Continuous Synthesis and Purification by Coupling a Multistep Flow Reaction with Centrifugal Partition Chromatography

Abstract

Continuous-flowm ultistep synthesis is combined with quasi-continuous final-product purification to produce pure products from crude reaction mixtures.I nt he nucleophilic aromatic substitution of 2,4-difluoronitrobenzene with morpholine followed by aheterogeneous catalytic hydrogenation, the desired monosubstituted product can be continuously separated from the co-and by-products in apurity of over 99 % by coupling af low reactor sequence to am ultiple dual-mode (MDM) centrifugal partition chromatography (CPC) device. This purification technique has many advantages over HPLC, such as higher resolution and no need for column replacement or silica recycling,a nd it does not suffer from irreversible adsorption.

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

“…Continuous purification is one of the key challenges to conducting multistep end-to-end reactions in a truly continuous regime. 13,49–53 However, there are limited existing continuous flow purification methods; these can be classified as inline workup and final-product purification depending on their primary place of application within a multistep process. 51 Continuous flow purification is associated with challenges such as resolving the desired product from by-products, unused starting materials and side products with minimal contamination, solvent compatibility with purification device and interference with the steady state performance of the entire continuous flow process.…”

“…However, this can be achieved by final-product purification using techniques such as multicolumn chromatography catch-and-release chromatography, simulated moving bed (SMB), crystallisation, recrystallisation and centrifugal partition chromatography (CPC). 51,54–59 Adding to scalability concerns of some of these purification methodologies, these techniques have their drawbacks; crystallization and recrystallisation usually requires semi-batch processing, catch-and-release chromatography needs automated multiple columns switching and the SMB chromatography operation is technically complex and it uses expensive absorbents. 12,51,60 The application of various downstream continuous flow processing strategies examples are reviewed herein.…”

“…51,54–59 Adding to scalability concerns of some of these purification methodologies, these techniques have their drawbacks; crystallization and recrystallisation usually requires semi-batch processing, catch-and-release chromatography needs automated multiple columns switching and the SMB chromatography operation is technically complex and it uses expensive absorbents. 12,51,60 The application of various downstream continuous flow processing strategies examples are reviewed herein.…”

Integrated Continuous Pharmaceutical Technologies—A Review

“…Nevertheless, the telescoped synthesis of APIs under flow conditions has a growing body of literature 70,72,80,83,85,86 and due to the challenge of the integration of in-line purification into a flow system, this topic is also gaining more and more attention. 59,87,88 In Table 1 APIs with reported continuous flow total synthesis are summarized. Regarding the industrial application of flow chemistry, in 2018 Hughes collected seven examples from the patent literature for API synthesis, during which at least one reaction step is carried out under flow conditions.…”

Application of reactor engineering concepts in continuous flow chemistry: a review

“…An arguably more attractive approach is the use of centrifugal partition chromatography (CPC), such as was described by Greiner and co-workers wherein they were able to achieve a semicontinuous purification of aniline 169 which was produced in two steps under flow conditions (Scheme 49). 179 The final product stream was continuously collected and diluted with appropriate solvents to afford an appropriate biphasic liquid system prior to being pumped into a CPC column in a portion-wise fashion. Fortuitously, aniline 169 could readily be separated from by-products 170 and 171 in both ascending (eluted first) and descending (eluted last) mode.…”