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

10 May 2024 | 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...

Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization

10 May 2024 | Contributor(s): Polster, Christopher S., Cole, Kevin P., Burcham, Christopher L., Campbell, Bradley M., Frederick, Andrea L., Hansen, Marvin M., Harding, Molly, Heller, Michael R., Miller, Michael T., Phillips, Joseph L., Pollock, Patrick M., Zaborenko, Nikolay

The design, development, and implementation of a pilot-scale continuous Schotten–Baumann amide bond formation and reactive crystallization to afford LY2886721 is described. The material met all API quality attributes and was comparable to material produced by a defined batch process. The...

Process Intensification of a Napabucasin Manufacturing Method Utilizing Microflow Chemistry

10 May 2024 | 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...

Process Intensive Synthesis of Propofol Enabled by Continuous Flow Chemistry

10 May 2024 | 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...

Redesign of a Grignard-Based Active Pharmaceutical Ingredient (API) Batch Synthesis to a Flow Process for the Preparation of Melitracen HCl

10 May 2024 | Contributor(s): Pedersen, Michael J., Skovby, Tommy, Mealy, Michael J., Dam-Johansen, Kim, Kiil, Søren

A Grignard-based batch process, for the preparation of Melitracen HCl, has been redesigned to fit a continuous reactor system. The Grignard addition is carried out at room temperature, with subsequent hydrolysis of the magnesium alkoxide intermediate followed by dehydration of the resulting...

Scale-Up of a Continuous Manufacturing Process of Edaravone

10 May 2024 | Contributor(s): Zhou, Shuhao, Hong, Qingxia, Mei, Wenliu, He, Yan, Wu, Chengjun, Sun, Tiemin

Edaravone belongs to a class of brain-protective agents, which can scavenge free radicals. To reduce impurities and improve the yield, a continuous flow production process of edaravone was developed. The synthesis is continuously carried out in two steps. The throughput can reach 11.328 kg/day...

Semi-continuous multi-step synthesis of lamivudine

10 May 2024 | Contributor(s): Mandala, Devender, Chadaa, Sravanthi, Watts, Paul

We report the first continuous flow synthesis of lamivudine, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B. The key intermediate (5-acetoxy oxathiolane) was prepared by an integrated two step continuous flow process from L-menthyl glyoxalate hydrate in a single solvent,...

Synthesis of Celecoxib, Mavacoxib, SC-560, Fluxapyroxad, and Bixafen Enabled by Continuous Flow Reaction Modules

10 May 2024 | Contributor(s): Britton, Joshua, Jamison, Timothy F.

Multi-step continuous flow synthesis enables a parallel approach to obtain agrochemicals and pharmaceuticals containing 3-fluoroalkyl pyrazole cores. In this system, fluorinated amines are transformed into pyrazole cores through a telescoped in situ generation and consumption of diazoalkanes....

Continuous Flow Total Synthesis of Rufinamide

10 May 2024 | Contributor(s): Zhang, Ping, Russell, M. Grace, Jamison, Timothy F.

Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and...

Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols

10 May 2024 | Contributor(s): Borukhova, Svetlana, Noël, Timothy, Hessel, Volker

Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting...

Flow-oriented synthetic design in the continuous preparation of the aryl piperazine drug flibanserin

10 May 2024 | Contributor(s): Bana, Péter, Szigetvári, Áron, Kóti, János, Éles, János, Greiner, István

An uninterrupted, four-step continuous-flow sequence was developed for the preparation of the aryl piperazine-type serotonin receptor modulator drug, flibanserin. The unprecedented route was designed for efficient operation in flow, consisting of heterogeneously catalyzed reductive amination...

From p-Xylene to Ibuprofen in Flow: Three-Step Synthesis by a Unified Sequence of Chemoselective C−H Metalations

10 May 2024 | Contributor(s): Lee, Hyune-Jea, Kim, Dong-Pyo, Kim, Heejin

Ibuprofen was prepared from an inactive and inexpensive p-xylene by three-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated the comprehensive...

Heating under High-Frequency Inductive Conditions: Application to the Continuous Synthesis of the Neurolepticum Olanzapine (Zyprexa)

10 May 2024 | Contributor(s): Hartwig, Jan, Ceylan, Sascha, Kupracz, Lukas, Coutable, Ludovic, Kirschning, Andreas

Hot chemistry! High-frequency inductive heating and flow chemistry are an ideal match for high-temperature synthesis. This is demonstrated in the multistep flow synthesis of the neurolepticum olanzapine (Zyprexa) that included three reactions with inductive heating and two purification steps...

Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing

10 May 2024 | 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...

Multiple Organolithium Generation in the Continuous Flow Synthesis of Amitriptyline

10 May 2024 | Contributor(s): Kupracz, Lukas, Kirschning, Andreas

A continuous flow protocol for the preparation of the tricyclic antidepressant (TCA) amitriptyline is reported. The advantages of flow chemistry when handling organometallic agents as well as when performing reaction with gases are demonstrated. Continuous multilithiation combined with...

A Three-Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous-Flow Processing

10 May 2024 | 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...

Batch–flow hybrid synthesis of the antipsychotic clozapine

10 May 2024 | Contributor(s): Neyt, N.C., Riley, D.L.

The development of batch–flow hybrid processes is becoming an attractive prospect through which chemists can make use of the best aspects of both technologies. We have reported the implementation of an on-the-fly purification by trituration which can also be utilised to perform solvent swaps. We...

Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril

10 May 2024 | Contributor(s): De Vitis, Valerio, Dall'Oglio, Federica, Pinto, Andrea, De Micheli, Carlo, Molinari, Francesco, Conti, Paola, Romano, Diego, Tamborini, Lucia

The chemoenzymatic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio- and stereoselective oxidation of cheap prochiral...

Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

10 May 2024 | Contributor(s): Silva-Brenes, Diana V., Reyes-Vargas, Stephanie K., Duconge, Jorge, Vlaar, Cornelis, Stelzer, Torsten, Monbaliu, Jean-Christophe M.

While racemic warfarin was initially commercialized as a rodenticide, it has become the most prescribed anticoagulant drug for prevention of blood clots and is part of the World Health Organization’s list of essential medicines. The synthesis of warfarin appears straightforward, consisting of a...

Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability

10 May 2024 | Peer-reviewed journal | 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...

Continuous flow synthesis of the URAT1 inhibitor lesinurad

10 May 2024 | Peer-reviewed journal | Contributor(s): Damião, Mariana C. F. C. B., Marçon, Henrique M., Pastre, Julio Cezar

Herein, the urate anion exchange transporter 1 (URAT1) inhibitor lesinurad is synthesized from commercially available building blocks by a five-step linear continuous flow sequence. Our previously developed continuous flow platform was successfully applied to generate the 3-thio-1,2,4-triazole...

A Concise Flow Synthesis of Efavirenz

10 May 2024 | Peer-reviewed journal | Contributor(s): Correia, Camille A., Gilmore, Kerry, McQuade, D. Tyler, Seeberger, Peter H.

Efavirenz is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. A novel, semi-continuous process provides rac-Efavirenz with an overall yield of 45 %. This streamlined proof-of-principle synthesis relies on the efficient copper-catalyzed...

A Continuous Flow Process for the Synthesis of Hymexazol

10 May 2024 | Peer-reviewed journal | Contributor(s): Ma, Xin-peng, Chen, Jin-sha, Du, Xiao-hua

Hymexazol is an efficient and low-toxicity soil fungicide. In this work, a fully continuous flow process for the synthesis of hymexazol has been developed. This process begins with combining ethyl acetoacetate and hydroxylamine hydrochloride to form a hydroxamic acid intermediate. The reaction...

A flow-based synthesis of telmisartan

10 May 2024 | Peer-reviewed journal | Contributor(s): Martin, Alex D., Siamaki, Ali R., Belecki, Katherine, Gupton, B. Frank

A highly efficient continuous synthesis has been developed for telmisartan, the active ingredient in the antihypertensive drug, Micardis. This synthetic route employs a convergent strategy that requires no intermediate purifications or solvent exchanges. The key step in the reaction scheme is a...

A Practical and Convenient Synthesis of the Essential Antibiotic Drug Cefazolin under Sequential One-Flow Conditions

10 May 2024 | Peer-reviewed journal | Contributor(s): Sugita, Shoichi, Ishitani, Haruro, Kobayashi, Shū

A sequential continuous-flow synthesis of cefazolin, which isavital first-choice drug used for the prevention of primary infection in most surgeries, was investigated. Rapid flow and efficient mixing of substrates in suitable flow reactors enabled the target compound to be obtained in a short...