Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir

25 Jun 2024 | 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

25 Jun 2024 | 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...

Using Flow To Outpace Fast Proton Transfer in an Organometallic Reaction for the Manufacture of Verubecestat (MK-8931)

25 Jun 2024 | 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...

Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry

25 Jun 2024 | 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...

Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19

25 Jun 2024 | 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...

Highly Efficient Synthesis of HIV NNRTI Doravirine

25 Jun 2024 | 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...

Development of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed Hydrogenolysis

25 Jun 2024 | 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...

Development of a Direct Photocatalytic C–H Fluorination for the Preparative Synthesis of Odanacatib

25 Jun 2024 | 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...

Operation Strategy Development for Grignard Reaction in a Continuous Stirred Tank Reactor

25 Jun 2024 | 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...

Development and Manufacturing GMP Scale-Up of a Continuous IrCatalyzed Homogeneous Reductive Amination Reaction

25 Jun 2024 | 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...

The Synthesis of Bromomethyltrifluoroborates through Continuous Flow Chemistry

25 Jun 2024 | 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...

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

25 Jun 2024 | 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...

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

25 Jun 2024 | 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

25 Jun 2024 | 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...

Improvement of a pharmaceutical powder mixing process in a tote blender via DEM simulations

04 Jun 2024 | Peer-reviewed journal | Contributor(s): Benedict Benque, Luca Orefice, Thomas Forgber, Matthias Habeler, Beate Schmid, Johan Remmelgas, Johannes Khinast

An industrial-scale pharmaceutical powder blending process was studied via discrete element method (DEM) simulations. A DEM model of two active pharmaceutical ingredient (API) components and a combined excipient component was calibrated by matching the simulated response in a dynamic angle of...

Development and Application of Control Concepts for Twin-Screw Wet Granulation in the ConsiGmaTM-25: Part 2 Granule Size

04 Jun 2024 | Peer-reviewed journal | Contributor(s): Selma Celikovic, Johannes Poms, Johannes Khinast, Martin Horn, Jakob Rehrl

Traditional operation modes, such as running the production processes at constant process settings or within a narrow design space, do not fully exploit the advantages of continuous pharmaceutical manufacturing. Integrating Quality by Control (QbC) algorithms as a standard component of...

Embracing continuous manufacturing in the pharmaceutical industry

03 Jun 2024 | Website | Contributor(s): Joelle Anselmo

"Drugmakers have been slow to adopt the production process, which experts say can streamline operations, boost data quality and reduce time to market."

A modified Kushner-Moore approach to characterising small-scale blender performance impact on tablet compaction

03 Jun 2024 | Peer-reviewed journal | Contributor(s): Hikaru G. Jolliffe, Martin Prostredny, Carlota Mendez Torrecillas, Ecaterina Bordos, Collette Tierney, Ebenezer Ojo, Richard Elkes, Gavin Reynolds, Yunfei Li Song, Bernhard Meir, Sara Fathollahi, John Robertson

Continuous Direct Compaction (CDC) has emerged as a promising route towards producing solid dosage forms while reducing material, development time and energy consumption. Understanding the response of powder processing unit operations, especially blenders, is crucial. There is a substantial body...

Synthesis of Dolutegravir Exploiting Continuous Flow Chemistry

10 May 2024 | Peer-reviewed journal | Contributor(s): Nqeketo, Sinazo, Watts, Paul

An efficient continuous flow process for the synthesis of dolutegravir, an active pharmaceutical ingredient (API) for HIV treatment, was investigated. The synthetic procedure starts from a readily available benzyl-protected pyran via six chemical transformations using continuous flow reactors....

Synthesis of treprostinil: key Claisen rearrangement and catalytic Pauson–Khand reactions in continuous flow

10 May 2024 | Peer-reviewed journal | Contributor(s): García-Lacuna, Jorge, Domínguez, Gema, Blanco-Urgoiti, Jaime, Pérez-Castells, Javier

A new synthesis of treprostinil is described using a plug flow reactor in two of the key steps. First, a Claisen rearrangement reaction is described in scaled flow at multigram amounts. Yields and selectivity of this step are sharply improved compared to those from previous syntheses. Second, the...

The Application of a Continuous Grignard Reaction in the Preparation of Fluconazole

10 May 2024 | Peer-reviewed journal | Contributor(s): Korwar, Sudha, Amir, Somi, Tosso, Perrer N., Desai, Bimbisar K., Kong, Caleb J., Fadnis, Swara, Telang, Nakul S., Ahmad, Saeed, Roper, Thomas D., Gupton, B. Frank

The application of continuous methods in the synthesis of active pharmaceutical ingredients continues to receive significant attention in the academic as well as the industrial research communities. One of the major advantages of continuous methods is the ability to safely access kinetic synthons...

Use of a “Catalytic” Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch

10 May 2024 | Peer-reviewed journal | Contributor(s): Yang, Jeffrey C., Niu, Dawen, Karsten, Bram P., Lima, Fabio, Buchwald, Stephen L.

A general, efficient method for C−N cross-coupling has been developed using N,N-dimethyloctanamide as a catalytic cosolvent for biphasic continuous-flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two-step sequence which converted...

Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608

10 May 2024 | Peer-reviewed journal | Contributor(s): Biyani, Shruti A., Qi, Qingqing, Wu, Jingze, Moriuchi, Yuta, Larocque, Elizabeth A., Sintim, Herman O., Thompson, David H.

Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia....

Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts

10 May 2024 | Peer-reviewed journal | Contributor(s): Tsubogo, Tetsu, Oyamada, Hidekazu, Kobayashi, Shū

Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility. However, for over half a century, pharmaceutical...

One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine

10 May 2024 | Peer-reviewed journal | Contributor(s): Harsanyi, Antal, Conte, Annelyse, Pichon, Laurent, Rabion, Alain, Grenier, Sandrine, Sandford, Graham

In Africa around 625 000 mortalities per annum (20% of HIV/AIDS related deaths) are due to the affects of the Cryptococcal meningitis (CM) fungal infection. Recently, the World Health Organisation (WHO) and the Infectious Disease Society of America (IDSA) recommended that the first line treatment...