-
Axial Chirality in the Sotorasib Drug Substance, Part 2: Leveraging a High-Temperature Thermal Racemization to Recycle the Classical Resolution Waste Stream
Contributor(s):: Beaver, Matthew G., Brown, Derek B., Campbell, Kiersten, Fang, Yuan-Qing, Ford, David D., Mardirossian, Narbe, Nagy, Kevin D., Rötheli, Andreas R., Sheeran, Jillian W., Telmesani, Reem, Parsons, Andrew T.
The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described. Part 1 of this two-part series details the design and execution of a classical resolution to generate...
-
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...
-
Fast Claisen condensation reaction optimization in a continuous flow reactor
Contributor(s):: Michałek, Stanisław, Powała, Antoni, Gurba-Bryśkiewicz, Lidia, Piórkowska, Natalia, Olejkowska, Patrycja, Yamani, Abdellah, Ochal, Zbigniew, Dubiel, Krzysztof, Wieczorek, Maciej
In our previous study, we described the batch synthesis of CPL304110, an innovative pan-FGFR inhibitor. Herein, we transferred the Claisen condensation reaction, one of the synthesis steps to a continuous flow reactor. A simple solvent switch from ethanol to tetrahydrofuran shortened the original...
-
Flash Chemistry Approach to Organometallic C-Glycosylation for the Synthesis of Remdesivir
Contributor(s):: Keutz, Timo von, Williams, Jason D., Kappe, C. Oliver
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...
-
Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonist†
Contributor(s):: Prieschl, Michael, García-Lacuna, Jorge, Munday, Rachel, Leslie, Kevin, O'Kearney-McMullan, Anne, Hone, Christopher A., Kappe, C. Oliver
The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the reduction of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clinical trials for the...
-
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...
-
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...
-
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...
-
Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib
Contributor(s):: Kaldre, Dainis, Stocker, Severin, Linder, David, Reymond, Helena, Schuster, Andreas, Lamerz, Jens, Hildbrand, Stefan, Püntener, Kurt, Berry, Malcolm, Sedelmeier, Jörg
This article outlines the development of a continuous flow process for the manufacture of a key intermediate of the active pharmaceutical ingredient ipatasertib for the treatment of metastatic castration-resistant prostate cancer and triple-negative metastatic breast cancer. The reaction sequence...
-
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...
-
Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control
Contributor(s):: Marzijarani, Nastaran Salehi, Fine, Adam J., Dalby, Stephen M., Gangam, Rekha, Poudyal, Samiksha, Behre, Taylor, Ekkati, Anil R., Armstrong, Brittany M., Shultz, C. Scott, Dance, Zachary E. X., Stone, Kevin
A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity of the reduction reaction toward the CO2 byproduct. Special effort was required to design a scale-insensitive process for the removal of...
-
Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions
Contributor(s):: Franco, Marcelo S., Silva, Rodrigo C., Rosa, Gabriel H. S., Flores, Lara M., Oliveira, Kleber T. de, Assis, Francisco F. de
An original total synthesis of the antiepileptic drug brivaracetam (BRV) is reported. The key step in the synthesis consists of an enantioselective photochemical Giese addition, promoted by visible-light and the chiral bifunctional photocatalyst Δ-RhS. Continuous flow conditions were employed to...
-
A Flow Process Built upon a Batch Foundation—Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis
Contributor(s):: Lim, John Jin, Arrington, Kenneth, Dunn, Anna L., Leitch, David C., Andrews, Ian, Curtis, Neil R., Hughes, Mark J., Tray, Daniel R., Wade, Charles E., Whiting, Matthew P., Goss, Charles, Liu, Yangmu Chloe, Roesch, Brian M.
This paper describes recent efforts to apply flow technology in the preparation of the key amino alcohol intermediate 3b so as to address manufacturability issues present in the batch process of a PRMT5 inhibitor. The continuous process, one of the first reported pharmaceutical processes to use...
-
A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process
Contributor(s):: Içten, Elçin, Maloney, Andrew J., Beaver, Matthew G., Zhu, Xiaoxiang, Shen, Dongying E., Robinson, Jo Anna, Parsons, Andrew T., Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.
This article details efforts to characterize and develop a process control strategy for the manufacture of enone 2, a carfilzomib drug substance intermediate obtained through a Barbier-type Grignard reaction of morpholine amide 1. This includes the development of a novel mechanistic model for the...
-
A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration
Contributor(s):: Maloney, Andrew J., Içten, Elçin, Capellades, Gerard, Beaver, Matthew G., Zhu, Xiaoxiang, Graham, Lauren R., Brown, Derek B., Griffin, Daniel J., Sangodkar, Rahul, Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.
This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated...
-
Continuous Multiphase Flow Nitration and Cryogenic Flow Formylation: Enabling Process Development and Manufacturing of Pharmaceutical Intermediates
Contributor(s):: Cardinal-David, Benoit, Harper, Kaid C., Verma, Anuj, Hanna, David, Caspi, Daniel D., Vitale, Christopher, Bien, Jeffrey T., Wang, Zhe, Diwan, Moiz
Manufacturing API and pharmaceutical intermediates requires the development of scalable, safe, and environmentally friendly processes. Reactions with high exothermicity or otherwise hazardous in nature, as well as reactions involving the formation of unstable intermediates, can benefit from...
-
Integrated Batch and Continuous Flow Process for the Synthesis of Goniothalamin
Contributor(s):: Pastre, Julio C., Murray, Philip R. D., Browne, Duncan L., Brancaglion, Guilherme A., Galaverna, Renan S., Pilli, Ronaldo A., Ley, Steven V.
An integrated batch and continuous flow process has been developed for the gram-scale synthesis of goniothalamin. The synthetic route hinges upon a telescoped continuous flow Grignard addition followed by an acylation reaction capable of delivering a racemic goniothalamin precursor (16) (20.9 g...
-
Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-methoxyaniline to Prepare a Key Building Block of Osimertinib
Contributor(s):: Köckinger, Manuel, Wyler, Benjamin, Aellig, Christof, Roberge, Dominique M., Hone, Christopher A., Kappe, C. Oliver
The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro-2-methoxy-5-nitroaniline, a key building block in the synthesis of osimertinib, a third-generation...
-
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...
-
Continuous Flow Synthesis of 16-Dehydropregnenolone Acetate, a Key Synthon for Natural Steroids and Drugs
Contributor(s):: Mancino, Valentina, Cerra, Bruno, Piccinno, Alessandro, Gioiello, Antimo
A telescoped multistep process to provide the continuous delivery of 16-dehydropregnenolone acetate (16-DPA) from diosgenin is described. The method was evaluated through batch screenings that helped to identify critical bottlenecks and flowability, and the best conditions were optimized in flow...
-
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...
-
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 4: Formylation–Cyclization as a Flow–Batch Process Leads to Significant Improvements in Process Mass Intensity (PMI) and CO Generated versus the Batch–
Contributor(s):: Otte, Douglas A. L., Basu, Kallol, Jellett, Lisa, Whittington, Michael, Spencer, Glenn, Burris, Matthew, Corcoran, Emily B., Stone, Kevin, Nappi, Jarod, Arvary, Rebecca A., Donoghue, David, Ren, Hong, Maloney, Kevin M., Naber, John R.
Gefapixant citrate (MK-7264) is a P2X3 antagonist for the treatment of chronic cough. The second generation manufacturing route developed for the Step 3A/3B formylation–cyclization reaction to generate the key intermediate diaminopyrimidine (1) (AF-072) required a significant excess of ethyl...
-
Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir
Contributor(s):: Vieira, Tiago, Stevens, Andrew C., Chtchemelinine, Andrei, Gao, Detian, Badalov, Pavel, Heumann, Lars
The implementation of cyanation chemistry at manufacturing scales using batch equipment can be challenging because of the hazardous nature of the reagents employed and the tight control of reaction parameters, including cryogenic temperatures, that help to afford acceptable selectivity and...
-
Semicontinuous Process for GMP Manufacture of a Carbapenem Intermediate via Carbene Insertion Using an Immobilized Rhodium Catalyst
Contributor(s):: Gage, James R., Chen, Furong, Dong, Changming, Gonzalez, Miguel A., Jiang, Yong, Luo, Yong, McLaws, Mark D., Tao, Jian
A two-stage flow process for cGMP manufacture of a commercially important carbapenem intermediate was developed. Stage 1 featured an intramolecular N–H insertion reaction catalyzed by an immobilized rhodium catalyst. In stage 2, phosphorylation of the resulting keto ester intermediate afforded...
-
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...