-
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...
-
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...
-
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,...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...
-
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...