A continuous flow synthesis of [1.1.1]propellane and bicyclo[1.1.1]pentane derivatives

Donnelly, Kian; Baumann, Marcus

doi:10.1039/d0cc08124h

Cited by 23 publications

(12 citation statements)

References 44 publications

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“…As a potential application of our previously reported synthesis of useful bicyclo[1.1.1]pentane (BCP) building blocks [ 36 ], we investigated their use in the oxadiazole-forming reaction. The BCP acid chloride 5 was synthesised from [1.1.1]propellane ( 3 ) via the photochemical reaction with isopropyl 2-chloro-2-oxoacetate ( Scheme 4 ).…”

Section: Resultsmentioning

confidence: 99%

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

Donnelly¹,

Baumann²

2022

Beilstein J. Org. Chem.

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An efficient continuous flow process is reported for the synthesis of various 1,3,4-oxadiazoles via an iodine-mediated oxidative cyclisation approach. This entails the use of a heated packed-bed reactor filled with solid K2CO3 as a base. Using DMSO as solvent, this flow method generates the target heterocycles within short residence times of 10 minutes and in yields up to 93%. Scale-up of this flow process was achieved (34 mmol/h) and featured an integrated quenching and extraction step. Lastly, the use of an automated in-line chromatography system was exploited to realise a powerful flow platform for the generation of the heterocyclic targets.

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Section: Resultsmentioning

confidence: 99%

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

Donnelly¹,

Baumann²

2022

Beilstein J. Org. Chem.

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“…The work details the continuous generation of [1.1.1]propellane and its subsequent reaction with mixed oxalyl chlorides to generate non-symmetrical bicyclopentane species (BCP, Scheme 6). 22 Crucially, this flow process tolerates various alkyl ester moieties and conserves the acid chloride functionality thus enabling direct coupling reactions towards various BCP ester and amide products. Compared to previous methods to generate analogous products from diacetyl and [1.1.1]propellane, this new approach is a single-step process and thus avoids time-and waste-intensive multistep sequences.…”

Section: Scheme 5 Photo-oxygenations Of C-h Bonds Via Hat Catalysismentioning

confidence: 99%

Evaluating the Green Credentials of Flow Chemistry towards Industrial Applications

et al. 2021

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Continuous flow chemistry is becoming an established technology platform that finds frequent application in industrial chemical manufacture with support and endorsements by the FDA for pharmaceuticals. Amongst the various advantages that are commonly cited for flow chemistry over batch processing, sustainability continues to require further advances and joint efforts by chemists and chemical engineers in both academia and industry. This short review highlights developments within the last 5 years that positively impact on the green credentials associated with flow chemistry, specifically when applied to the preparation of pharmaceuticals. An industrial perspective on current challenges is provided to whet discussion and stimulate further investment towards achieving greener modern synthetic technologies.

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“…Starting from acetophenone 23, an advanced building block (24) was prepared in batch mode. This material was then converted into pyrazole 25 via a hydrazine-mediated high-temperature condensation reaction.…”

Section: Prexasertibmentioning

confidence: 99%

“…Compared to batch manufacturing, continuous manufacturing offers higher quality products and less batch-to-batch variability because of the high control over reaction conditions (e.g., temperature, pressure, and reaction time). For the same reason, flow technology enables chemists to easily perform reactions that would be very challenging in batch mode [19] due to extreme conditions, such as high-and low-temperature conditions [20][21][22][23], high pressure [24][25][26], the presence of highly reactive and unstable intermediates [27], as well as photo-or electrochemical processing at scale [28][29][30][31][32]. The modular nature of this technology and the robustness of individual reactor components not only provide flexibility but also facilitate the expansion of the applications of flow reactors to different industrial processes, which can mitigate production-chain incidents [7].…”

Section: Introductionmentioning

confidence: 99%

Continuous Flow Synthesis of Anticancer Drugs

Filippo

Baumann

2021

Molecules

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Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the improved preparation of a variety of molecular structures. Benefits such as better heat and mass transfer, improved process control and safety, a small equipment footprint, as well as the ability to integrate in-line analysis and purification tools into telescoped sequences are often cited when comparing flow to analogous batch processes. In this short review, the latest developments regarding the exploitation of continuous flow protocols towards the synthesis of anticancer drugs are evaluated. Our efforts focus predominately on the period of 2016–2021 and highlight key case studies where either the final active pharmaceutical ingredient (API) or its building blocks were produced continuously. It is hoped that this manuscript will serve as a useful synopsis showcasing the impact of continuous flow chemistry towards the generation of important anticancer drugs.

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A continuous flow synthesis of [1.1.1]propellane and bicyclo[1.1.1]pentane derivatives

Abstract: A continuous flow process to generate [1.1.1]propellane on demand in yields up to 50% is presented. As an alternative to cumbersome low-temperature vacuum distillation, an aqueous work-up was developed rendering...

Cited by 23 publications

References 44 publications

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

Evaluating the Green Credentials of Flow Chemistry towards Industrial Applications

Continuous Flow Synthesis of Anticancer Drugs

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