Active Pharmaceutical Ingredients (APIs) in Flow

Continuous flow processes form the basis of the petrochemical and bulk chemicals industry where strong competition, stringent environmental and safety regulations, and low profit margins drive the need for highly performing, cost effective, safe and atom efficient chemical operations. In contrast to the commodity chemical industry, however, the fine chemical industry primarily relies on its existing infrastructure of multipurpose batch or semi-batch reactors. Fine chemicals, such as drug substances and active pharmaceutical ingredients (APIs), are generally considerably more complex than commodity chemicals and usually require numerous, widely diverse reaction steps for their synthesis (typically 6 to 10 synthetic steps), and multiple rounds of quenching, separation and purification. These requirements, together with the comparatively low production volumes and often short life time of many of these materials, make versatile and reconfigurable multipurpose batch reactors the technology of choice for their preparation. However, the advantages of continuous flow processing are increasingly being appreciated also by the pharmaceutical industry and, thus, a growing number of scientists, from research chemists in academia to process chemists and chemical engineers in pharmaceutical companies, are now starting to employ continuous flow technologies on a more routine basis. Together with our industrial partners, the Kappe laboratories are involved in numerous flow API synthesis projects.


Key Publications

Review: Continuous-Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients
B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54, 6688-6729. DOI: 10.1002/anie.201409318 (Web of Science “Highly Cited Paper”).

Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut and Fluorophenibut
S. Ötvös, P. Llanes, M. Pericàs, C. O. Kappe, Org. Lett. 2020, 22, 8122−8126DOI: 10.1021/acs.orglett.0c03100.

Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-methoxyaniline to Prepare a Key Building Block of Osimertinib
M. Kockinger, B. Wyler, C. Aellig, D. M. Roberge, C. A. Hone, C. O. Kappe, Org. Process Res. Dev. 2020, 24, 2217−2227DOI: 10.1021/acs.oprd.0c00254.

Continuous Flow C-Glycosylation via Metal-Halogen Exchange – Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir
T. von Keutz, J. D. Williams, C. O. Kappe Org. Process Res. Dev. 2020, 24, 2362−2368DOI: 10.1021/acs.oprd.0c00370.

A Continuous-flow Protocol for the Synthesis of Enantiomerically Pure Intermediates of Anti Epilepsy and Anti Tuberculosis Active Pharmaceutical Ingredients
R. M. Aguiar, R. A. C. Leão, A. Mata-Gomez, D. Cantillo, C. O. Kappe, L. S. M. Miranda, R. O. M. A. de Souza, Org. Biomol. Chem. 2019, 17, 1552-1557. DOI: 10.1039/C8OB03088J.

Scalable Continuous Flow Process for the Synthesis of Eflornithine using Fluoroform as Difluoromethyl Source
M. Köckinger, C. Hone, B. Gutmann, P. Hanselmann, M. Bersier, A. Torvisco, C. O. Kappe, Org. Process Res. Dev. 2018, 22, 1553–1563. DOI: 10.1021/acs.oprd.8b00318.

Process Intensification and Integration Studies for the Generation of a Key Aminoimidazole Intermediate in the Synthesis of Lanabecestat
D. Znidar, D. Cantillo, P. Inglesby, A. Boyd, C. O. Kappe, Org. Process Res. Dev. 2018, 22, 633-640. DOI: 10.1021/acs.oprd.8b00089.

Synthesis of Mepivacaine and its Analogues by a Continuous Flow Tandem Hydrogenation−Reductive Amination Strategy
N.S. Suveges, R. O. M. A. de Souza, B. Gutmann, C. O. Kappe, Eur. J. Org. Chem. 2017, 24, in press. DOI: 10.1002/ejoc.201700824.

An Integrated Continuous Flow Synthesis of a Key Oxazolidine Intermediate to Noroxymorphone from Naturally Occurring Opioids
A. Mata, D. Cantillo, C. O. Kappe, Eur. J. Org. Chem. 2017, 24, in press. DOI: 10.1002/ejoc.201700811.

Design and Development of Pd-catalyzed Aerobic N-Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode
B. Gutmann, D. Cantillo, U. Weigl, D. P. Cox, C. O. Kappe, Eur. J. Org. Chem. 2017, 914-927. DOI: 10.1002/ejoc.201601453.

Towards the Synthesis of Noroxymorphone via Aerobic Palladium-Catalyzed Continuous Flow N-Demethylation Strategies. B. Gutmann, P. Elsner, D. P. Cox, U. Weigl, D. M. Roberge, C. O. Kappe, ACS Sust. Chem. Eng. 2016, 4, 6048-6061. DOI: 10.1021/acssuschemeng.6b01371

Batch and Continuous Flow Aerobic Oxidation of 14-Hydroxy Opioids to 1,3-Oxazolidines – A Concise Synthesis of Noroxymorphone
B. Gutmann, U. Weigl, D. P. Cox, C. O. Kappe, Chem. Eur. J. 2016, 22, 10393–10398. DOI:10.1002/chem.201601902 (selected as ”Hot Paper” by the Editors).

Selective Olefin Reduction in Thebaine Using Hydrazine Hydrate and O2 under Intensified Continuous Flow Conditions
B. Pieber, D. P. Cox, C. O. Kappe, Org. Process Res. Develop. 2016, 20, 376−385. DOI: 10.1021/acs.oprd.5b00370

Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles: Toward the Continuous Production of Daclatasvir
P. F. Carneiro, B. Gutmann, R. O. M. A. de  Souza, C. O. Kappe, ACS Sust. Chem. Eng. 2015, 3, 3445−3453. DOI: 10.1021/acssuschemeng.5b01191

Continuous Flow Reduction of Artemisinic Acid Utilizing Multi-Injection Strategies – Closing the Gap Towards a Fully Continuous Synthesis of Antimalarial Drugs
B. Pieber, T. Glasnov, C. O. Kappe, Chem. Eur. J. 2015, 21, 4368-4376. DOI: 10.1002/chem.201406439 (selected as “Hot Paper“ by the Editors, covered by Chemical & Engineering News).

Development of a Continuous Flow Sulfoxide Imidation Protocol Using Azide Sources under Superacidic Conditions
B. Gutmann, P. Elsner, A. O’Kearney-McMullan, W. Goundry, D. M. Roberge, C. O. Kappe, Org. Process Res. Develop. 2015, 19, 1062-1067. DOI: 10.1021/acs.oprd.5b00217

Continuous Flow Synthesis of alpha-Haloketones – Essential Building Blocks of Antiretroviral Agents
V. D. Pinho, B. Gutmann, L. S. M. Miranda, R. O. M. A. de Souza, C. O. Kappe, J. Org. Chem. 2014, 79, 1555-1562. DOI: 10.1021/jo402849z (selected as “Featured Article” by the Editors).

Combined Batch and Continuous Flow Procedure to the Chemo-Enzymatic Synthesis of Biaryl Moiety of Odanacatib.
R. de Oliveira Lopes, A. S. de Miranda, B. Reichart, T. Glasnov, C. O. Kappe, R. C. Simon, W. Kroutil, L. S. M. Miranda, I. C. R.Leal, R. O. M. A. de Souza, J. Mol. Catal. B. 2014, 104, 101-107. DOI: 10.1016/j.molcatb.2014.03.017

On the Fischer Indole Synthesis of 7-Ethyltryptophol- Mechanistic and Process Intensification Studies under Continuous Flow Conditions.
B. Gutmann, M. Gottsponer, P. Elsner, D. Cantillo, D. M. Roberge, C. O. Kappe, Org. Process Res. Develop. 2013, 17, 294-302. DOI: 10.1021/op300363s

A Three Step Continuous Flow Synthesis of the Biaryl Unit of the HIV Protease Inhibitor Atazanavir.
L. Dalla-Vechia, B. Reichart, T. N. Glasnov, L. S. M. Miranda, C. O. Kappe, R. O. M. A. de Souza, Org. Biomol. Chem. 2013, 11, 6806-6813. DOI: 10.1039/c3ob41464g

A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones.
M. Viviano, T. N. Glasnov, B. Reichart, G. Tekautz, C. O. Kappe, Org. Process Res. Develop. 2011, 15, 858-870. DOI: 10.1021/op2001047