Seven‐Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification

Russell, M. Grace; Jamison, Timothy F.

doi:10.1002/ange.201901814

Cited by 15 publications

(14 citation statements)

References 38 publications

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“…Linezolid was synthesized in a seven step synthesis through three flow segments with 73 % isolated yield. [64] As shown, recent interdisciplinary approaches for the development of sustainable synthesis have been realized in a matrix-like procedure and complemented the toolbox for synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…The product could be isolated with 73 % yield (average yield per step over 95 %) and the total residence time was 27 min which is significantly shorter than for batch-processes (> 60 h) and an average E-factor per reaction step of 3.75 (Figure 8). [64] Figure 7. Example of a chemo-enzymatic cascade for the stereoselective synthesis of secondary alcohols via Suzuki coupling and subsequent enzymatic reduction both in DES derived solvents.…”

Section: Showcasesmentioning

confidence: 99%

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Sustainable Chemistry – An Interdisciplinary Matrix Approach

2020

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Within the framework of green chemistry, the continuous development of new and advanced tools for sustainable synthesis is essential. For this, multi-facetted underlying demands pose inherent challenges to individual chemical disciplines. As a solution, both interdisciplinary technology screening and research can enhance the possibility for groundbreaking innovation. To illustrate the stages from discovery to the implementing of combined technologies, a SusChem matrix model is proposed inspired by natural product biosynthesis. The model describes a multi-dimensional and dynamic exploratory space where necessary interaction is exclusively provided and guided by sustainable themes.

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Section: Discussionmentioning

confidence: 99%

Section: Showcasesmentioning

confidence: 99%

Sustainable Chemistry – An Interdisciplinary Matrix Approach

2020

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“…Providing better control on reaction parameters such as mixing, mass and heat transfer and online purification, downstream processing help minimize solvent usage, waste and manual handling. [15][16][17] In this context, our research group 16,18,19 have been involved in the development of flow chemistry methodologies for organic synthesis and biocatalysis 15,16 and here in we report our effort on optimizing -terpineol synthesis starting from readily available starting materials (limonene and -pinene) by the use of continuous flow technology. 10,20,21…”

Section: Introductionmentioning

confidence: 99%

Two-step continuous-flow synthesis of α-terpineol

Carvalho

Aguillón

Leão

et al. 2020

Preprint

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α-Terpineol is a monoterpene naturally present in essential oils, of high value on the market as it is a compound widely used as a flavoring, aromatic substance in the cosmetics and food industry. This study aims to produce α-terpineol by two different synthetic strategies, using both batch and continuous flow systems, focusing on the optimization of the process, improving the reaction conversion and selectivity. The first strategy adopted was a one-stage hydration reaction of α-pinene by an aqueous solution of chloroacetic acid (molar ratio 1:1 between pinene and the acid) in continuous flow conditions. This reaction was carried out at 80 ºC with a residence time of 15 min, obtaining good values of conversion (72 %) and selectivity (76 %), and productivity of 0.67 Kg.day-1. The second strategy accomplished was a two-step cascade reaction with limonene as starting material, where the first step is a chemo specific double bond addition using trifluoroacetic acid, and the second step is the basic hydrolysis of the ester promoted by a solution of sodium hydroxide (2.25 M) in methanol (1:1). This reaction was adapted to a continuous flow condition, where all steps happen in a residence time of 40 min, at 25 ºC, with no quenching between steps required, giving a conversion of 97 % and selectivity of 81 %, with productivity of 0.12 Kg.day-1.

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“…Multistep continuous-flow syntheses also enable the telescoping of several steps into a single and uninterrupted synthetic process, which circumvents the need to purify and isolate intermediates [16][17][18] . However, it is worth noting that fully continuous-flow syntheses rarely exceed two steps before offline purification 19 . To realize a fully multistep continuous-flow synthesis is enormously challenging, mainly due to issues originating from solvent and reagent incompatibility, the accumulation of side-products, risk of clogging and mismatch of timescales between steps in a processing chain 20,21 .…”

mentioning

confidence: 99%

“…Although in-line purification strategies such as phase separators 12 have been applied (Supplementary Fig. 1), solvent and reagent incompatibilities between steps still limit the maximum number of steps in continuous-flow syntheses 19 . The Ley group has pioneered multistep flow syntheses enabled by flowing reactants through polymer-immobilized reagents and scavengers, thereby avoiding interference of leftover reagents in subsequent transformations 22,23 ; however, the downside of this method is the requirement of the efficient preparation and regeneration of a number of reagent and scavenger columns (Supplementary Fig.…”

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confidence: 99%

Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis

Liu

Xie

et al. 2021

Nat. Chem.

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Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.

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Seven‐Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification

Cited by 15 publications

References 38 publications

Sustainable Chemistry – An Interdisciplinary Matrix Approach

Sustainable Chemistry – An Interdisciplinary Matrix Approach

Two-step continuous-flow synthesis of α-terpineol

Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis

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