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...

Process Development for Synthesizing the Cephalosporin Antibiotic Cefotaxime in Batch and Flow Mode

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Pieper, Matthias, Kumpert, Mario, König, Burghard, Schleich, Herbert, Bayer, Thomas, Gröger, Harald

The pharmaceutically active substance cefotaxime, a commercial cephalosporin-type antibiotic, is accessible in an amide-bond-forming reaction from 7-aminocephalosporanic acid as the amine donor and nonactivated (Z)-(2-aminothiazol-4-yl)-methoxyiminoacetic acid as the acid component with...

Rapid production of the anaesthetic mepivacaine through continuous, portable technology

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Díaz-Kruik, Pablo, Paradisi, Francesca

Local anaesthetics such as mepivacaine are key molecules in the medical sector, so ensuring their supply chain is crucial for every health care system. Rapid production of mepivacaine from readily available commercial reagents and (non-dry) solvents under safe conditions using portable,...

Scalable and Sustainable Synthesis of Calcium Dobesilate via Integrated Five-Step Continuous-Flow Chemistry

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Liu, Minjie, Wan, Li, Gao, Liang, Cheng, Dang, Jiang, Meifen, Chen, Fen-Er

Calcium dobesilate is a widely prescribed veno-tonic drug in over 60 countries for treating chronic venous disease, diabetic retinopathy, and hemorrhoidal attack symptoms. Although two batchwise manufacturing routes to this treatment have been developed, the drawbacks, such as poor...

Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Russel, M. Grace, Jamison, Timothy F.

Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations. This is the highest total number of distinct reaction steps ever performed in continuous flow without conducting...

Synthesis of (±)-Pregabalin by Utilizing a Three-Step Sequential-Flow System with Heterogeneous Catalysts

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Ishitani, Haruro, Kanai, Kan, Saito, Yuki, Tsubogo, Tetsu, Kobayashi, Shū

(±)-Pregabalin, a γ-amino acid derivative, has been synthesized by utilizing flow methods. A three-step sequential-flow reaction starting from commercial isovaleraldehyde and methyl malonate proceeded smoothly with heterogeneous catalysts to afford the precursor of pregabalin in yields of 75–100...

The Continuous-Flow Synthesis of Ibuprofen

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Bogdan, Andrew R., Poe, Sarah L, Kubis, Daniel C., Broadwater, Steven J., McQuade, D. Tyler

Let relief flow forth! A three-step, continuous-flow synthesis of ibuprofen was accomplished using a simplified microreactor. By designing a synthesis in which excess reagents and byproducts are compatible with downstream reactions, no intermediate purification or isolation steps are required.

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Marsini, Maurice A., Buono, Frederic G., Lorenz, Jon C., Yang, Bing-Shiou, Reeves, Jonathan T., Sidhu, Kanwar, Sarvestani, Max, Tan, Zhulin, Zhang, Yongda, Li, Ning, Lee, Heewon, Brazzillo, Jason, Nummy, Laurence J., Chung, J. C., Luvaga, Irungu K., Narayanan, Bikshandarkoil A., Wei, Xudong, Song, Jinhua J., Roschangar, Frank, Yee, Nathan K., Senanayake, Chris H.

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis...

Development of a Continuous Flow Process for the Efficient Preparation of Anti-Tuberculosis-Specific Drug TBAJ-876

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Gao, Feng, Zhang, Guowei, Gu, Wenting, Zhang, Zhenfeng, Liu, Zhiqing, Zhang, Wanbin, Li, Jing

Previously, the first asymmetric synthesis of anti-tuberculosis agent TBAJ-876 had been successfully achieved using a synergistic Li/Li catalysis approach, yielding excellent results on a 5 g scale. However, scaling up the process presents significant challenges due to its poor repeatability and...

Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide

24 Apr 2024 | Peer-reviewed journal | Contributor(s): White, Timothy D., Berglund, K. Derek, Groh, Jennifer McClary, Johnson, Martin D., Yates, Matthew H.

The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten–Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API...

Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Heider, Patrick L., Born, Stephen C., Basak, Soubir, Benyahia, Brahim, Lakerveld, Richard, Zhang, Haitao, Hogan, Rachael, - Buchbinder, Louis, Wolfe, Aaron, Mascia, Salvatore, Evans, James M. B., Jamison, Timothy F., Jensen, Klavs F.

The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active...

Enzyme synthesis of cephalexin in continuous-flow microfluidic device in ATPS environment

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Vobecká, Lucie, Tichá, Linda, Atanasova, Aleksandra, Slouka, Zdeněk, Hasal, Pavel, Přibyl, Michal

We present an experimental study dealing with the transfer of the enzyme synthesis of cephalexin from a batch arrangement to a continuous-flow microfluidic system with integrated reaction product separation and enzyme recovery. Cephalexin is synthesized by penicillin acylase in a kinetic regime...

Integrated multi-step continuous flow synthesis of daclatasvir without intermediate purification and solvent exchange

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Rana, Abhilash, Mahajan, Bhushan, Ghosh, Subhash, Srihari, Pabbaraja, Singh, Ajay K.

The rapid transmission of viral diseases can cause massive economic damage and loss of life. The manufacture of most anti-viral drugs is normally carried out using batch synthesis which typically requires long production times (3–15 days) and significant manpower and infrastructure. The...

Multi-step Flow Synthesis of the Anthelmintic Drug Praziquantel

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Phull, Manjinder Singh, Bohara, Chander Singh, Gundla, Rambabu, Mainkar, Prathama S., Jadav, Surender Singh

Praziquantel (PZQ; Brand name: Biltricide) is categorized as an anthelminthic drug, and it is used for the treatment of Schistosomiasis and other parasitic infections. The World Health Organization (WHO) has classified it as one of the essential and emergency medicines needed across the globe....

Preparation of fluoxetine by multiple flow processing steps

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Ahmed-Omer, Batoul, Sanderson, Adam J.

Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an...

Automated and continuous synthesis of drug substances

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Sacher, Stephan, Castillo, Ismael, Rehrl, Jakob, Sagmeister, Peter, Lebl, René, Kruisz, Julia, Celikovic, Selma, Sipek, Martin, Williams, Jason D., Kirschneck, Dirk, Kappe, C. Oliver, Horn, Martin

A continuous synthesis line was developed integrating different common reaction steps namely nitration, substitution and hydrogenation. Mesalazine as model drug substance was produced from 2-chlorobenzoic acid in continuous flow mode. A multi-instrument PAT strategy was implemented to equip the...

Biotransformation with whole microbial systems in a continuous flow reactor: resolution of (RS)-flurbiprofen using Aspergillus oryzae by direct esterification with ethanol in organic solvent

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Tamborini, Lucia, Romano, Diego, Pinto, Andrea, Contente, Martina, Iannuzzi, Maria C., Conti, Paola, Molinari, Francesco

Cell-bound lipases of dry mycelium of Aspergillus oryzae were used in organic solvent for the resolution of racemic flurbiprofen by direct esterification with ethanol in a flow-chemistry reactor. Under flow conditions a significant reduction of the reaction time and an increase of the...

Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 2: Cyclization, Chlorination, and Amination

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Prieschl, Michael, Sagmeister, Peter, Moessner, Christian, Sedelmeier, Joerg, Williams, Jason D., Kappe, C. Oliver

A new route to the cannabinoid receptor type 2 agonist, RG7774, has been developed circumventing an alkylation with poor regioselectivity as the final step. In the new synthetic route, this side chain is incorporated from the beginning. In this article, the development of the final four...

Continuous GMP Manufacturing for Grignard Reagent/Zincate Synthesis and Negishi Coupling Reaction

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Calvin, Joel R., Boyse, Raymond, Braden, Timothy M., Brewer, Alison C, Changi, Shujauddin, Harrold, Donal, Johnson, Martin, Kerr, Mark S., Lambertus, Gordon R., Luciani, Carla V., May, Scott A., Moloney, Harold, Murphy, John D., Roberts, Jeffrey C., Schafer, John P., Spencer, Richard D., Webster, Luke P.

A synthetic route to API was designed containing a Negishi cross-coupling reaction, where the zincate reagent was generated by transmetalation of a Grignard reagent. In order to manage the poor stability of the Grignard reagent, as well as safety concerns, the chemistry was developed as a flow...

Continuous synthesis of artemisinin-derived medicines

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Gilmore, Kerry, Kopetzki, Daniel, Lee, Ju Weon, Horváth, Zoltán, McQuade, D. Tyler, Seidel-Morgenstern, Andreas, Seeberger, Peter H.

Described is a continuous, divergent synthesis system which is coupled to continuous purification and is capable of producing four anti-malarial APIs. The system is comprised of three linked reaction modules for photooxidation/cyclization, reduction, and derivatization. A fourth module couples...