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Synthesis of Dolutegravir Exploiting Continuous Flow Chemistry
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....
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Synthesis of treprostinil: key Claisen rearrangement and catalytic Pauson–Khand reactions in continuous flow
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...
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The Application of a Continuous Grignard Reaction in the Preparation of Fluconazole
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...
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Use of a “Catalytic” Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch
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...
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Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608
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....
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Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts
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...
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One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine
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...
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Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization
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...
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Process Intensification of a Napabucasin Manufacturing Method Utilizing Microflow Chemistry
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...
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Process Intensive Synthesis of Propofol Enabled by Continuous Flow Chemistry
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...
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Redesign of a Grignard-Based Active Pharmaceutical Ingredient (API) Batch Synthesis to a Flow Process for the Preparation of Melitracen HCl
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...
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Scale-Up of a Continuous Manufacturing Process of Edaravone
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...
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Semi-continuous multi-step synthesis of lamivudine
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,...
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Synthesis of Celecoxib, Mavacoxib, SC-560, Fluxapyroxad, and Bixafen Enabled by Continuous Flow Reaction Modules
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....
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Continuous Flow Total Synthesis of Rufinamide
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...
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Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols
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...
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Flow-oriented synthetic design in the continuous preparation of the aryl piperazine drug flibanserin
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...
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From p-Xylene to Ibuprofen in Flow: Three-Step Synthesis by a Unified Sequence of Chemoselective C−H Metalations
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...
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Heating under High-Frequency Inductive Conditions: Application to the Continuous Synthesis of the Neurolepticum Olanzapine (Zyprexa)
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...
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Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing
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...
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Multiple Organolithium Generation in the Continuous Flow Synthesis of Amitriptyline
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...
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A Three-Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous-Flow Processing
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...
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Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing
| Contributor(s):: Zhang, Ping, Weeranoppanant, Nopphon, Thomas, Dale A., Tahara, Kohei, Stelzer, Torsten, Russell, Mary Grace, O'Mahony, Marcus, Myerson, Allan S., Lin, Hongkun, Kelly, Liam P., Jensen, Klavs F., Jamison, Timothy F., Dai, Chunhui, Cui, Yuqing, Briggs, Naomi, Beingessner, Rachel L., Adamo, Andrea
As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building...
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Batch–flow hybrid synthesis of the antipsychotic clozapine
| 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...
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Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril
| 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...