feng, Joy Y.; Barauskas, Ona; Xu, Yili; Wong, Pamela; Braun, Molly R.; Flint, Mike; McMullan, Laura K.; Chen, Shan-Shan; Fearns, Rachel; Swaminathan, Swami; Mayers, Douglas L.; Spiropoulou, Christina F.; Lee, William A.; Nichol, Stuart T.; Cihlar, Tomas; Bavari, SinaNature (London, United Kingdom) (2016), 531 (7594), 381-385CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)The most recent Ebola virus outbreak in West Africa, which was unprecedented in the no. of cases and fatalities, geog. distribution, and no. of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clin. efficacy. Here we report the discovery of a novel small mol. GS-5734, a monophosphoramidate prodrug of an adenosine analog, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacol. active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. I.v. administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily i.v. administration of 10 mg kg-1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clin. disease signs and pathophysiol. markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-mol. antiviral compd. against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufg., and clin. studies investigating the drug safety and pharmacokinetics are ongoing.(b) Siegel, D.; Hui, H. C.; Doerffler, E.; Clarke, M. O.; Chun, K.; Zhang, L.; Neville, S.; Carra, E.; Lew, W.; Ross, B. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][Triazin-4-Amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J. Med. Chem. 2017, 60, 1648– 1661, DOI: 10.1021/acs.jmedchem.6b01594Google Scholar8bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Gjsb4%253D&md5=b2a05cfeb4fd30fbca0d1d584ddcc220Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging VirusesSiegel, Dustin; Hui, Hon C.; Doerffler, Edward; Clarke, Michael O.; Chun, Kwon; Zhang, Lijun; Neville, Sean; Carra, Ernest; Lew, Willard; Ross, Bruce; Wang, Queenie; Wolfe, Lydia; Jordan, Robert; Soloveva, Veronica; Knox, John; Perry, Jason; Perron, Michel; Stray, Kirsten M.; Barauskas, Ona; Feng, Joy Y.; Xu, Yili; Lee, Gary; Rheingold, Arnold L.; Ray, Adrian S.; Bannister, Roy; Strickley, Robert; Swaminathan, Swami; Lee, William A.; Bavari, Sina; Cihlar, Tomas; Lo, Michael K.; Warren, Travis K.; Mackman, Richard L.Journal of Medicinal Chemistry (2017), 60 (5), 1648-1661CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clin. candidate. Structure activity relationships established that the 1'-CN group and C-linked nucleobase were crit. for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclin. efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3-14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [ Nature 2016, 531, 381-385]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.(c) Paymode, D. J.; Cardoso, F. S. P.; Agrawal, T.; Tomlin, J. W.; Cook, D. W.; Burns, J. M.; Stringham, R. W.; Sieber, J. D.; Gupton, B. F.; Snead, D. R. Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis. Org. Lett. 2020, 22, 7656– 7661, DOI: 10.1021/acs.orglett.0c02848Google Scholar8chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVKnu7jI&md5=3d4ed0d2e3a3f71066b2c7258f63520eExpanding access to remdesivir via an improved pyrrolotriazine synthesis: Supply centered synthesisPaymode, Dinesh J.; Cardoso, Flavio S. P.; Agrawal, Toolika; Tomlin, John W.; Cook, Daniel W.; Burns, Justina M.; Stringham, Rodger W.; Sieber, Joshua D.; Gupton, B. Frank; Snead, David R.Organic Letters (2020), 22 (19), 7656-7661CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Pyrrolo[2,1-f][1,2,4]triazine is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.
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See also examples from the patent literature:
(a) Mackman, R. L.; Parrish, J. P.; Ray, A. S.; Theodore, D. A. Methods and Compounds for Treating Paramyxoviridae Virus Infections. U.S. Patent US20110451022011.Google ScholarThere is no corresponding record for this reference.(b) Butler, T.; Cho, A.; Kim, C. U.; Saunders, O. L.; Zhang, L. 1′-Substituted Carba-Nucleoside Analogs for Antiviral Treatment, U.S. Patent US20090414472009.Google ScholarThere is no corresponding record for this reference.(c) Mackman, R. L.; Parrish, J. P.; Ray, A.; Theodore, D. A. Methods and Compounds for Treating Paramyxoviridae Virus Infections. WO2012/012776A12012.Google ScholarThere is no corresponding record for this reference.(d) Chun, B. K.; Clarke, M. O. H.; Doerffler, E.; Hui, H. C.; Jordon, R.; Mackman, R. L.; Parrish, J. P.; Ray, A. S.; Siegel, D. Methods for Treating Filoviridae Virus Infections. WO2016/069826A12016.Google ScholarThere is no corresponding record for this reference.(e) Clarke, M. O. H.; Jordan, R.; Mackman, R. L.; Ray, A.; Siegel, D. Methods for Treating Filoviridae Virus Infections. WO2017/184668A12017.Google ScholarThere is no corresponding record for this reference.(f) Chun, B. K.; Clarke, M. O. H.; Doerffler, E.; Hui, H. C.; Jordon, R.; Mackman, R. L.; Parrish, J. P.; Ray, A. S.; Siegel, D. Methods for Treating Filoviridae Virus Infections. U.S. Patent US2019/0275063A12019.Google ScholarThere is no corresponding record for this reference. - 10von Keutz, T.; Williams, J. D.; Kappe, C. O. Continuous Flow C -Glycosylation via Metal–Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir. Org. Process Res. Dev. 2020, 24, 2362– 2368, DOI: 10.1021/acs.oprd.0c00370Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvV2jsb3J&md5=0ffa1c3afee0430b1a3ec7fe93510405Continuous Flow C-Glycosylation via Metal-Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivirvon Keutz, Timo; Williams, Jason D.; Kappe, C. OliverOrganic Process Research & Development (2020), 24 (10), 2362-2368CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)As the first approved treatment for COVID-19 (SARS-CoV-2), the prodn. of remdesivir is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technol. in manufg. high vol. active pharmaceutical ingredients and is considered for use in this synthetic sequence. In particular, the challenging C-glycosylation of a pyrrolotriazinamine via metal-halogen exchange was identified as a transformation with significant potential benefit, as exemplified by calorimetric anal. of each reaction step. Multiple simplifications to this process were attempted in batch, but in general were found to be unfruitful. The 5-feed process was then transferred to a flow setup, where specific conditions were found to circumvent solid formation and permit stable processing in the prepn. of nucleoside I as synthon of Remdesivir. Detailed optimization of stoichiometries provided an improvement upon batch conditions, with a total residence time of <1 min.
- 11Xue, F.; Zhou, X.; Zhou, R.; Zhou, X.; Xiao, D.; Gu, E.; Guo, X.; Xiang, J.; Wang, K.; Yang, L.; Zhong, W.; Qin, Y. Improvement of the C-Glycosylation Step for the Synthesis of Remdesivir. Org. Process Res. Dev. 2020, 24, 1772– 1777, DOI: 10.1021/acs.oprd.0c00310Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFaqtr3P&md5=c2c47399f070136a55b3cd02d520af86Improvement of the C-glycosylation Step for the Synthesis of RemdesivirXue, Fei; Zhou, Xinbo; Zhou, Ruijie; Zhou, Xiaohan; Xiao, Dian; Gu, Eric; Guo, Xiaowen; Xiang, Ji; Wang, Ke; Yang, Likai; Zhong, Wu; Qin, YongOrganic Process Research & Development (2020), 24 (9), 1772-1777CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The bulk supply of C-nucleoside analog antiviral Covid-19 drug remdesivir I is largely hampered by a low-yielding C-glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodol. for this crit. transformation. By utilizing diisopropylamine as a cost-effective additive, the addn. reaction furnishes an optimal yield of 75% of the desired ribofuranoside adduct II, representing the highest yield obtained thus far for this key step. The method proved suitable for hectogram scale synthesis without column chromatog. operations.
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For selected reviews and representative examples, see:
(a) Plouffe, P.; Macchi, A.; Roberge, D. M. From Batch to Continuous Chemical Synthesis-a Toolbox Approach. Org. Process Res. Dev. 2014, 18, 1286– 1294, DOI: 10.1021/op5001918Google Scholar12ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFamsrnN&md5=92f3093d118ee29cda5bf76a8cc2fc7aFrom Batch to Continuous Chemical Synthesis-A Toolbox ApproachPlouffe, Patrick; Macchi, Arturo; Roberge, Dominique M.Organic Process Research & Development (2014), 18 (11), 1286-1294CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A toolbox approach for the transfer of batch to continuous chem. synthesis is presented. The approach considers reaction kinetics (Type A, B, C), reacting phases (single phase, liq.-liq., gas-liq. and liq.-solid), and the reaction network (parallel and consecutive reactions) in order to select the most appropriate reactor module (Plate, Coil, or CSTR) for continuous operation. Then, three case studies using these three fundamental reactors are presented but require special considerations. For the reaction of dimethyl-oxalate with ethylmagnesium chloride, a plug-flow multi-injection technol. must be used to decrease the local heat generation and improve yield. For the nitration of salicylic acid, a Plate reactor with mixing elements favoring some back-mixing followed by a plug-flow system at elevated temps. is used instead of a tandem mixed-flow CSTR and plug-flow Coil reactor in order to minimize the risk of thermal decompn. of intermediates with a reduced vol. penalty. Finally, a ring-closing metathesis reaction is discussed for which the utilization of a CSTR allows the removal of catalyst-poisoning ethylene formed during the reaction and keeps the substrate concn. low to increase the yield above that of a batch or plug-flow system.(b) Hafner, A.; Filipponi, P.; Piccioni, L.; Meisenbach, M.; Schenkel, B.; Venturoni, F.; Sedelmeier, J. A Simple Scale-up Strategy for Organolithium Chemistry in Flow Mode: From Feasibility to Kilogram Quantities. Org. Process Res. Dev. 2016, 20, 1833– 1837, DOI: 10.1021/acs.oprd.6b00281Google Scholar12bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFKmsLrM&md5=cfa5a1b1d293af64b2d751d9b69314c2A Simple Scale-up Strategy for Organolithium Chemistry in Flow Mode: From Feasibility to Kilogram QuantitiesHafner, Andreas; Filipponi, Paolo; Piccioni, Lorenzo; Meisenbach, Mark; Schenkel, Berthold; Venturoni, Francesco; Sedelmeier, JoergOrganic Process Research & Development (2016), 20 (10), 1833-1837CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A platform for conducting organolithium chem. in continuous flow mode, covering the scales from medicinal chem. to later phase process development, is described. The use of this flow setup, which mimics the concept of flash chem. on scale, was demonstrated by the exemplary, large-scale prepn. of (4-fluoro-2-(trifluoromethyl)phenyl)boronic acid following a reaction sequence of halogen/lithium exchange, borylation, and semibatch workup. Also, the key factors and corresponding practical assessments required for the streamlined and seamless scale-up from lab. environment to higher productivity are highlighted.(c) Colella, M.; Nagaki, A.; Luisi, R. Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents. Chem.–Eur. J. 2020, 26, 19– 32, DOI: 10.1002/chem.201903353Google Scholar12chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFWntrjI&md5=f0cf6f1e3d71ff7b3fc7e4e9d6b50eb9Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic ReagentsColella, Marco; Nagaki, Aichiiro; Luisi, RenzoChemistry - A European Journal (2020), 26 (1), 19-32CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This concept article highlights the impact of flow chem. for exploiting highly reactive organometallic reagents and that how the well-known advantages concerning safety, scalability, and productivity, flow chem. make possible processes that are impossible to control by using the traditional batch approach.(d) Power, M.; Alcock, E.; McGlacken, G. P. Organolithium Bases in Flow Chemistry: A Review. Org. Process Res. Dev. 2020, 24, 1814– 1838, DOI: 10.1021/acs.oprd.0c00090Google Scholar12dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXot1Wmtrk%253D&md5=71d6546354b297a71f7455e7c2edad70Organolithium Bases in Flow Chemistry: A ReviewPower, Mark; Alcock, Emma; McGlacken, Gerard P.Organic Process Research & Development (2020), 24 (10), 1814-1838CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review discusses the use of organolithium compds. such as butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, phenyllithium, sec-butyllithium, and hexyllithium as bases for deprotonation reactions in continuous flow. - 13
For selected reviews of flash chemistry, see:
(a) Yoshida, J. I.; Nagaki, A.; Yamada, T. Flash Chemistry: Fast Chemical Synthesis by Using Microreactors. Chem.-Eur. J. 2008, 14, 7450– 7459, DOI: 10.1002/chem.200800582Google Scholar13ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFeisL%252FP&md5=bc6cdad1ed531455a1687e9079c0a44aFlash chemistry: fast chemical synthesis by using microreactorsYoshida, Jun-ichi; Nagaki, Aiichiro; Yamada, TakeshiChemistry - A European Journal (2008), 14 (25), 7450-7459CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)This review provides a brief outline of the concept of flash chem. for carrying out extremely fast reactions in org. synthesis by using microreactors. Generation of highly reactive species is one of the key elements of flash chem. Another important element of flash chem. is the control of extremely fast reactions to obtain the desired products selectively. Fast reactions are usually highly exothermic, and heat removal is an important factor in controlling such reactions. Heat transfer occurs very rapidly in microreactors by virtue of a large surface area per unit vol., making precise temp. control possible. Fast reactions often involve highly unstable intermediates, which decomp. very quickly, making reaction control difficult. The residence time can be greatly reduced in microreactors, and this feature is quite effective in controlling such reactions. For extremely fast reactions, kinetics often cannot be used because of the lack of homogeneity of the reaction environment when they are conducted in conventional reactors such as flasks. Fast mixing using micromixers solves such problems. The concept of flash chem. has been successfully applied to various org. reactions including: highly exothermic reactions that are difficult to control in conventional reactors; reactions in which a reactive intermediate easily decomps. in conventional reactors; reactions in which undesired byproducts are produced in the subsequent reactions in conventional reactors; and reactions whose products easily decomp. in conventional reactors. The concept of flash chem. can be also applied to polymer synthesis. Cationic polymn. can be conducted with an excellent level of mol.-wt. control and mol.wt. distribution control.(b) Yoshida, J.; Takahashi, Y.; Nagaki, A. Flash Chemistry: Flow Chemistry That Cannot Be Done in Batch. Chem. Commun. 2013, 49, 9896– 9904, DOI: 10.1039/c3cc44709jGoogle Scholar13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFOisbjE&md5=a249ebf59bd5beadf45e0545abfe6c2dFlash chemistry: flow chemistry that cannot be done in batchYoshida, Jun-ichi; Takahashi, Yusuke; Nagaki, AiichiroChemical Communications (Cambridge, United Kingdom) (2013), 49 (85), 9896-9904CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Flash chem. based on high-resoln. reaction time control using flow microreactors enables chem. reactions that cannot be done in batch and serves as a powerful tool for lab. synthesis of org. compds. and for prodn. in chem. and pharmaceutical industries.(c) Fanelli, F.; Parisi, G.; Degennaro, L.; Luisi, R. Contribution of Microreactor Technology and Flow Chemistry to the Development of Green and Sustainable Synthesis. Beilstein. J. Org. Chem. 2017, 13, 520– 542, DOI: 10.3762/bjoc.13.51Google Scholar13chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFagt7rL&md5=f9e152aac9de38893826aa8a8bd5ea34Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesisFanelli, Flavio; Parisi, Giovanna; Degennaro, Leonardo; Luisi, RenzoBeilstein Journal of Organic Chemistry (2017), 13 (), 520-542CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)Microreactor technol. and flow chem. could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chem., catalysis, hazardous chem. and continuous flow processing are described. Selected examples highlight the role that flow chem. could play in the near future for a sustainable development.(d) Nagaki, A. Recent Topics of Functionalized Organolithiums Using Flow Microreactor Chemistry. Tetrahedron Lett. 2019, 60, 150923 DOI: 10.1016/j.tetlet.2019.07.014Google Scholar13dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlOgsr7P&md5=b5576d14bf42b723e2e31f576dec2bcfRecent topics of functionalized organolithiums using flow microreactor chemistryNagaki, AiichiroTetrahedron Letters (2019), 60 (32), 150923CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)A review. Examples in this mini-review illustrate the potential of flow microreactor chem. in chem. science and chem. prodn. Flow microreactors provide a powerful method for novel transformations via functional organolithiums that cannot be achieved using a conventional macro batch reactor. - 14
Although handling solids in flow remains a challenge, commercial reactors do exist to achieve this purpose. For selected examples, see:
(a) Bianchi, P.; Williams, J. D.; Kappe, C. O. Oscillatory Flow Reactors for Synthetic Chemistry Applications. J. Flow Chem. 2020, 10, 475– 490, DOI: 10.1007/s41981-020-00105-6Google Scholar14ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFClsbvJ&md5=851b47b5f9f3ecdb5406522fcf29a457Oscillatory flow reactors for synthetic chemistry applicationsBianchi, Pauline; Williams, Jason D.; Kappe, C. OliverJournal of Flow Chemistry (2020), 10 (3), 475-490CODEN: JFCOBJ; ISSN:2063-0212. (Akademiai Kiado)Abstr.: 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 liq.-liq. 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 technol. and overviews the synthetic applications of OFRs for liq.-liq. and solid-liq. biphasic systems.(b) Browne, D. L.; Deadman, B. J.; Ashe, R.; Baxendale, I. R.; Ley, S. V. Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell Reactor. Org. Process Res. Dev. 2011, 15, 693– 697, DOI: 10.1021/op2000223Google Scholar14bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFyis7s%253D&md5=a6a2a00190be2525f694e9767d4ab607Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell ReactorBrowne, Duncan L.; Deadman, Benjamin J.; Ashe, Robert; Baxendale, Ian R.; Ley, Steven V.Organic Process Research & Development (2011), 15 (3), 693-697CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A general method for the continuous processing of suspensions and particulates is reported. A com. available agitating cell reactor which uses a transverse mixing motion to maintain solids in suspension was successfully applied to a salt-forming reaction. The flow device delivered 208 g of N-iodomorpholinium hydroiodide salt over a 9-h period (equating to 3.88 kg/wk) under optimized conditions. The reactor is suitable for the medium-scale (5 kg) processing of solid-forming reactions and appears to offer the potential for a variety of more complex applications.(c) Pomberger, A.; Mo, Y.; Nandiwale, K. Y.; Schultz, V. L.; Duvadie, R.; Robinson, R. I.; Altinoglu, E. I.; Jensen, K. F. A Continuous Stirred-Tank Reactor (CSTR) Cascade for Handling Solid-Containing Photochemical Reactions. Org. Process Res. Dev. 2019, 23, 2699– 2706, DOI: 10.1021/acs.oprd.9b00378Google Scholar14chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitV2hs7fN&md5=f65f76a0a8fce80855407cb46f7388a2A Continuous Stirred-Tank Reactor (CSTR) Cascade for Handling Solid-Containing Photochemical ReactionsPomberger, Alexander; Mo, Yiming; Nandiwale, Kakasaheb Y.; Schultz, Victor L.; Duvadie, Rohit; Robinson, Richard I.; Altinoglu, Erhan I.; Jensen, Klavs F.Organic Process Research & Development (2019), 23 (12), 2699-2706CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Visible-light photoredox reactions have been demonstrated to be powerful synthetic tools to access pharmaceutically relevant compds. However, many photoredox reactions involve insol. starting materials or products that complicate the use of continuous flow methods. By integrating a new solid-feeding strategy and a continuous stirred-tank reactor (CSTR) cascade, we realize a new solid-handling platform for conducting heterogeneous photoredox reactions in flow. Residence time distributions for single phase and solid particles characterize the hydrodynamics of the heterogeneous flow in the CSTR cascade. Silyl radical-mediated metallaphotoredox cross-electrophile coupling reactions with an inorg. base as the insol. starting material demonstrate the use of the platform. Gram-scale synthesis is achieved in 13 h of stable operation. - 15(a) Kockmann, N.; Roberge, D. M. Scale-up Concept for Modular Microstructured Reactors Based on Mixing, Heat Transfer, and Reactor Safety. Chem. Eng. Process. 2011, 50, 1017– 1026, DOI: 10.1016/j.cep.2011.05.021Google Scholar15ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFKrs7rL&md5=6eb42307019749fad81b037dddb9daf4Scale-up concept for modular microstructured reactors based on mixing, heat transfer, and reactor safetyKockmann, Norbert; Roberge, Dominique M.Chemical Engineering and Processing (2011), 50 (10), 1017-1026CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)Microstructured reactors are characterized by rapid mixing processes and excellent temp. control of chem. reactions. These properties allow the safe operation of hazardous chem. in intensified processes. Problems occur during scale-up of these processes, where heat transfer becomes the limiting effect. With high flow rates and transitional or even turbulent flow regimes in small channels, rapid mixing and excellent heat transfer can be maintained up to high prodn. rates. For exothermic reactions, limits for parametric sensitivity and safe operation are shown from literature and combined with convective heat transfer for consistent scale-up. Good knowledge of reaction kinetics, thermodn. and heat transfer is essential to det. runaway regions for exothermic reactions. From these correlations, consistent channel design and continuous-flow reactor setup is shown.(b) Plouffe, P.; Roberge, D. M.; Macchi, A. Liquid-Liquid Flow Regimes and Mass Transfer in Various Micro-Reactors. Chem. Eng. J. 2016, 300, 9– 19, DOI: 10.1016/j.cej.2016.04.072Google Scholar15bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmslSnsL8%253D&md5=2bcbcbef1e5bc869c2658117517b4cceLiquid-liquid flow regimes and mass transfer in various micro-reactorsPlouffe, Patrick; Roberge, Dominique M.; Macchi, ArturoChemical Engineering Journal (Amsterdam, Netherlands) (2016), 300 (), 9-19CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)The flow regimes and mass transfer rates in five complex micro-reactors with different mixing mechanisms were investigated using the two-phase alk. hydrolysis of 4-nitrophenyl acetate. N-Butanol and toluene were used as org. solvents. Using n-butanol in curvature-based micro-mixers, the flow regime evolved from slug to parallel to drop/dispersed flow with increasing flow rates. In obstacle-based micro-mixers, no parallel flow was obsd. Using toluene, no parallel flow was obsd. for all reactors. The conversion of 4-nitrophenyl acetate was found to be strongly dependent on the flow regime. In slug and parallel flow, the conversion generally decreased with an increase in flow rate whereas it typically increased in drop flow and was const. or slightly decreased in dispersed flow. The different micro-mixers were compared using the overall volumetric mass transfer coeff., Korga, which was primarily a function of the rate of energy dissipation within the dispersed flow regime. The geometry itself impacts the resulting flow regime and rate of energy dissipation at a given flow rate. The micro-reactors were then compared using modified Damk.ovrddot.ohler's nos. Curvature-based reactors were found to be inadequate for liq.-liq. reactions under the studied conditions, as they favor parallel flow patterns and yield relatively low interphase mass transfer rates.
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For selected examples of chemistry carried out in this reactor platform, see:
(a) Sagmeister, P.; Williams, J. D.; Hone, C. A.; Kappe, C. O. Laboratory of the Future: A Modular Flow Platform with Multiple Integrated PAT Tools for Multistep Reactions. React. Chem. Eng. 2019, 4, 1571– 1578, DOI: 10.1039/c9re00087aGoogle Scholar16ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmvFeltb0%253D&md5=4a048b44692aad146c3b8cd9f20fa411Laboratory of the future: a modular flow platform with multiple integrated PAT tools for multistep reactionsSagmeister, Peter; Williams, Jason D.; Hone, Christopher A.; Kappe, C. OliverReaction Chemistry & Engineering (2019), 4 (9), 1571-1578CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Currently, the monitoring of multistep continuous flow processes by multiple anal. sources is still seen as a resource intensive and specialized activity. In this article, the coupling of a modular microreactor platform with real-time monitoring by inline IR and NMR, in addn. to online UPLC, is described. Using this platform, we rapidly generated exptl. data (17 iterations in under 2 h) to access information on the different chem. species at multiple points within the reactor and to generate process understanding. We highlight the application of the platform in the optimization of a multistep organolithium transformation. The optimized continuous flow conditions were demonstrated in a scale-out expt. with in-process monitoring to afford the desired product in 70% isolated yield and provided a throughput of 4.2 g h-1.(b) Sagmeister, P.; Poms, J.; Williams, J. D.; Kappe, C. O. Multivariate Analysis of Inline Benchtop NMR Data Enables Rapid Optimization of a Complex Nitration in Flow. React. Chem. Eng. 2020, 5, 677– 684, DOI: 10.1039/d0re00048eGoogle Scholar16bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjsVyjsbs%253D&md5=793e67482ebaa5004295d70f361aa98aMultivariate analysis of inline benchtop NMR data enables rapid optimization of a complex nitration in flowSagmeister, Peter; Poms, Johannes; Williams, Jason D.; Kappe, C. OliverReaction Chemistry & Engineering (2020), 5 (4), 677-684CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Inline benchtop NMR anal. is established as a powerful tool for reaction monitoring, but its capabilities are somewhat limited by low spectral resoln., often leading to overlapping peaks and difficulties in quantification. Using a multivariate anal. (MVA) statistical approach to data processing these hurdles can be overcome, enabling accurate quantification of complex product mixts. By employing rapid data acquisition (2.0 s recording time per spectrum), we demonstrate the use of inline benchtop NMR to guide the optimization of a complex nitration reaction in flow. Accurate quantification of four overlapping species was possible, enabling generation of a robust DoE model along with accurate evaluation of dynamic expts.(c) von Keutz, T.; Cantillo, D.; Kappe, C. O. Continuous Flow Synthesis of Terminal Epoxides from Ketones Using in Situ Generated Bromomethyl Lithium. Org. Lett. 2019, 21, 10094– 10098, DOI: 10.1021/acs.orglett.9b04072Google Scholar16chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1OhurjE&md5=f247b28ff31fafc99b8483937d225c25Continuous Flow Synthesis of Terminal Epoxides from Ketones Using in Situ Generated Bromomethyl Lithiumvon Keutz, Timo; Cantillo, David; Kappe, C. OliverOrganic Letters (2019), 21 (24), 10094-10098CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A scalable procedure for the direct prepn. of epoxides from ketones has been developed. The method is based on the carefully controlled generation of (bromomethyl)lithium (LiCH2Br) from inexpensive CH2Br2 and MeLi in a continuous flow reactor. The reaction has shown excellent selectivity for a variety of substrates, including α-chloroketones, which typically fail under classic Corey-Chaykovsky conditions. This advantage has been used to develop a novel route toward the drug fluconazole.(d) von Keutz, T.; Cantillo, D.; Kappe, C. O. Organomagnesium Based Flash Chemistry: Continuous Flow Generation and Utilization of Halomethylmagnesium Intermediates. Org. Lett. 2020, 22, 7537– 7541, DOI: 10.1021/acs.orglett.0c02725Google Scholar16dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVSkurfL&md5=d6ea59261d53707252ade018bda83518Organomagnesium Based Flash Chemistry: Continuous Flow Generation and Utilization of Halomethylmagnesium Intermediatesvon Keutz, Timo; Cantillo, David; Kappe, C. OliverOrganic Letters (2020), 22 (19), 7537-7541CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The generation of highly unstable chloromethylmagnesium chloride in a continuous flow reactor and its reaction with aldehydes and ketones is reported. With this strategy, chlorohydrins and epoxides were synthesized within a total residence time of only 2.6 s. The outcome of the reaction can be tuned by simply using either a basic or an acidic quench. Very good to excellent isolated yields, up to 97%, have been obtained for most cases (30 examples).See also reference (10)
- 17(a) Reckamp, J. M.; Bindels, A.; Duffield, S.; Liu, Y. C.; Bradford, E.; Ricci, E.; Susanne, F.; Rutter, A. Mixing Performance Evaluation for Commercially Available Micromixers Using Villermaux-Dushman Reaction Scheme with the Interaction by Exchange with the Mean Model. Org. Process Res. Dev. 2017, 21, 816– 820, DOI: 10.1021/acs.oprd.6b00332Google Scholar17ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnt1Cht7w%253D&md5=6aab5c1f14c5f9b4b6db36b4fb44d46dMixing Performance Evaluation for Commercially Available Micromixers Using Villermaux-Dushman Reaction Scheme with the Interaction by Exchange with the Mean ModelReckamp, Joseph M.; Bindels, Ashira; Duffield, Sophie; Liu, Yangmu Chloe; Bradford, Eric; Ricci, Eric; Susanne, Flavien; Rutter, AndrewOrganic Process Research & Development (2017), 21 (6), 816-820CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The development of low-vol. continuous processes for the pharmaceutical industry requires a greater understanding of mixing in microreactors. In this paper, numerous com. available micromixers are evaluated using the Villermaux-Dushman reaction scheme and the interaction by exchange with the mean (IEM) mixing model to quantify the mixing time. The work presents the mixing times as a function of flow rate and energy dissipation for mixers including T-Mixers, Ehrfeld Mikrotechnik BTS micromixers, and Syrris Asia microchips.(b) Macchi, A.; Plouffe, P.; Patience, G. S.; Roberge, D. M. Experimental Methods in Chemical Engineering: Micro-Reactors. Can. J. Chem. Eng. 2019, 97, 2578– 2587, DOI: 10.1002/cjce.23525Google Scholar17bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1SiurvI&md5=eefd68d6cbb4f1bee667d066fbfdcfd8Experimental methods in chemical engineering: Micro-reactorsMacchi, Arturo; Plouffe, Patrick; Patience, Gregory S.; Roberge, Dominique M.Canadian Journal of Chemical Engineering (2019), 97 (10), 2578-2587CODEN: CJCEA7; ISSN:0008-4034. (John Wiley & Sons, Inc.)Where as the bulk chem. industry has historically sought economic advantage through economies of scale, a paradigm shift has researchers developing systems on smaller scales. Nano-cages and nano-actuators increase selectivity and robustness at the mol. scale. In parallel, micro-contactors with sub-millimeter lateral dimensions are decreasing boundary layers that restrict heat and mass transfer and thus meet the objectives of process intensification with great increases in productivity with a smaller footprint. These contactors continue to serve chem. engineers and chemists to synthesize fine chems. and characterize catalysts; however, they have now been adopted for sensors in biol. and biochem. systems. A bibliometric anal. of articles indexed in the Web of Science in 2016 and 2017 identified five major clusters of research: catalysis and bulk chems.; nanoparticles; org. synthesis and flow chem.; systems and micro-fluidics applied to biochem.; and micro-channel reactors and mass transfer. In the early 1990s, less than 100 articles a year mentioned micro-reactors, while over 943 articles mentioned it in 2017. Here, we introduce micro-reactors and their role in the continuous synthesis of fine chems. across the various scales to commercialization.
- 18Köckinger, M.; Wyler, B.; Aellig, C.; Roberge, D. M.; Hone, C. A.; Kappe, C. O. Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-Methoxyaniline to Prepare a Key Building Block of Osimertinib. Org. Process Res. Dev. 2020, 24, 2217– 2227, DOI: 10.1021/acs.oprd.0c00254Google ScholarThere is no corresponding record for this reference.
- 19
For selected examples of organometallic processes run at higher temperatures in continuous flow, see:
(a) Hafner, A.; Mancino, V.; Meisenbach, M.; Schenkel, B.; Sedelmeier, J. Dichloromethyllithium: Synthesis and Application in Continuous Flow Mode. Org. Lett. 2017, 19, 786– 789, DOI: 10.1021/acs.orglett.6b03753Google Scholar19ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFeqsbs%253D&md5=a2e8d661d499f68b7e0291ed5ffef41eDichloromethyllithium: Synthesis and Application in Continuous Flow ModeHafner, Andreas; Mancino, Valentina; Meisenbach, Mark; Schenkel, Berthold; Sedelmeier, JoergOrganic Letters (2017), 19 (4), 786-789CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)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 temps. of -30 °C, whereas typical temps. 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 chromatog.(b) Murray, P. R. D.; Browne, D. L.; Pastre, J. C.; Butters, C.; Guthrie, D.; Ley, S. V. Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen. Org. Process Res. Dev. 2013, 17, 1192– 1208, DOI: 10.1021/op4001548Google Scholar19bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ymt7nJ&md5=9971d8ef8e035e947bed0537c44e3791Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-TamoxifenMurray, Philip R. D.; Browne, Duncan L.; Pastre, Julio C.; Butters, Chris; Guthrie, Duncan; Ley, Steven V.Organic Process Research & Development (2013), 17 (9), 1192-1208CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. A new enabling technol. for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilizes a newly developed, chem. resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal-halogen exchange, addn., addn.-elimination, conjugate addn., and partial redn., are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations. - 20Based on 0.6 equiv, at a price of £122 (∼€139) per 100g, Fluorochem. http://www.fluorochem.co.uk/Products/Product?code=S01325 (accessed 02-04-2021).Google ScholarThere is no corresponding record for this reference.
- 21(a) NdCl3 (anhydrous) based on 1 equiv, at a price of €708 per 100 g, Alfa Aesar. https://www.alfa.com/de/catalog/018680/ (accessed 02-04-2021).Google ScholarThere is no corresponding record for this reference.(b) Tetrabutylammonium chloride based on 1 equiv, at a price of €113 per 100 g, Sigma Aldrich. https://www.sigmaaldrich.com/catalog/product/mm/814645 (accessed 02-04-2021).Google ScholarThere is no corresponding record for this reference.
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Abstract
Scheme 1
Scheme 1. Reported C-Glycosylation Processes toward the Synthesis of Remdesivir (4)a,baScheme showing the C-glycosylation of pyrrolotriazinamine 1/1a with lactone 2 to furnish key intermediate 3 as part of the synthesis of remdesivir (4). The different literature approaches using Grignard or organolithium chemistry are highlighted.
bReproduction of published organolithium procedure, (11) focusing on the intermediates formed and any potential obstacles to developing a continuous flow process.
Figure 1
Figure 1. Internal quenching of heteroaryllithium and its prevention by varying LDA stoichiometry (a) Proposed mechanism of internal quenching to 1-H arising from the rapid Li–Br exchange, which competes with deprotonation. (b) Results of experiments with varying LDA stoichiometry in an attempt to separate the deprotonation and lithium–halogen exchange steps.
Figure 2
Figure 2. Side reaction of heteroaryllithium with silyl chloride (a) Observed side products arising from the reaction of heteroaryllithium with BCDSE. Structures are proposed based on LCMS analysis. (b) Results of experiments with varying BCDSE stoichiometry to minimize the formation of side products 6–8. Yields of 3 and 1-H are calibrated versus an internal standard, while the yield of 6 + 7 + 8 is based only on area%.
Figure 3
Figure 3. Schematic layout of the flow setup with optimized reaction conditions and long-run stability (a) Schematic layout of Ehrfeld FlowPlate (TG mixer), showing the optimized reaction conditions used for the long run. (b) Reaction performance over time during long-run operation. The yield was determined by HPLC analysis versus an internal standard.
References
This article references 21 other publications.
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- 2(a) Liu, C.; Zhou, Q.; Li, Y.; Garner, L. V.; Watkins, S. P.; Carter, L. J.; Smoot, J.; Gregg, A. C.; Daniels, A. D.; Jervey, S.; Albaiu, D. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent. Sci. 2020, 6, 315– 331, DOI: 10.1021/acscentsci.0c002722ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkslWrsbo%253D&md5=fa29fb4cc3353a140e3a6a74059a99b1Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus DiseasesLiu, Cynthia; Zhou, Qiongqiong; Li, Yingzhu; Garner, Linda V.; Watkins, Steve P.; Carter, Linda J.; Smoot, Jeffrey; Gregg, Anne C.; Daniels, Angela D.; Jervey, Susan; Albaiu, DanaACS Central Science (2020), 6 (3), 315-331CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)A review. Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Considering the potential threat of a pandemic, scientists and physicians have been racing to understand this new virus and the pathophysiol. of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small mols. and biologics targeting complex mol. interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent anal. of coronavirus-related biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines.(b) De Savi, C.; Hughes, D. L.; Kvaerno, L. Quest for a COVID-19 Cure by Repurposing Small-Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for Supply. Org. Process Res. Dev. 2020, 24, 940– 976, DOI: 10.1021/acs.oprd.0c002332bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVKntL%252FP&md5=53f88289330637bed07a4c4e361de3fbQuest for a COVID-19 Cure by Repurposing Small-Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for SupplyDe Savi, Chris; Hughes, David L.; Kvaerno, LisbetOrganic Process Research & Development (2020), 24 (6), 940-976CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. The outbreak of the COVID-19 pandemic has spurred an intense global effort to repurpose existing approved drugs for its treatment. In this review, we highlight the development of seven small-mol. drugs that are currently being assessed in clin. trials for the treatment of COVID-19. Three sections are presented for each drug: (1) history, mechanism of action, and status of clin. trials; (2) scalable synthetic routes and final forms; and (3) outlook for supply should clin. trials show treatment efficacy. A brief overview of diagnostic testing and vaccine development is also presented.
- 3(a) First COVID-19 treatment recommended for EU authorisation, European Medicines Agency, June 25, 2020, https://www.ema.europa.eu/en/news/first-covid-19-treatment-recommended-eu-authorisation (accessed 01-20-2021).There is no corresponding record for this reference.(b) European Commission secures EU access to Remdesivir for treatment of COVID-19. European Commission, July 29, 2020, https://ec.europa.eu/commission/presscorner/detail/en/ip_20_1416 (accessed 01-20-2021).There is no corresponding record for this reference.
- 4Gilead’s revenue rises 17% driven by sales of coronavirus treatment remdesivir, CNBC News, October 28, 2020, https://www.cnbc.com/2020/10/28/remdesivir-gileads-revenue-rises-17percent-on-sales-of-coronavirus-treatment.html (accessed 01-20-2021).There is no corresponding record for this reference.
- 5(a) On the remdesivir manufacturing process: “The process is both resource- and time-intensive, with some individual manufacturing steps taking weeks to complete.” See: Working to Supply Veklury for COVID-19. Gilead, October 22, 2020, https://www.gilead.com/purpose/advancing-global-health/covid-19/working-to-supply-veklury-for-covid-19 (accessed 01-20-2021).There is no corresponding record for this reference.(b) Jarvis, L. M. Scaling up remdesivir amid the coronavirus crisis. Chem. Eng. News, April 20. 2020, https://cen.acs.org/biological-chemistry/infectious-disease/Scaling-remdesivir-amid-coronavirus-crisis/98/web/2020/04 (accessed 01-20-2021).There is no corresponding record for this reference.
- 6(a) Hardy, M. A.; Wright, B. A.; Bachman, J. L.; Boit, T. B.; Haley, H. M. S.; Knapp, R. R.; Lusi, R. F.; Okada, T.; Tona, V.; Garg, N. K.; Sarpong, R. Treating a Global Health Crisis with a Dose of Synthetic Chemistry. ACS Cent. Sci. 2020, 6, 1017– 1030, DOI: 10.1021/acscentsci.0c006376ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXht1Kns77P&md5=50e111f011424ffb1c2eeda44ee540d5Treating a Global Health Crisis with a Dose of Synthetic ChemistryHardy, Melissa A.; Wright, Brandon A.; Bachman, J. Logan; Boit, Timothy B.; Haley, Hannah M. S.; Knapp, Rachel R.; Lusi, Robert F.; Okada, Taku; Tona, Veronica; Garg, Neil K.; Sarpong, RichmondACS Central Science (2020), 6 (7), 1017-1030CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)The SARS-CoV-2 pandemic has prompted scientists from many disciplines to work collaboratively toward an effective response. As academic synthetic chemists, we examine how best to contribute to this ongoing effort. The current pandemic draws comparisons to past global health crises where synthetic chemists have made significant translational contributions through fundamental research. In the context of manufg. compds. like remdesivir, several research areas are outlined herein which require further development and creativity from chemists in order to drive advances in antiviral research during this time of need. As a community, driving future innovations in synthetic chem. will be imperative if we are to tackle global health threats such as COVID-19. The SARS-CoV-2 pandemic has prompted scientists from many disciplines to work collaboratively toward an effective response. As academic synthetic chemists, we examine how best to contribute to this ongoing effort.(b) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-Flow Technology - A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients. Angew. Chem., Int. Ed. 2015, 54, 6688– 6728, DOI: 10.1002/anie.2014093186bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosVGnt7k%253D&md5=49251387f0f3378dff4e710afe9fbca8Continuous-Flow Technology-A Tool for the Safe Manufacturing of Active Pharmaceutical IngredientsGutmann, Bernhard; Cantillo, David; Kappe, C. OliverAngewandte Chemie, International Edition (2015), 54 (23), 6688-6728CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in org. synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor vols., the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technol. offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow org. synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the prepn. of pharmaceuticals.(c) Baumann, M.; Baxendale, I. R. The Synthesis of Active Pharmaceutical Ingredients (APIs) Using Continuous Flow Chemistry. Beilstein. J. Org. Chem. 2015, 11, 1194– 1219, DOI: 10.3762/bjoc.11.1346chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht12qur7N&md5=cc70c6db28d1139d8b20791e4f58d99cThe synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistryBaumann, Marcus; Baxendale, Ian R.Beilstein Journal of Organic Chemistry (2015), 11 (), 1194-1219CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A review. This review article aims to illustrate the holistic systems approach and diverse applications of flow chem. to the prepn. of pharmaceutically active mols., demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line anal. and purifn. to final formulation and tableting. Although this review will primarily conc. on large scale continuous processing, addnl. selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technol. and transformational nature that flow chem. can leverage to an overall process.(d) McWilliams, J. C.; Allian, A. D.; Opalka, S. M.; May, S. A.; Journet, M.; Braden, T. M. The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations. Org. Process Res. Dev. 2018, 22, 1143– 1166, DOI: 10.1021/acs.oprd.8b001606dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVOjsL%252FP&md5=22f54c6115477d8d83a74c4e7cc737c0The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing OrganizationsMcWilliams, J. Christopher; Allian, Ayman D.; Opalka, Suzanne M.; May, Scott A.; Journet, Michel; Braden, Timothy M.Organic Process Research & Development (2018), 22 (9), 1143-1166CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufg. Organizations (CMOs). The survey includes staffing (personnel), chem., reaction platforms, postreaction processing, anal., regulatory, and factors that influence the adoption of continuous manufg. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufg. executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chem., while postprocessing and anal. remain in the very early stages of development and implementation.(e) Porta, R.; Benaglia, M.; Puglisi, A. Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products. Org. Process Res. Dev. 2016, 20, 2– 25, DOI: 10.1021/acs.oprd.5b003256ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFWmurfL&md5=2dbb53679df39f79b957a244c5d57fc5Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical ProductsPorta, Riccardo; Benaglia, Maurizio; Puglisi, AlessandraOrganic Process Research & Development (2016), 20 (1), 2-25CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. Recently, application of the flow technologies for the prepn. of fine chems., such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, esp. in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufg. of org. mols., including highly functionalized and chiral compds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradn., supported reagents or catalysts, photochem., inductive heating, electrochem., new solvent systems, 3D printing, or microreactor technol. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufg. of org. intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with min. risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of org. mols. which found application as APIs, esp. highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufg. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.(f) Lee, S. L.; O’Connor, T. F.; Yang, X.; Cruz, C. N.; Chatterjee, S.; Madurawe, R. D.; Moore, C. M. V.; Yu, L. X.; Woodcock, J. Modernizing Pharmaceutical Manufacturing: From Batch to Continuous Production. J. Pharm. Innov. 2015, 10, 191– 199, DOI: 10.1007/s12247-015-9215-8There is no corresponding record for this reference.
- 7Vieira, T.; Stevens, A. C.; Chtchemelinine, A.; Gao, D.; Badalov, P.; Heumann, L. Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir. Org. Process Res. Dev. 2020, 24, 2113– 2121, DOI: 10.1021/acs.oprd.0c001727https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvFWqtr4%253D&md5=907a03ede0c17d37f29f90d2eb46dae8Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of RemdesivirVieira, Tiago; Stevens, Andrew C.; Chtchemelinine, Andrei; Gao, Detian; Badalov, Pavel; Heumann, LarsOrganic Process Research & Development (2020), 24 (10), 2113-2121CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The implementation of cyanation chem. at manufg. scales using batch equipment can be challenging due to the hazardous nature of the reagents employed, and the tight control of reaction parameters, including cryogenic temps., that help to afford acceptable selectivity and conversion for the desired reaction. Application of continuous flow chem. offers a means to mitigate the risk assocd. with handling large amts. of hazardous reagents and to better control the reaction parameters. A case study describing the stereoselective cyanation of a glycoside I with Trimethylsilyl cyanide using continuous flow chem. to give glycoside II towards the synthesis of the drug candidate remdesivir is presented.
- 8(a) Warren, T. K.; Jordan, R.; Lo, M. K.; Ray, A. S.; Mackman, R. L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H. C. Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys. Nature 2016, 531, 381– 385, DOI: 10.1038/nature171808ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjvVGnu70%253D&md5=ab121d827ac0a40cc1fed3dd1df905b6Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeysWarren, Travis K.; Jordan, Robert; Lo, Michael K.; Ray, Adrian S.; Mackman, Richard L.; Soloveva, Veronica; Siegel, Dustin; Perron, Michel; Bannister, Roy; Hui, Hon C.; Larson, Nate; Strickley, Robert; Wells, Jay; Stuthman, Kelly S.; Van Tongeren, Sean A.; Garza, Nicole L.; Donnelly, Ginger; Shurtleff, Amy C.; Retterer, Cary J.; Gharaibeh, Dima; Zamani, Rouzbeh; Kenny, Tara; Eaton, Brett P.; Grimes, Elizabeth; Welch, Lisa S.; Gomba, Laura; Wilhelmsen, Catherine L.; Nichols, Donald K.; Nuss, Jonathan E.; Nagle, Elyse R.; Kugelman, Jeffrey R.; Palacios, Gustavo; Doerffler, Edward; Neville, Sean; Carra, Ernest; Clarke, Michael O.; Zhang, Lijun; Lew, Willard; Ross, Bruce; Wang, Queenie; Chun, Kwon; Wolfe, Lydia; Babusis, Darius; Park, Yeojin; Stray, Kirsten M.; Trancheva, Iva; Feng, Joy Y.; Barauskas, Ona; Xu, Yili; Wong, Pamela; Braun, Molly R.; Flint, Mike; McMullan, Laura K.; Chen, Shan-Shan; Fearns, Rachel; Swaminathan, Swami; Mayers, Douglas L.; Spiropoulou, Christina F.; Lee, William A.; Nichol, Stuart T.; Cihlar, Tomas; Bavari, SinaNature (London, United Kingdom) (2016), 531 (7594), 381-385CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)The most recent Ebola virus outbreak in West Africa, which was unprecedented in the no. of cases and fatalities, geog. distribution, and no. of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clin. efficacy. Here we report the discovery of a novel small mol. GS-5734, a monophosphoramidate prodrug of an adenosine analog, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacol. active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. I.v. administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily i.v. administration of 10 mg kg-1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clin. disease signs and pathophysiol. markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-mol. antiviral compd. against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufg., and clin. studies investigating the drug safety and pharmacokinetics are ongoing.(b) Siegel, D.; Hui, H. C.; Doerffler, E.; Clarke, M. O.; Chun, K.; Zhang, L.; Neville, S.; Carra, E.; Lew, W.; Ross, B. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][Triazin-4-Amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J. Med. Chem. 2017, 60, 1648– 1661, DOI: 10.1021/acs.jmedchem.6b015948bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Gjsb4%253D&md5=b2a05cfeb4fd30fbca0d1d584ddcc220Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging VirusesSiegel, Dustin; Hui, Hon C.; Doerffler, Edward; Clarke, Michael O.; Chun, Kwon; Zhang, Lijun; Neville, Sean; Carra, Ernest; Lew, Willard; Ross, Bruce; Wang, Queenie; Wolfe, Lydia; Jordan, Robert; Soloveva, Veronica; Knox, John; Perry, Jason; Perron, Michel; Stray, Kirsten M.; Barauskas, Ona; Feng, Joy Y.; Xu, Yili; Lee, Gary; Rheingold, Arnold L.; Ray, Adrian S.; Bannister, Roy; Strickley, Robert; Swaminathan, Swami; Lee, William A.; Bavari, Sina; Cihlar, Tomas; Lo, Michael K.; Warren, Travis K.; Mackman, Richard L.Journal of Medicinal Chemistry (2017), 60 (5), 1648-1661CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clin. candidate. Structure activity relationships established that the 1'-CN group and C-linked nucleobase were crit. for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclin. efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3-14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [ Nature 2016, 531, 381-385]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.(c) Paymode, D. J.; Cardoso, F. S. P.; Agrawal, T.; Tomlin, J. W.; Cook, D. W.; Burns, J. M.; Stringham, R. W.; Sieber, J. D.; Gupton, B. F.; Snead, D. R. Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis. Org. Lett. 2020, 22, 7656– 7661, DOI: 10.1021/acs.orglett.0c028488chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVKnu7jI&md5=3d4ed0d2e3a3f71066b2c7258f63520eExpanding access to remdesivir via an improved pyrrolotriazine synthesis: Supply centered synthesisPaymode, Dinesh J.; Cardoso, Flavio S. P.; Agrawal, Toolika; Tomlin, John W.; Cook, Daniel W.; Burns, Justina M.; Stringham, Rodger W.; Sieber, Joshua D.; Gupton, B. Frank; Snead, David R.Organic Letters (2020), 22 (19), 7656-7661CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Pyrrolo[2,1-f][1,2,4]triazine is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.
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See also examples from the patent literature:
(a) Mackman, R. L.; Parrish, J. P.; Ray, A. S.; Theodore, D. A. Methods and Compounds for Treating Paramyxoviridae Virus Infections. U.S. Patent US20110451022011.There is no corresponding record for this reference.(b) Butler, T.; Cho, A.; Kim, C. U.; Saunders, O. L.; Zhang, L. 1′-Substituted Carba-Nucleoside Analogs for Antiviral Treatment, U.S. Patent US20090414472009.There is no corresponding record for this reference.(c) Mackman, R. L.; Parrish, J. P.; Ray, A.; Theodore, D. A. Methods and Compounds for Treating Paramyxoviridae Virus Infections. WO2012/012776A12012.There is no corresponding record for this reference.(d) Chun, B. K.; Clarke, M. O. H.; Doerffler, E.; Hui, H. C.; Jordon, R.; Mackman, R. L.; Parrish, J. P.; Ray, A. S.; Siegel, D. Methods for Treating Filoviridae Virus Infections. WO2016/069826A12016.There is no corresponding record for this reference.(e) Clarke, M. O. H.; Jordan, R.; Mackman, R. L.; Ray, A.; Siegel, D. Methods for Treating Filoviridae Virus Infections. WO2017/184668A12017.There is no corresponding record for this reference.(f) Chun, B. K.; Clarke, M. O. H.; Doerffler, E.; Hui, H. C.; Jordon, R.; Mackman, R. L.; Parrish, J. P.; Ray, A. S.; Siegel, D. Methods for Treating Filoviridae Virus Infections. U.S. Patent US2019/0275063A12019.There is no corresponding record for this reference. - 10von Keutz, T.; Williams, J. D.; Kappe, C. O. Continuous Flow C -Glycosylation via Metal–Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir. Org. Process Res. Dev. 2020, 24, 2362– 2368, DOI: 10.1021/acs.oprd.0c0037010https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvV2jsb3J&md5=0ffa1c3afee0430b1a3ec7fe93510405Continuous Flow C-Glycosylation via Metal-Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivirvon Keutz, Timo; Williams, Jason D.; Kappe, C. OliverOrganic Process Research & Development (2020), 24 (10), 2362-2368CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)As the first approved treatment for COVID-19 (SARS-CoV-2), the prodn. of remdesivir is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technol. in manufg. high vol. active pharmaceutical ingredients and is considered for use in this synthetic sequence. In particular, the challenging C-glycosylation of a pyrrolotriazinamine via metal-halogen exchange was identified as a transformation with significant potential benefit, as exemplified by calorimetric anal. of each reaction step. Multiple simplifications to this process were attempted in batch, but in general were found to be unfruitful. The 5-feed process was then transferred to a flow setup, where specific conditions were found to circumvent solid formation and permit stable processing in the prepn. of nucleoside I as synthon of Remdesivir. Detailed optimization of stoichiometries provided an improvement upon batch conditions, with a total residence time of <1 min.
- 11Xue, F.; Zhou, X.; Zhou, R.; Zhou, X.; Xiao, D.; Gu, E.; Guo, X.; Xiang, J.; Wang, K.; Yang, L.; Zhong, W.; Qin, Y. Improvement of the C-Glycosylation Step for the Synthesis of Remdesivir. Org. Process Res. Dev. 2020, 24, 1772– 1777, DOI: 10.1021/acs.oprd.0c0031011https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFaqtr3P&md5=c2c47399f070136a55b3cd02d520af86Improvement of the C-glycosylation Step for the Synthesis of RemdesivirXue, Fei; Zhou, Xinbo; Zhou, Ruijie; Zhou, Xiaohan; Xiao, Dian; Gu, Eric; Guo, Xiaowen; Xiang, Ji; Wang, Ke; Yang, Likai; Zhong, Wu; Qin, YongOrganic Process Research & Development (2020), 24 (9), 1772-1777CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The bulk supply of C-nucleoside analog antiviral Covid-19 drug remdesivir I is largely hampered by a low-yielding C-glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodol. for this crit. transformation. By utilizing diisopropylamine as a cost-effective additive, the addn. reaction furnishes an optimal yield of 75% of the desired ribofuranoside adduct II, representing the highest yield obtained thus far for this key step. The method proved suitable for hectogram scale synthesis without column chromatog. operations.
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For selected reviews and representative examples, see:
(a) Plouffe, P.; Macchi, A.; Roberge, D. M. From Batch to Continuous Chemical Synthesis-a Toolbox Approach. Org. Process Res. Dev. 2014, 18, 1286– 1294, DOI: 10.1021/op500191812ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFamsrnN&md5=92f3093d118ee29cda5bf76a8cc2fc7aFrom Batch to Continuous Chemical Synthesis-A Toolbox ApproachPlouffe, Patrick; Macchi, Arturo; Roberge, Dominique M.Organic Process Research & Development (2014), 18 (11), 1286-1294CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A toolbox approach for the transfer of batch to continuous chem. synthesis is presented. The approach considers reaction kinetics (Type A, B, C), reacting phases (single phase, liq.-liq., gas-liq. and liq.-solid), and the reaction network (parallel and consecutive reactions) in order to select the most appropriate reactor module (Plate, Coil, or CSTR) for continuous operation. Then, three case studies using these three fundamental reactors are presented but require special considerations. For the reaction of dimethyl-oxalate with ethylmagnesium chloride, a plug-flow multi-injection technol. must be used to decrease the local heat generation and improve yield. For the nitration of salicylic acid, a Plate reactor with mixing elements favoring some back-mixing followed by a plug-flow system at elevated temps. is used instead of a tandem mixed-flow CSTR and plug-flow Coil reactor in order to minimize the risk of thermal decompn. of intermediates with a reduced vol. penalty. Finally, a ring-closing metathesis reaction is discussed for which the utilization of a CSTR allows the removal of catalyst-poisoning ethylene formed during the reaction and keeps the substrate concn. low to increase the yield above that of a batch or plug-flow system.(b) Hafner, A.; Filipponi, P.; Piccioni, L.; Meisenbach, M.; Schenkel, B.; Venturoni, F.; Sedelmeier, J. A Simple Scale-up Strategy for Organolithium Chemistry in Flow Mode: From Feasibility to Kilogram Quantities. Org. Process Res. Dev. 2016, 20, 1833– 1837, DOI: 10.1021/acs.oprd.6b0028112bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFKmsLrM&md5=cfa5a1b1d293af64b2d751d9b69314c2A Simple Scale-up Strategy for Organolithium Chemistry in Flow Mode: From Feasibility to Kilogram QuantitiesHafner, Andreas; Filipponi, Paolo; Piccioni, Lorenzo; Meisenbach, Mark; Schenkel, Berthold; Venturoni, Francesco; Sedelmeier, JoergOrganic Process Research & Development (2016), 20 (10), 1833-1837CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A platform for conducting organolithium chem. in continuous flow mode, covering the scales from medicinal chem. to later phase process development, is described. The use of this flow setup, which mimics the concept of flash chem. on scale, was demonstrated by the exemplary, large-scale prepn. of (4-fluoro-2-(trifluoromethyl)phenyl)boronic acid following a reaction sequence of halogen/lithium exchange, borylation, and semibatch workup. Also, the key factors and corresponding practical assessments required for the streamlined and seamless scale-up from lab. environment to higher productivity are highlighted.(c) Colella, M.; Nagaki, A.; Luisi, R. Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents. Chem.–Eur. J. 2020, 26, 19– 32, DOI: 10.1002/chem.20190335312chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFWntrjI&md5=f0cf6f1e3d71ff7b3fc7e4e9d6b50eb9Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic ReagentsColella, Marco; Nagaki, Aichiiro; Luisi, RenzoChemistry - A European Journal (2020), 26 (1), 19-32CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This concept article highlights the impact of flow chem. for exploiting highly reactive organometallic reagents and that how the well-known advantages concerning safety, scalability, and productivity, flow chem. make possible processes that are impossible to control by using the traditional batch approach.(d) Power, M.; Alcock, E.; McGlacken, G. P. Organolithium Bases in Flow Chemistry: A Review. Org. Process Res. Dev. 2020, 24, 1814– 1838, DOI: 10.1021/acs.oprd.0c0009012dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXot1Wmtrk%253D&md5=71d6546354b297a71f7455e7c2edad70Organolithium Bases in Flow Chemistry: A ReviewPower, Mark; Alcock, Emma; McGlacken, Gerard P.Organic Process Research & Development (2020), 24 (10), 1814-1838CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review discusses the use of organolithium compds. such as butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, phenyllithium, sec-butyllithium, and hexyllithium as bases for deprotonation reactions in continuous flow. - 13
For selected reviews of flash chemistry, see:
(a) Yoshida, J. I.; Nagaki, A.; Yamada, T. Flash Chemistry: Fast Chemical Synthesis by Using Microreactors. Chem.-Eur. J. 2008, 14, 7450– 7459, DOI: 10.1002/chem.20080058213ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFeisL%252FP&md5=bc6cdad1ed531455a1687e9079c0a44aFlash chemistry: fast chemical synthesis by using microreactorsYoshida, Jun-ichi; Nagaki, Aiichiro; Yamada, TakeshiChemistry - A European Journal (2008), 14 (25), 7450-7459CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)This review provides a brief outline of the concept of flash chem. for carrying out extremely fast reactions in org. synthesis by using microreactors. Generation of highly reactive species is one of the key elements of flash chem. Another important element of flash chem. is the control of extremely fast reactions to obtain the desired products selectively. Fast reactions are usually highly exothermic, and heat removal is an important factor in controlling such reactions. Heat transfer occurs very rapidly in microreactors by virtue of a large surface area per unit vol., making precise temp. control possible. Fast reactions often involve highly unstable intermediates, which decomp. very quickly, making reaction control difficult. The residence time can be greatly reduced in microreactors, and this feature is quite effective in controlling such reactions. For extremely fast reactions, kinetics often cannot be used because of the lack of homogeneity of the reaction environment when they are conducted in conventional reactors such as flasks. Fast mixing using micromixers solves such problems. The concept of flash chem. has been successfully applied to various org. reactions including: highly exothermic reactions that are difficult to control in conventional reactors; reactions in which a reactive intermediate easily decomps. in conventional reactors; reactions in which undesired byproducts are produced in the subsequent reactions in conventional reactors; and reactions whose products easily decomp. in conventional reactors. The concept of flash chem. can be also applied to polymer synthesis. Cationic polymn. can be conducted with an excellent level of mol.-wt. control and mol.wt. distribution control.(b) Yoshida, J.; Takahashi, Y.; Nagaki, A. Flash Chemistry: Flow Chemistry That Cannot Be Done in Batch. Chem. Commun. 2013, 49, 9896– 9904, DOI: 10.1039/c3cc44709j13bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFOisbjE&md5=a249ebf59bd5beadf45e0545abfe6c2dFlash chemistry: flow chemistry that cannot be done in batchYoshida, Jun-ichi; Takahashi, Yusuke; Nagaki, AiichiroChemical Communications (Cambridge, United Kingdom) (2013), 49 (85), 9896-9904CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Flash chem. based on high-resoln. reaction time control using flow microreactors enables chem. reactions that cannot be done in batch and serves as a powerful tool for lab. synthesis of org. compds. and for prodn. in chem. and pharmaceutical industries.(c) Fanelli, F.; Parisi, G.; Degennaro, L.; Luisi, R. Contribution of Microreactor Technology and Flow Chemistry to the Development of Green and Sustainable Synthesis. Beilstein. J. Org. Chem. 2017, 13, 520– 542, DOI: 10.3762/bjoc.13.5113chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFagt7rL&md5=f9e152aac9de38893826aa8a8bd5ea34Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesisFanelli, Flavio; Parisi, Giovanna; Degennaro, Leonardo; Luisi, RenzoBeilstein Journal of Organic Chemistry (2017), 13 (), 520-542CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)Microreactor technol. and flow chem. could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chem., catalysis, hazardous chem. and continuous flow processing are described. Selected examples highlight the role that flow chem. could play in the near future for a sustainable development.(d) Nagaki, A. Recent Topics of Functionalized Organolithiums Using Flow Microreactor Chemistry. Tetrahedron Lett. 2019, 60, 150923 DOI: 10.1016/j.tetlet.2019.07.01413dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlOgsr7P&md5=b5576d14bf42b723e2e31f576dec2bcfRecent topics of functionalized organolithiums using flow microreactor chemistryNagaki, AiichiroTetrahedron Letters (2019), 60 (32), 150923CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)A review. Examples in this mini-review illustrate the potential of flow microreactor chem. in chem. science and chem. prodn. Flow microreactors provide a powerful method for novel transformations via functional organolithiums that cannot be achieved using a conventional macro batch reactor. - 14
Although handling solids in flow remains a challenge, commercial reactors do exist to achieve this purpose. For selected examples, see:
(a) Bianchi, P.; Williams, J. D.; Kappe, C. O. Oscillatory Flow Reactors for Synthetic Chemistry Applications. J. Flow Chem. 2020, 10, 475– 490, DOI: 10.1007/s41981-020-00105-614ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFClsbvJ&md5=851b47b5f9f3ecdb5406522fcf29a457Oscillatory flow reactors for synthetic chemistry applicationsBianchi, Pauline; Williams, Jason D.; Kappe, C. OliverJournal of Flow Chemistry (2020), 10 (3), 475-490CODEN: JFCOBJ; ISSN:2063-0212. (Akademiai Kiado)Abstr.: 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 liq.-liq. 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 technol. and overviews the synthetic applications of OFRs for liq.-liq. and solid-liq. biphasic systems.(b) Browne, D. L.; Deadman, B. J.; Ashe, R.; Baxendale, I. R.; Ley, S. V. Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell Reactor. Org. Process Res. Dev. 2011, 15, 693– 697, DOI: 10.1021/op200022314bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFyis7s%253D&md5=a6a2a00190be2525f694e9767d4ab607Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell ReactorBrowne, Duncan L.; Deadman, Benjamin J.; Ashe, Robert; Baxendale, Ian R.; Ley, Steven V.Organic Process Research & Development (2011), 15 (3), 693-697CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A general method for the continuous processing of suspensions and particulates is reported. A com. available agitating cell reactor which uses a transverse mixing motion to maintain solids in suspension was successfully applied to a salt-forming reaction. The flow device delivered 208 g of N-iodomorpholinium hydroiodide salt over a 9-h period (equating to 3.88 kg/wk) under optimized conditions. The reactor is suitable for the medium-scale (5 kg) processing of solid-forming reactions and appears to offer the potential for a variety of more complex applications.(c) Pomberger, A.; Mo, Y.; Nandiwale, K. Y.; Schultz, V. L.; Duvadie, R.; Robinson, R. I.; Altinoglu, E. I.; Jensen, K. F. A Continuous Stirred-Tank Reactor (CSTR) Cascade for Handling Solid-Containing Photochemical Reactions. Org. Process Res. Dev. 2019, 23, 2699– 2706, DOI: 10.1021/acs.oprd.9b0037814chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitV2hs7fN&md5=f65f76a0a8fce80855407cb46f7388a2A Continuous Stirred-Tank Reactor (CSTR) Cascade for Handling Solid-Containing Photochemical ReactionsPomberger, Alexander; Mo, Yiming; Nandiwale, Kakasaheb Y.; Schultz, Victor L.; Duvadie, Rohit; Robinson, Richard I.; Altinoglu, Erhan I.; Jensen, Klavs F.Organic Process Research & Development (2019), 23 (12), 2699-2706CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)Visible-light photoredox reactions have been demonstrated to be powerful synthetic tools to access pharmaceutically relevant compds. However, many photoredox reactions involve insol. starting materials or products that complicate the use of continuous flow methods. By integrating a new solid-feeding strategy and a continuous stirred-tank reactor (CSTR) cascade, we realize a new solid-handling platform for conducting heterogeneous photoredox reactions in flow. Residence time distributions for single phase and solid particles characterize the hydrodynamics of the heterogeneous flow in the CSTR cascade. Silyl radical-mediated metallaphotoredox cross-electrophile coupling reactions with an inorg. base as the insol. starting material demonstrate the use of the platform. Gram-scale synthesis is achieved in 13 h of stable operation. - 15(a) Kockmann, N.; Roberge, D. M. Scale-up Concept for Modular Microstructured Reactors Based on Mixing, Heat Transfer, and Reactor Safety. Chem. Eng. Process. 2011, 50, 1017– 1026, DOI: 10.1016/j.cep.2011.05.02115ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFKrs7rL&md5=6eb42307019749fad81b037dddb9daf4Scale-up concept for modular microstructured reactors based on mixing, heat transfer, and reactor safetyKockmann, Norbert; Roberge, Dominique M.Chemical Engineering and Processing (2011), 50 (10), 1017-1026CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)Microstructured reactors are characterized by rapid mixing processes and excellent temp. control of chem. reactions. These properties allow the safe operation of hazardous chem. in intensified processes. Problems occur during scale-up of these processes, where heat transfer becomes the limiting effect. With high flow rates and transitional or even turbulent flow regimes in small channels, rapid mixing and excellent heat transfer can be maintained up to high prodn. rates. For exothermic reactions, limits for parametric sensitivity and safe operation are shown from literature and combined with convective heat transfer for consistent scale-up. Good knowledge of reaction kinetics, thermodn. and heat transfer is essential to det. runaway regions for exothermic reactions. From these correlations, consistent channel design and continuous-flow reactor setup is shown.(b) Plouffe, P.; Roberge, D. M.; Macchi, A. Liquid-Liquid Flow Regimes and Mass Transfer in Various Micro-Reactors. Chem. Eng. J. 2016, 300, 9– 19, DOI: 10.1016/j.cej.2016.04.07215bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmslSnsL8%253D&md5=2bcbcbef1e5bc869c2658117517b4cceLiquid-liquid flow regimes and mass transfer in various micro-reactorsPlouffe, Patrick; Roberge, Dominique M.; Macchi, ArturoChemical Engineering Journal (Amsterdam, Netherlands) (2016), 300 (), 9-19CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)The flow regimes and mass transfer rates in five complex micro-reactors with different mixing mechanisms were investigated using the two-phase alk. hydrolysis of 4-nitrophenyl acetate. N-Butanol and toluene were used as org. solvents. Using n-butanol in curvature-based micro-mixers, the flow regime evolved from slug to parallel to drop/dispersed flow with increasing flow rates. In obstacle-based micro-mixers, no parallel flow was obsd. Using toluene, no parallel flow was obsd. for all reactors. The conversion of 4-nitrophenyl acetate was found to be strongly dependent on the flow regime. In slug and parallel flow, the conversion generally decreased with an increase in flow rate whereas it typically increased in drop flow and was const. or slightly decreased in dispersed flow. The different micro-mixers were compared using the overall volumetric mass transfer coeff., Korga, which was primarily a function of the rate of energy dissipation within the dispersed flow regime. The geometry itself impacts the resulting flow regime and rate of energy dissipation at a given flow rate. The micro-reactors were then compared using modified Damk.ovrddot.ohler's nos. Curvature-based reactors were found to be inadequate for liq.-liq. reactions under the studied conditions, as they favor parallel flow patterns and yield relatively low interphase mass transfer rates.
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For selected examples of chemistry carried out in this reactor platform, see:
(a) Sagmeister, P.; Williams, J. D.; Hone, C. A.; Kappe, C. O. Laboratory of the Future: A Modular Flow Platform with Multiple Integrated PAT Tools for Multistep Reactions. React. Chem. Eng. 2019, 4, 1571– 1578, DOI: 10.1039/c9re00087a16ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmvFeltb0%253D&md5=4a048b44692aad146c3b8cd9f20fa411Laboratory of the future: a modular flow platform with multiple integrated PAT tools for multistep reactionsSagmeister, Peter; Williams, Jason D.; Hone, Christopher A.; Kappe, C. OliverReaction Chemistry & Engineering (2019), 4 (9), 1571-1578CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Currently, the monitoring of multistep continuous flow processes by multiple anal. sources is still seen as a resource intensive and specialized activity. In this article, the coupling of a modular microreactor platform with real-time monitoring by inline IR and NMR, in addn. to online UPLC, is described. Using this platform, we rapidly generated exptl. data (17 iterations in under 2 h) to access information on the different chem. species at multiple points within the reactor and to generate process understanding. We highlight the application of the platform in the optimization of a multistep organolithium transformation. The optimized continuous flow conditions were demonstrated in a scale-out expt. with in-process monitoring to afford the desired product in 70% isolated yield and provided a throughput of 4.2 g h-1.(b) Sagmeister, P.; Poms, J.; Williams, J. D.; Kappe, C. O. Multivariate Analysis of Inline Benchtop NMR Data Enables Rapid Optimization of a Complex Nitration in Flow. React. Chem. Eng. 2020, 5, 677– 684, DOI: 10.1039/d0re00048e16bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjsVyjsbs%253D&md5=793e67482ebaa5004295d70f361aa98aMultivariate analysis of inline benchtop NMR data enables rapid optimization of a complex nitration in flowSagmeister, Peter; Poms, Johannes; Williams, Jason D.; Kappe, C. OliverReaction Chemistry & Engineering (2020), 5 (4), 677-684CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)Inline benchtop NMR anal. is established as a powerful tool for reaction monitoring, but its capabilities are somewhat limited by low spectral resoln., often leading to overlapping peaks and difficulties in quantification. Using a multivariate anal. (MVA) statistical approach to data processing these hurdles can be overcome, enabling accurate quantification of complex product mixts. By employing rapid data acquisition (2.0 s recording time per spectrum), we demonstrate the use of inline benchtop NMR to guide the optimization of a complex nitration reaction in flow. Accurate quantification of four overlapping species was possible, enabling generation of a robust DoE model along with accurate evaluation of dynamic expts.(c) von Keutz, T.; Cantillo, D.; Kappe, C. O. Continuous Flow Synthesis of Terminal Epoxides from Ketones Using in Situ Generated Bromomethyl Lithium. Org. Lett. 2019, 21, 10094– 10098, DOI: 10.1021/acs.orglett.9b0407216chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1OhurjE&md5=f247b28ff31fafc99b8483937d225c25Continuous Flow Synthesis of Terminal Epoxides from Ketones Using in Situ Generated Bromomethyl Lithiumvon Keutz, Timo; Cantillo, David; Kappe, C. OliverOrganic Letters (2019), 21 (24), 10094-10098CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A scalable procedure for the direct prepn. of epoxides from ketones has been developed. The method is based on the carefully controlled generation of (bromomethyl)lithium (LiCH2Br) from inexpensive CH2Br2 and MeLi in a continuous flow reactor. The reaction has shown excellent selectivity for a variety of substrates, including α-chloroketones, which typically fail under classic Corey-Chaykovsky conditions. This advantage has been used to develop a novel route toward the drug fluconazole.(d) von Keutz, T.; Cantillo, D.; Kappe, C. O. Organomagnesium Based Flash Chemistry: Continuous Flow Generation and Utilization of Halomethylmagnesium Intermediates. Org. Lett. 2020, 22, 7537– 7541, DOI: 10.1021/acs.orglett.0c0272516dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVSkurfL&md5=d6ea59261d53707252ade018bda83518Organomagnesium Based Flash Chemistry: Continuous Flow Generation and Utilization of Halomethylmagnesium Intermediatesvon Keutz, Timo; Cantillo, David; Kappe, C. OliverOrganic Letters (2020), 22 (19), 7537-7541CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The generation of highly unstable chloromethylmagnesium chloride in a continuous flow reactor and its reaction with aldehydes and ketones is reported. With this strategy, chlorohydrins and epoxides were synthesized within a total residence time of only 2.6 s. The outcome of the reaction can be tuned by simply using either a basic or an acidic quench. Very good to excellent isolated yields, up to 97%, have been obtained for most cases (30 examples).See also reference (10)
- 17(a) Reckamp, J. M.; Bindels, A.; Duffield, S.; Liu, Y. C.; Bradford, E.; Ricci, E.; Susanne, F.; Rutter, A. Mixing Performance Evaluation for Commercially Available Micromixers Using Villermaux-Dushman Reaction Scheme with the Interaction by Exchange with the Mean Model. Org. Process Res. Dev. 2017, 21, 816– 820, DOI: 10.1021/acs.oprd.6b0033217ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnt1Cht7w%253D&md5=6aab5c1f14c5f9b4b6db36b4fb44d46dMixing Performance Evaluation for Commercially Available Micromixers Using Villermaux-Dushman Reaction Scheme with the Interaction by Exchange with the Mean ModelReckamp, Joseph M.; Bindels, Ashira; Duffield, Sophie; Liu, Yangmu Chloe; Bradford, Eric; Ricci, Eric; Susanne, Flavien; Rutter, AndrewOrganic Process Research & Development (2017), 21 (6), 816-820CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)The development of low-vol. continuous processes for the pharmaceutical industry requires a greater understanding of mixing in microreactors. In this paper, numerous com. available micromixers are evaluated using the Villermaux-Dushman reaction scheme and the interaction by exchange with the mean (IEM) mixing model to quantify the mixing time. The work presents the mixing times as a function of flow rate and energy dissipation for mixers including T-Mixers, Ehrfeld Mikrotechnik BTS micromixers, and Syrris Asia microchips.(b) Macchi, A.; Plouffe, P.; Patience, G. S.; Roberge, D. M. Experimental Methods in Chemical Engineering: Micro-Reactors. Can. J. Chem. Eng. 2019, 97, 2578– 2587, DOI: 10.1002/cjce.2352517bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1SiurvI&md5=eefd68d6cbb4f1bee667d066fbfdcfd8Experimental methods in chemical engineering: Micro-reactorsMacchi, Arturo; Plouffe, Patrick; Patience, Gregory S.; Roberge, Dominique M.Canadian Journal of Chemical Engineering (2019), 97 (10), 2578-2587CODEN: CJCEA7; ISSN:0008-4034. (John Wiley & Sons, Inc.)Where as the bulk chem. industry has historically sought economic advantage through economies of scale, a paradigm shift has researchers developing systems on smaller scales. Nano-cages and nano-actuators increase selectivity and robustness at the mol. scale. In parallel, micro-contactors with sub-millimeter lateral dimensions are decreasing boundary layers that restrict heat and mass transfer and thus meet the objectives of process intensification with great increases in productivity with a smaller footprint. These contactors continue to serve chem. engineers and chemists to synthesize fine chems. and characterize catalysts; however, they have now been adopted for sensors in biol. and biochem. systems. A bibliometric anal. of articles indexed in the Web of Science in 2016 and 2017 identified five major clusters of research: catalysis and bulk chems.; nanoparticles; org. synthesis and flow chem.; systems and micro-fluidics applied to biochem.; and micro-channel reactors and mass transfer. In the early 1990s, less than 100 articles a year mentioned micro-reactors, while over 943 articles mentioned it in 2017. Here, we introduce micro-reactors and their role in the continuous synthesis of fine chems. across the various scales to commercialization.
- 18Köckinger, M.; Wyler, B.; Aellig, C.; Roberge, D. M.; Hone, C. A.; Kappe, C. O. Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-Methoxyaniline to Prepare a Key Building Block of Osimertinib. Org. Process Res. Dev. 2020, 24, 2217– 2227, DOI: 10.1021/acs.oprd.0c00254There is no corresponding record for this reference.
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For selected examples of organometallic processes run at higher temperatures in continuous flow, see:
(a) Hafner, A.; Mancino, V.; Meisenbach, M.; Schenkel, B.; Sedelmeier, J. Dichloromethyllithium: Synthesis and Application in Continuous Flow Mode. Org. Lett. 2017, 19, 786– 789, DOI: 10.1021/acs.orglett.6b0375319ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFeqsbs%253D&md5=a2e8d661d499f68b7e0291ed5ffef41eDichloromethyllithium: Synthesis and Application in Continuous Flow ModeHafner, Andreas; Mancino, Valentina; Meisenbach, Mark; Schenkel, Berthold; Sedelmeier, JoergOrganic Letters (2017), 19 (4), 786-789CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)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 temps. of -30 °C, whereas typical temps. 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 chromatog.(b) Murray, P. R. D.; Browne, D. L.; Pastre, J. C.; Butters, C.; Guthrie, D.; Ley, S. V. Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen. Org. Process Res. Dev. 2013, 17, 1192– 1208, DOI: 10.1021/op400154819bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ymt7nJ&md5=9971d8ef8e035e947bed0537c44e3791Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-TamoxifenMurray, Philip R. D.; Browne, Duncan L.; Pastre, Julio C.; Butters, Chris; Guthrie, Duncan; Ley, Steven V.Organic Process Research & Development (2013), 17 (9), 1192-1208CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)A review. A new enabling technol. for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilizes a newly developed, chem. resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal-halogen exchange, addn., addn.-elimination, conjugate addn., and partial redn., are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations. - 20Based on 0.6 equiv, at a price of £122 (∼€139) per 100g, Fluorochem. http://www.fluorochem.co.uk/Products/Product?code=S01325 (accessed 02-04-2021).There is no corresponding record for this reference.
- 21(a) NdCl3 (anhydrous) based on 1 equiv, at a price of €708 per 100 g, Alfa Aesar. https://www.alfa.com/de/catalog/018680/ (accessed 02-04-2021).There is no corresponding record for this reference.(b) Tetrabutylammonium chloride based on 1 equiv, at a price of €113 per 100 g, Sigma Aldrich. https://www.sigmaaldrich.com/catalog/product/mm/814645 (accessed 02-04-2021).There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.1c00024.
Further details of reaction setup, experimental results, and characterization data (PDF)
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