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Catalytic Static Mixers for the Continuous Flow Hydrogenation of a Key Intermediate of Linezolid (Zyvox)
Contributor(s):: Gardiner, James, Nguyen, Xuan, Genet, Charlotte, Horne, Mike D., Hornung, Christian H., Tsanaktsidis, John
Catalytic static mixers (CSMs) were used for the efficient preparation of a key intermediate of the antimicrobial drug linezolid (Zyvox). The approach combines 3D printing and additive manufacturing techniques with continuous flow processing to produce a general method for catalytic...
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Scalable continuous flow hydrogenations using Pd/Al2O3-coated rectangular cross-section 3D-printed static mixers
Contributor(s):: Lebl, René, Zhu, Yutong, Ng, Derrick, Hornung, Christian H., Cantillo, David, Kappe, C. Oliver
A novel type of catalytic static mixers with rectangular cross-section coated with Pd/Al2O3 has been developed. The catalytic mixers, produced by additive manufacturing and coated with the metal catalyst, have shown excellent catalytic performance for continuous flow hydrogenation of...
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Continuous Selective Hydrogenation of Refametinib Iodo-nitroaniline Key Intermediate DIM-NA over Raney Cobalt Catalyst at kg/day Scale with Online UV–Visible Conversion Control
Contributor(s):: Said, Mourad Ben, Baramov, Todor, Herrmann, Tanja, Gottfried, Michael, Hassfeld, Jorma, Roggan, Stefan
The continuous selective hydrogenation of the iodo-nitroaromatic refametinib active pharmaceutical ingredient (API) intermediate (2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (DIM-NA) to the corresponding iodo-aniline...
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Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation
Contributor(s):: Johnson, Martin D., May, Scott A., Calvin, Joel R., Remacle, Jacob, Stout, James R., Diseroad, William D., Zaborenko, Nikolay, Haeberle, Brian D., Sun, Wei-Ming, Miller, Michael T., Brennan, John
A fully continuous process including an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization was designed, developed, and demonstrated at pilot scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and...
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Development and Manufacturing GMP Scale-Up of a Continuous IrCatalyzed Homogeneous Reductive Amination Reaction
Contributor(s):: May, Scott A., Johnson, Martin D., Buser, Jonas Y., Campbell, Alison N., Frank, Scott A., Haeberle, Brian D., Hoffman, Philip C., Lambertus, Gordon R., McFarland, Adam D., Moher, Eric D., White, Timothy D., Hurley, D. Declan, Corrigan, Aoife P., Gowran, Olivia, Kerrigan, Niall G., Kissane, Marie G., Lynch, Regina R., Sheehan, Paul, Spencer, Richard D., Pulley, Shon R., Stout, James R.
The design, development, and scale-up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at...
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Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound
Contributor(s):: Chen, Jian, Przyuski, Katrin, Roemmele, Renee, Bakale, Roger P.
In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation...
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A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones
Contributor(s):: Viviano, Monica, Glasnov, Toma N., Reichart, Benedik, Tekautz, Guenter, Kappe, C. Oliver
Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivatives including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compounds raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its methyl ether...
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Latent Variables-Based Process Modeling of a Continuous Hydrogenation Reaction in API Synthesis of Small Molecules
Contributor(s):: Shi, Zhenqi, Zaborenko, Nikolay, Reed, David
Continuous manufacturing can be benefited by the use of the Quality by Design (QbD) strategy for robust process development and by the use of Process Analytical Technology (PAT) for real-time process monitoring and control. A successful implementation of QbD and PAT for continuous processes...
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High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine
Contributor(s):: Yu, E, Mangunuru, HPRTelang, NS, Kong, CJ, Verghese, J, Gilliland, SE, Ahmad, S, Dominey, RN, Gupton, BF
Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API's) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial...