Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• applications by synthetic chemists include porous capillary separators to separate different mixtures of organic and aqueous solvents [65], a concentric annular liquid–liquid phase separation approach for continuous processing [66] and a single-stage extraction device based on a vertical apparatus with

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• drawbacks currently account for a large proportion of the research being conducted within the flow chemistry community. The continuous processing of slurries, for example, is now routinely performed [44][45][46][47][48], also, the use of scavengers (e.g., solid support reagents) [49][50][51] and devices

Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

• Nicole C. Neyt and
• Darren L. Riley

Beilstein J. Org. Chem. 2018, 14, 1529–1536, doi:10.3762/bjoc.14.129

• the selective reduction of aldehydes in the presence of ketones and has been demonstrated as a continuous process. Keywords: aldehyde reduction; flow chemistry; selective reduction; sodium dithionite; Introduction Flow chemistry and continuous processing has been acknowledged by the American

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• for continuous processing. The main issue that has to be solved in such set-up is the tolerability of the catalyst to water (its solubility, its activity, etc.) [55]. A strategy to overcome this problem is the inclusion and confinement of the homogeneous catalysts into a host nano-architecture [56

Diels–Alder reactions of myrcene using intensified continuous-flow reactors

• Christian H. Hornung,
• Miguel Á. Álvarez-Diéguez,
• Thomas M. Kohl and
• John Tsanaktsidis

Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

• continuous-flow approach provides a facile alternative scale-up route to conventional batch processing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times. Keywords: continuous processing; flow chemistry; renewable feedstock; surfactant

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

• Olga C. Dennehy,
• Valérie M. Y. Cacheux,
• Benjamin J. Deadman,
• Denis Lynch,
• Stuart G. Collins,
• Humphrey A. Moynihan and
• Anita R. Maguire

Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

• key α-thio-β-chloroacrylamide casade as a continuous flow reaction on a multi-gram scale is described, while the tuneable nature of the cascade, facilitated by continuous processing, is highlighted by selective generation of established intermediates and byproducts. Keywords: α-thio-β

• efficient rapid heating poses practical difficulties for scale-up and, furthermore, chromatographic separation is required to remove product impurities. The nature of the aforementioned difficulties outlined are, however, largely specific to the scale-up of batch chemistry. A continuous processing approach

• facilitate significant ease of scale-up. The reaction control afforded by use of high surface-area-to-volume ratio tubular reactors, specifically with respect to dissipation of heat, offers a safety profile unique to flow chemistry. Continuous processing also provides the capacity to continuously generate

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional

• : continuous processing; flow synthesis; in-line analysis; manufacture; pharmaceuticals; scalability; Introduction The last 20 years have witnessed a true renaissance in the way synthetic chemistry is performed due to the implementation of various enabling technologies allowing the modern synthesis chemist to

• , regulation of many parameters such as heat and mass transfer, mixing and residence times are much improved over related batch processes. Advantageously the flow reactor configuration can also be readily customised to meet the specific demands of the reaction and the continuous processing requirements. The

Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide

• Richard J. Ingham,
• Claudio Battilocchio,
• Joel M. Hawkins and
• Steven V. Ley

Beilstein J. Org. Chem. 2014, 10, 641–652, doi:10.3762/bjoc.10.56

• rarely provided in a format that can be readily extended by the user to implement control of additional hardware. Whilst the control of multiple devices and instruments is well-developed and standard practice for multi-step continuous processing on a large scale, these control systems tend to be custom

• required to perform a number of different trials. In the previous case, we had a significant amount of the intermediate so this was not considered to be a problem, but we would like to avoid stockpiling of intermediates in this way. One major advantage of continuous processing is that material can be used

Continuous-flow Heck synthesis of 4-methoxybiphenyl and methyl 4-methoxycinnamate in supercritical carbon dioxide expanded solvent solutions

• Phei Li Lau,
• Ray W. K. Allen and
• Peter Styring

Beilstein J. Org. Chem. 2013, 9, 2886–2897, doi:10.3762/bjoc.9.325

• catalysts also lend themselves particularly well to continuous processing. One such example is reported by Karbass et al. [26], who carried out continuous flow reaction using Pd(0) derived from [Pd3(OAc)6] supported on polymeric monoliths containing methylimidazole, an ionic-liquid (IL) moiety in near

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

• Mark C. Bagley,
• Vincenzo Fusillo,
• Robert L. Jenkins,
• M. Caterina Lubinu and
• Christopher Mason

Beilstein J. Org. Chem. 2013, 9, 1957–1968, doi:10.3762/bjoc.9.232

• Microwave Technology Ltd, 2 Middle Slade, Buckingham, MK18 1WA, UK 10.3762/bjoc.9.232 Abstract The Bohlmann–Rahtz pyridine synthesis and the Hantzsch dihydropyridine synthesis can be carried out in a microwave flow reactor or using a conductive heating flow platform for the continuous processing of

• the microwave batch reaction conditions, the most efficient parameters were transferred to the microwave flow reactor for continuous processing (Figure 1). The Pyrex tube was filled with sand, connected to a back-pressure regulator (100 psi) and primed with solvent at a flow rate of 0.6 mL min−1 (for

• flow reactions were slightly lower than their batch mode counterparts, (96% batch yield vs 85% yield under flow processing for the synthesis of 15c) the continuous processing of Hantzsch DHPs had been realized. Reviewing all of our methods for the microwave-assisted preparation of DHP derivatives, the

Ethyl diazoacetate synthesis in flow

• Mariëlle M. E. Delville,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 1813–1818, doi:10.3762/bjoc.9.211

• nature of diazomethane and EDA [3][4][5], however, synthetic routes that involve large scale batchwise handling of such diazo compounds is generally avoided in industrial processes. With the advent of continuous processing over the past decade, new approaches have appeared to conceptually change the way

Controlled synthesis of poly(3-hexylthiophene) in continuous flow

• Helga Seyler,
• Jegadesan Subbiah,
• David J. Jones,
• Andrew B. Holmes and
• Wallace W. H. Wong

Beilstein J. Org. Chem. 2013, 9, 1492–1500, doi:10.3762/bjoc.9.170

• -flow synthesis methods offer several advantages over traditional batch methods [14][15][16][17][18]. The scale-up of reactions is not only straightforward in continuous processing, but there are also benefits in high reaction reproducibility through accurate parameter control, superior heating and

• compatible nickel catalyst systems for the Kumada polymerization step in flow. Both o-tolyl–Ni catalyst 3 in THF and Ni(dppp)Cl2 in o-DCB were highly active in continuous processing conditions, and high-molecular-weight P3HT was obtained for both catalysts. Apart from the molecular weight of the polymers

Camera-enabled techniques for organic synthesis

• Steven V. Ley,
• Richard J. Ingham,
• Matthew O’Brien and
• Duncan L. Browne

Beilstein J. Org. Chem. 2013, 9, 1051–1072, doi:10.3762/bjoc.9.118

• , traditional research facilities are extremely expensive to commission and run, and yet for a significant proportion of their lives they are under-used or even lying vacant. To overcome some of these inefficient practices, continuous processing methods such as flow chemistry [26][27][28][29][30][31][32] and