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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...
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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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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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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...
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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...
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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...
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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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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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End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts†
Contributor(s):: Snead, David R., Jamison, Timothy F.
A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1 : 1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional...
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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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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 of an Organometallic Flow Chemistry Reaction at PilotPlant Scale for the Manufacture of Verubecestat
Contributor(s):: Thaisrivongs, David A., Naber, John R., Rogus, Nicholas J., Spencer, Glenn
We report the development of an organolithium addition to a chiral ketimine at pilot-plant scale using flow chemistry. Given the mixing sensitivity of this process, established previously at both lab and kilogram scale, we conducted critical experiments to understand the impact of flow rate,...
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Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir
Contributor(s):: Susanne, Flavien, Martin, Benjamin, Aubry, Michel, Sedelmeier, Joerg, Lima, Fabio, Sevinc, Serbuelent, Piccioni, Lorenzo, Haber, Julien, Schenkel, Berthold, Venturoni, Francesco
Elbasvir is a potent NS5A antagonist for the treatment of chronic hepatitis C. A seemingly trivial indoline oxidation en route to the target compound was complicated by epimerization of a stereogenic hemiaminal center under most standard oxidation conditions. To address this issue, a novel...
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Match-Making Reactors to Chemistry: A Continuous Manufacturing-Enabled Sequence to a Key Benzoxazole Pharmaceutical Intermediate
Contributor(s):: Yayla, Hatice G., Peng, Feng, Mangion, Ian K., McLaughlin, Mark, Campeau, Louis-Charles, Davies, Ian W.DiRocco, Daniel A., Knowles, Robert R.
The focus of this study was to develop a chemical reaction sequence toward a key benzoxazole building block, required for clinical manufacturing of a lead candidate in the respiratory disease area. The chemistry consisted of initial low-temperature reactions with an organometallic reagent to...
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Using Flow To Outpace Fast Proton Transfer in an Organometallic Reaction for the Manufacture of Verubecestat (MK-8931)
Contributor(s):: Thaisrivongs, David A., Naber, John R., McMullen, Jonathan P.
We report that an organolithium addition to a chiral ketimine, which because of competitive proton transfer proceeds with only modest yield in batch, can be significantly improved in flow. The transformation was discovered to be highly mixing-sensitive but remarkably temperature-independent in...
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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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Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19
Contributor(s):: Bade, Rachel, Bothe, Jameson R., Sirota, Eric, Brunskill, Andrew P. J., Newman, Justin A., Zhang, Yongqian, Tan, Melissa, Zheng, Michelle, Brito, Gilmar, Poirier, Marc, Fier, Patrick S., Xu, Yingju, Ward, Michael D., Stone, Kevin, Lee, Ivan H., Gmitter, Andrew J., Bernardoni, Frank, Zompa, Michael A., Luo, Hanlin, Patel, Sanjaykumar, Masiuk, Tina, Mora, Jeff, Ni, Tong, Okoh, Grace A., Tarabokija, James, Liu, Jiaying, Lowinger, Michael B., Mahmood, Tariq
Molnupiravir is a small-molecule active pharmaceutical ingredient (API) prodrug of a nucleoside analog that was demonstrated to be efficacious for the treatment of patients with COVID-19. Early in the pandemic, Merck & Co. Inc. partnered with Ridgeback Biotherapeutics to accelerate the...
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Highly Efficient Synthesis of HIV NNRTI Doravirine
Contributor(s):: Gauthier, Donald R., Sherry, Benjamin D., Cao, Yang, Journet, Michel, Humphrey, Guy, Itoh, Tetsuji, Tschaen, David M.
The development of an efficient and robust process for the production of HIV NNRTI doravirine is described. The synthesis features a continuous aldol reaction as part of a de novo synthesis of the key pyridone fragment. Conditions for the continuous flow aldol reaction were derived using...
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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 Direct Photocatalytic C–H Fluorination for the Preparative Synthesis of Odanacatib
Contributor(s):: Halperin, Shira D., Kwon, Daniel, Holmes, Michael, Regalado, Erik L., Campeau, Louis-Charles, DiRocco, Daniel A., Britton, Robert
Late-stage C–H fluorination is an appealing reaction for medicinal chemistry. However, the application of this strategy to process research appears less attractive due to the formation and necessary purification of mixtures of organofluorines. Here we demonstrate that γ-fluoroleucine methyl...
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Operation Strategy Development for Grignard Reaction in a Continuous Stirred Tank Reactor
Contributor(s):: Wong, Sze-Wing, Changi, Shujauddin M., Shields, Richard, Bell, Willis, McGarvey, Bernard, Johnson, Martin D., Sun, Wei-Ming, Braden, Tim M., Kopach, Michael E., Spencer, Richard D., Flanagan, Gordon, Murray, Michael
This paper presents a case study in establishing the operation space of a Grignard reaction in a continuous stirred tank reactor (CSTR). The operation space is the multivariate space with the boundary defined by the proven acceptable range of every CSTR process parameter such as flow rates 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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The Synthesis of Bromomethyltrifluoroborates through Continuous Flow Chemistry
Contributor(s):: Broom, Toby, Hughes, Mark, Szczepankiewicz, Bruce G., Ace, Karl, Hagger, Ben, Lacking, Gary, Chima, Ranjit, Marchbank, Graeme, Alford, Gareth, Evans, Paul, Cunningham, Christopher, Roberts, John C., Perni, Robert B., Berry, Malcolm, Rutter, Andrew, Watson, Simon A
A continuous flow process was developed for the synthesis of potassium bromomethyltrifluoroborate, a key precursor for Suzuki–Miyaura coupling reagents. The continuous flow process was used to produce potassium bromomethyltrifluoroborate on scales from grams to kilograms, and the successful...
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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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Comparison of a Batch and Flow Approach for the Lipase-Catalyzed Resolution of a Cyclopropanecarboxylate Ester, A Key Building Block for the Synthesis of Ticagrelor
Contributor(s):: Hugentobler, Katharina G., Rasparini, Marcello, Thompson, Lisa A., Jolley, Katherine E., Blacker, A. John, Turner, Nicholas J.
In this study a batch reactor process is compared to a flow chemistry approach for lipase-catalyzed resolution of the cyclopropanecarboxylate ester (±)-3. (1R,2R)-3 is a precursor of the amine (1R,2S)-2 which is a key building block of the API ticagrelor. For both flow and batch operation, the...