Integrated Flow Processing

In an integrated (end-to-end) flow process multiple reactor and separation modules are arranged consecutively to form a single continuous operation unit. For continuous multistep API synthesis, reagents are fed into the assembly at specified points and the reaction stream is manipulated along the reaction path to suit the needs of individual transformations. Reaction intermediates are thus generated and directly consumed in the closed and, where necessary, pressurized reaction environment of the microreactor. In recent years, considerable efforts have been undertaken to devise uninterrupted multistep flow reaction sequences, and elaborate processes for the direct synthesis of complex molecules from simple starting materials have been demonstrated. Design and development of multistep continuous processes is challenging and requires a detailed understanding of the individual operations and a careful, “holistic” planning of the whole reaction sequence. An obvious advantage arises when a multistep sequence eliminates the need to isolate explosive or toxic intermediates. The Kappe laboratories have experience in the use of liquid-liquid and gas-liquid membrane-based separations in multistep flow chemistry, including the use of nanofiltration technology.

integrated flow

Key Publications

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, 8122−8126. DOI: 10.1021/acs.orglett.0c03100.

Continuous Flow Synthesis of Methyl Oximino Acetoacetate: Accessing Greener Purification Methods with Inline Liquid-Liquid Extraction and Membrane Separation Technology
R. Lebl, T. Murray, A. Adamo, D. Cantillo, C. O. Kappe, ACS Sustain. Chem. Eng. 2019, 7, 20088-20096DOI: 10.1021/acssuschemeng.9b05954.

Laboratory of the Future: A Modular Flow Platform with Multiple Integrated PAT Tools for Multistep Reactions
P. Sagmeister, J. D. Williams, C. A. Hone, C. O. Kappe, React. Chem. Eng. 2019, 4, 1571–1578. DOI: 10.1039/C9RE00087A.

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.

Development of Customized 3D Printed Stainless Steel Reactors with Inline Oxygen Sensors for Aerobic Oxidation of Grignard Reagents in Continuous Flow
M. C. Maier, R. Lebl, P. Sulzer, J. Lechner, T. Mayr, M. Zadravec, E. Slama, S. Pfanner, C. Schmölzer, P. Pöchlauer, C. O. Kappe, H. Gruber-Woelfler, React. Chem. Eng. 2019, 4, 393-401. DOI:10.1039/C8RE00278A.

Integration of Bromine and Cyanogen Bromide Generators for the Telescoped Continuous Synthesis of Cyclic Guanidines
G. Glotz, R. Lebl, D. Dallinger, C. O. Kappe, Angew. Chem. Int. Ed. 2017, 56, in press. DOI: 10.1002/anie.201708533.

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.

Continuous Flow Synthesis of a Key 1,4-Benzoxazinone Intermediate via a Nitration/Hydrogenation/Cyclization Sequence
D. Cantillo, B. Wolf, R. Goetz, C. O. Kappe, Org. Process Res. Dev. 2017, 21, 125-132. DOI: 10.1021/acs.oprd.6b00409.

Visible-Light Photoredox Catalysis using a Macromolecular Ruthenium Complex: Reactivity and Recovery by Size-Exclusion Nanofiltration in Continuous Flow.
J. Guerra, D. Cantillo, C. O. Kappe, Catal. Sci. Technol. 2016, 6, 4695–4699. DOI: 10.1039/c6cy00070c

A Sequential Ugi Multicomponent/Cu-Catalyzed Azide-Alkyne Cycloaddition Approach for the Continuous Flow Generation of Cyclic Peptoids
C. E. M. Salvador, B. Pieber, P. M. Neu, A. Torvisco, C. K. Z. Andrade, C. O. Kappe, J. Org. Chem. 2015, 80, 4590-4602. DOI: 10.1021/acs.joc.5b00445

Continuous Flow Synthesis of beta-Amino Acids from alpha-Amino Acids via Arndt-Eistert Homologation.
V. D. Pinho, B. Gutmann, C. O. Kappe, RSC Adv. 2014, 4, 37419-37422. DOI: 10.1039/c4ra08113g

A Sequential Nitration/Hydrogenation Protocol for the Synthesis of Triaminophloroglucinol − Safe Generation and Use of an Explosive Intermediate under Continuous Flow Conditions
D. Cantillo, M. Damm, D. Dallinger, M. Bauser, M. Berger, C. O. Kappe, Org. Process Res. Develop. 2014, 18, 1360-1366. DOI: 10.1021/op5001435

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).

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 Two-Step Continuous Flow Synthesis of N-(2-Aminoethyl)acylamides via Ring- Opening/Hydrogenation of Oxazolines.
B. Gutmann, J.-P. Roduit, D. Roberge, C. O. Kappe, Chem. Eur. J. 2011, 17, 13146–13150. DOI: 10.1002/chem.201102772 (featured in Synfacts 2012, 8, 221).

Microwave-Assisted and Continuous Flow Multistep Synthesis of 4-(Pyrazol-1-yl)carboxanilides.
D. Obermayer, T. N. Glasnov, C. O. Kappe, J. Org. Chem. 2011, 76, 6657-6669. DOI: 10.1021/jo2009824

Toward a Continuous Flow Synthesis of Boscalid.
T. N. Glasnov, C. O. Kappe, Adv. Synth. Catal. 2010, 352, 3089-3097. DOI: 10.1002/adsc.201000646