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Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination
Contributor(s):: Pratley, Cassie, Shaalan, Youssef, Boulton, Lee, Jamieson, Craig, Murphy, John A., Edwards, Lee J.
Flow reactors with enhanced mixing are of interest to the pharmaceutical industry for a range of photochemical applications. Taylor–Couette (vortex, dynamically mixed) reactors have been reported to have intensified mixing and have been used with heterogeneous systems. Our photochemical workflow...
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Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir
Contributor(s):: Kawajiri, Takahiro, Kijima, Akihito, Iimuro, Atsuhiro, Ohashi, Eisaku, Yamakawa, Katsuya, Agura, Kazushi, Masuda, Kengo, Kouki, Kensuke, Kasamatsu, Koji, Yanagisawa, Shuichi, Nakashima, Sho, Shibahara, Setsuya, Toyota, Takashi, Higuchi, Takafumi, Suto, Takahiro, Oohara, Tadashi, Maki, Toshikatsu, Sahara, Naoto, Fukui, Nobuaki, Wakamori, Hisayuki, Ikemoto, Hidaka, Murakami, Hiroaki, Ando, Hiroyasu, Hosoya, Masahiro, Sato, Mizuki, Suzuki, Yusuke, Nakagawa, Yuta, Unoh, Yuto, Hirano, Yoichi, Nagasawa, Yoshitomo, Goda, Satoshi, Ohara, Takafumi, Tsuritani, Takayuki
We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the...
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Establishment and Development of Organolithium-Mediated Continuous Flow Process for Intermediate of Canagliflozin
Contributor(s):: Yano, Gemba, Hyakumura, Mai, Nakano, Kimihiro, Yasukouchi, Hiroaki, Kawachi, Hideo, Funabashi, Makoto, Ohishi, Takahiro, Ogawa, Yu, Nishiyama, Akira
Organolithium species are among the most reactive and useful reagents in organic synthesis, performing a diverse array of valuable chemical transformations, including C–C bond formation in complex compounds. Organolithium-mediated reactions, however, typically require cryogenic conditions to...
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Process parameter and kinetic study for the azidation of a zidovudine intermediate with sodium azide in microreactors
Contributor(s):: Jiang, Rongkun, Xue, Xiao, Zhao, Fang, Zhu, Weiping, Shang, Minjing, Su, Yuanhai, Xu, Yufang, Qian, Xuhong
Zidovudine, i.e., AZT, is an indispensable anti-AIDS drug for highly active antiretroviral therapy. The azidation step is of the most vital importance in the synthetic route of zidovudine. Herein we report the use of microreactors in combination with the simplified azidation system instead of...
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Continuous Flow Chemistry of Metal Mediated Carboxylation and α-Arylation Reactions
Contributor(s):: Venkatraman, Sripathy, Tweedie, Scott, McLaws, Mark, Lathbury, David
Utility of continuous flow chemistry in a carboxylation reaction and palladium-mediated α-arylation reaction is described. A two-step carboxylation reaction of an aryl group involving an anion formation, followed by quench with gaseous carbon dioxide was developed on small scale using HDPE tubes...
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Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material
Contributor(s):: Usutani, Hirotsugu, Nihei, Takashi, Papageorgiou, Charles D., Cork, David G.
A flow chemistry process for the synthesis of a key boronic acid starting material was developed utilizing flow flash chemistry that allowed formation and subsequent productive reaction of an unstable organolithium intermediate. Rapid scale-up from Discovery Chemistry and process optimization to...
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Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology
Contributor(s):: Sagandira, Cloudius R., Watts, Paul
Tamiflu is one of the most effective anti-influenza drugs, which is currently manufactured by Hoffmann-La Roche from shikimic acid. Owing to its importance, more than 60 synthetic routes have been developed to date, however, most of the synthetic routes utilise the potentially hazardous azide...
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Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery
Contributor(s):: Li, Pengbin, Yang, Shaohui, Zhu, Ruiheng, Sun, Baoquan, Li, Zhongbo, Huang, Ping, Buser, Jonas Y., Minguez, Jose Miguel, Ryan, Sarah J.
We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular SNAr cyclization. Interestingly, traditional SNAr conditions resulted in impurity formation. When the starting...
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Use of Lithium Diisopropylamide in Flow: Operability and Safety Challenges Encountered on a Multigram Scale
Contributor(s):: Alonso, Marta, Garcia, Maria Cruz, McKay, Christopher, Thorp, Lee R., Webb, Michael, Edwards, Lee J.
A workflow for the development of organometallic processes in flow was applied to synthesize 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol, a pharmaceutical intermediate. Key factors and corresponding practical assessments required for the scale-up when transferring from batch to flow are...
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Development and Scale-Up of a Continuous Manufacturing Process for a Hydrazine Condensation Reaction
Contributor(s):: Zhu, Ruiheng, Reddy, Ramesh, Ding, Man, Xu, Ming, Deng, Chaoyi, Tadayon, Sam, Li, Hui, Depew, Kristopher, Lane, Benjamin
The development of a continuous manufacturing process for a hydrazine condensation reaction at high temperature is reported. This continuous process represents a safer approach to manufacture 3-phenyl-1H-pyrazol-5-amine at scale and exhibits better impurity control compared to a traditional batch...
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Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination
Contributor(s):: Bottecchia, Cecilia, Lévesque, François, McMullen, Jonathan P., Ji, Yining, Reibarkh, Mikhail, Peng, Feng, Tan, Lushi, Spencer, Glenn, Nappi, Jarod, Lehnherr, Dan, Narsimhan, Karthik, Wismer, Michael K., Chen, Like, Lin, Yipeng, Dalby, Stephen M.
We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical...
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A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine
Contributor(s):: Souza, Juliana M. de, Berton, Mateo, Snead, David R., McQuade, D. Tyler
We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines...
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Development of a Continuous Flow Process for a Matteson Reaction: From Lab Scale to Full-Scale Production of a Pharmaceutical Intermediate
Contributor(s):: Stueckler, Clemens, Hermsen, Peter, Ritzen, Bas, Vasiloiu, Maria, Poechlauer, Peter, Steinhofer, Stefan, Pelz, Andreas, Zinganell, Christopher, Felfer, Ulfried, Boyer, Serge, Goldbach, Michel, de Vries, André, Pabst, Thomas, Winkler, Georg, LaVopa, Vito, Hecker, Scott, Schuster, Christian
Within this paper, we present the design, development, and scale-up of a process for a continuous Matteson reaction to produce a key intermediate toward the β-lactamase inhibitor vaborbactam. This includes the successful implementation of the continuous concept at a multiton production scale for...
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Development and Scale-Up of a Continuous Reaction for Production of an Active Pharmaceutical Ingredient Intermediate
Contributor(s):: McMullen, Jonathan P., Marton, Christopher H., Sherry, Benjamin D., Spencer, Glenn, Kukura, Joseph, Eyke, Natalie S.
Examples of continuous flow reactions in the laboratory setting are becoming commonplace in pharmaceutical drug substance research. Developing these processes for robust commercialization and identifying the scale-up parameters remains a challenge. An aldol reaction in the formation of an active...
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Scaling-up Electroorganic Synthesis Using a Spinning Electrode Electrochemical Reactor in Batch and Flow Mode
Contributor(s):: Petrović, Nikola, Malviya, Bhanwar K., Kappe, C. Oliver, Cantillo, David
Technology for the rapid scale-up of synthetic organic electrochemistry from milligrams to multigrams or multi-100 g quantities is highly desirable. Traditional parallel plate flow electrolysis cells can produce large quantities of material, but transfer from batch to this flow technology...
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Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry
Contributor(s):: Lévesque, François, Rogus, Nicholas J., Spencer, Glenn, Grigorov, Plamen, McMullen, Jonathan P., Thaisrivongs, David A., Davies, Ian W., Naber, John R.
We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV–vis spectroscopy was developed to streamline analysis of the product distribution. As a result of these studies, we have...
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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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Development of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed Hydrogenolysis
Contributor(s):: Zaborenko, Nikolay, Linder, Ryan J., Braden, Timothy M., Campbell, Bradley M., Hansen, Marvin M., Johnson, Martin D.
The design, development, and implementation of a pilot-scale continuous hydrogenolysis in a catalytic packed bed to generate a starting material is described. Control of a critical defluorination impurity under the reaction conditions has been achieved by reducing residence time inside the...
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Development of a Continuous Plug Flow Process for Preparation of a Key Intermediate for Brivanib Alaninate
Contributor(s):: LaPorte, Thomas L., Spangler, LoriHamedi, Mourad, Lobben, Paul, Chan, Steven H., Muslehiddinoglu, Jale, Wang, Steve S. Y.
A thermal runaway potential was identified for the conversion of a tertiary alcohol to a hydroxypyrrolotriazine intermediate in the synthesis of brivanib alaninate. A continuous process was developed to mitigate the potential thermal runaway and allow for safer scale-up. This paper describes the...
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Process Intensification of a Napabucasin Manufacturing Method Utilizing Microflow Chemistry
Contributor(s):: Usutani, Hirotsugu, Yamamoto, Kenji, Hashimoto, Kazuki
Microflow chemistry is one of the newest and most efficient technologies used today for the safe and effective production of medicines. In this paper, we show the use of this technology in the development of a manufacturing method for napabucasin, which has potential in the treatment of...
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Process Intensive Synthesis of Propofol Enabled by Continuous Flow Chemistry
Contributor(s):: Vinet, Laurent, Di Marco, Lorenzo, Kairouz, Vanessa, Charette, André B.
A multi-step process using continuous flow chemistry to produce propofol is described. A scale-up of a 5-stage process (two continuous flow chemical steps, two extractions using a semi-batch approach, and one purification) provided propofol in high purity. This process minimizes the number of...
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Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing
Contributor(s):: Frederick, Michael O., Boyse, Raymond A., Braden, Timothy M., Calvin, Joel R., Campbell, Bradley M., Changi, Shujauddin M., Coffin, Stephanie R., Condon, Carmel, Gowran, Olivia, Groh, Jennifer McClary, Groskreutz, Stephen R., Harms, Zachary D., Humenik, Ashley A., Kallman, Neil J., Klitzing, Nicholas D., Kopach, Michael E., Kretsinger, Juliana K., Lambertus, Gordon R., Lampert, Jeffrey T., Maguire, Laura M., Moynihan, Humphrey A., Mullane, Nessa S., Murphy, John D., O’Mahony, Marie E., Richey, Rachel N., Seibert, Kevin D., Spencer, Richard D., Strege, Mark A., Tandogan, Nil, Torres Torres, Frank L., Tsukanov, Sergey V., Xia, Han
The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide...
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A Three-Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous-Flow Processing
Contributor(s):: Snead, David R., Jamison, Timothy F.
In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90 % for each step. A scale-up of this five-stage process (3 bond-forming steps, one work-up, and one in-line liquid–liquid separation) provided ibuprofen at a...
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Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability
| Contributor(s):: Boros, Zoltán, Nagy-Győr, László, Kátai-Fadgyas, Katalin, Kőhegyi, Imre, Ling, István, Nagy, Tamás, Iványi, Zoltán, Oláh, Márk, Ruzsics, György, Temesi, Ottó, Volk, Balázs
In this study, the piperazine formation step of vortioxetine synthesis was investigated under continuous flow conditions. The batch variant of this step could be carried out at laboratory scale at 130–135 °C with a long reaction time (27 h) followed by a laborious optimization...
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Development of a Continuous Flow Process for the Efficient Preparation of Anti-Tuberculosis-Specific Drug TBAJ-876
| Contributor(s):: Gao, Feng, Zhang, Guowei, Gu, Wenting, Zhang, Zhenfeng, Liu, Zhiqing, Zhang, Wanbin, Li, Jing
Previously, the first asymmetric synthesis of anti-tuberculosis agent TBAJ-876 had been successfully achieved using a synergistic Li/Li catalysis approach, yielding excellent results on a 5 g scale. However, scaling up the process presents significant challenges due to its poor repeatability and...