Continuous flow Buchwald–Hartwig amination of a pharmaceutical intermediate

Yaseneva, Polina; Hodgson, Paul B.; Zakrzewski, J.; Falß, Sebastian; Meadows, Rebecca A; Lapkin, Alexei

doi:10.1039/c5re00048c

Cited by 40 publications

(34 citation statements)

References 37 publications

(41 reference statements)

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“…Changing from batch to continuous processing in a flow synthesis process can considerably reduce the environmental burden of chemical manufacturing –. Nonetheless, the use of organic solvents was identified as one of the largest contributor to waste generation in flow synthesis –. The E‐factor and carbon footprint, defined in Equation and Equation , have pivotal roles in improving resource efficiency and waste minimization in the chemical industries …”

Section: Resultsmentioning

confidence: 99%

Nanofiltration‐Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous‐Flow Synthesis

et al. 2017

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Solvent usage in the pharmaceutical sector accounts for as much as 90 % of the overall mass during manufacturing processes. Consequently, solvent consumption poses significant costs and environmental burdens. Continuous processing, in particular continuous‐flow reactors, have great potential for the sustainable production of pharmaceuticals but subsequent downstream processing remains challenging. Separation processes for concentrating and purifying chemicals can account for as much as 80 % of the total manufacturing costs. In this work, a nanofiltration unit was coupled to a continuous‐flow rector for in situ solvent and reagent recycling. The nanofiltration unit is straightforward to implement and simple to control during continuous operation. The hybrid process operated continuously over six weeks, recycling about 90 % of the solvent and reagent. Consequently, the E‐factor and the carbon footprint were reduced by 91 % and 19 %, respectively. Moreover, the nanofiltration unit led to a solution of the product eleven times more concentrated than the reaction mixture and increased the purity from 52.4 % to 91.5 %. The boundaries for process conditions were investigated to facilitate implementation of the methodology by the pharmaceutical sector.

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Section: Resultsmentioning

confidence: 99%

Nanofiltration‐Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous‐Flow Synthesis

et al. 2017

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“…Another application of the Buchwald-Hartwig amination in the synthesis of a pharmaceutical intermediate was published by the research group of Lapkin. 32 The key intermediate in the synthesis of AR-A2 (a candidate drug previously under development at AstraZeneca for CNS disorders) was prepared considering environmental factors with waste minimisation. The authors developed a new flow reactor combining batch and flow for the lab-scale preparation of the target compound.…”

Section: Review Syn Thesismentioning

confidence: 99%

Recent Applications of Continuous Flow in Homogeneous Palladium Catalysis

Markovič¹,

Lopatka²,

Gracza³

et al. 2020

Synthesis

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Considerable advances have been made using continuous flow chemistry as an enabling tool in organic synthesis. Consequently, the number of articles reporting continuous flow methods has increased significantly in recent years. This review covers the progress achieved in homogeneous palladium catalysis using continuous flow conditions over the last five years, including C–C/C–N cross-coupling reactions, carbonylations and reductive/oxidative transformations.1 Introduction2 C–C Cross-Coupling Reactions3 C–N Coupling Reactions4 Carbonylation Reactions5 Miscellaneous Reactions6 Key to Schematic Symbols7 Conclusion

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“…[106] This new protocol led to asignificant reduction of the production cost with an overall yield that exceeds double that obtained in the first-generation synthesis,a nd allowed the preparation of up to 8.5 kilograms of 41 in asingle batch. [107] In addition to batch processes,P d-catalyzed couplings of aryl halides with amines have also been conducted in continuous flow on amulti-kilogram scale. [107]…”

Section: Applications In Scale-up Processesmentioning

confidence: 99%

“…[107] In addition to batch processes,P d-catalyzed couplings of aryl halides with amines have also been conducted in continuous flow on amulti-kilogram scale. [107]…”

Section: Applications In Scale-up Processesmentioning

confidence: 99%

The Buchwald–Hartwig Amination After 25 Years

2019

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The Pd‐catalyzed coupling of aryl (pseudo)halides and amines is one of the most powerful approaches for the formation of C(sp2)−N bonds. The pioneering reports from Migita and subsequently Buchwald and Hartwig on the coupling of aminostannanes and aryl bromides rapidly evolved into general and practical tin‐free protocols with broad substrate scope, which led to the establishment of what is now known as the Buchwald–Hartwig amination. This Minireview summarizes the evolution of this cross‐coupling reaction over the course of the past 25 years and illustrates some of the most recent applications of this well‐established methodology.

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Continuous flow Buchwald–Hartwig amination of a pharmaceutical intermediate

Abstract: A flow process for direct amination of a pharmaceutically relevant substrate using a Pd-NHC based catalyst was demonstrated in a lab-scale mini-plant and in a pilot-scale plant.

Cited by 40 publications

References 37 publications

Nanofiltration‐Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous‐Flow Synthesis

Nanofiltration‐Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous‐Flow Synthesis

Recent Applications of Continuous Flow in Homogeneous Palladium Catalysis

The Buchwald–Hartwig Amination After 25 Years

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