Optimizing the Deprotection of the Amine Protecting <i>p</i>-Methoxyphenyl Group in an Automated Microreactor Platform

Koch, Karl‐Heinz; Weerdenburg, Bram J. A. van; Verkade, Jorge M. M.; Nieuwland, Pieter J.; Rutjes, Floris P. J. T.; Hest, Jan C. M. van

doi:10.1021/op900139u

Cited by 36 publications

(31 citation statements)

References 19 publications

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“…of 7, 1.5 equiv. of NaOH) were applied in a gram- The same year, the DoE optimization of arylamine deprotection was reported by Rutjes group [17]. The objective of the work was to develop a mild protocol for the removal of pmethoxyphenyl (PMP) group, which would avoid the use of toxic and expensive reagents particularly needed in scale-up operations.…”

Section: Central Composite Designmentioning

confidence: 99%

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

Gioiello¹,

Filipponi²,

Mostarda³

et al. 2016

J Flow Chem

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The integration of flow systems with statistical design of experiments is emerging as a valuable strategy to develop new synthetic routes towards relevant building blocks, chemical probes, and drug compounds. Optimization by experimental design incorporates statistical algorithms, mathematical models and equations, predicting tools, feedback control, and validation to generate new optimal conditions. Continuous-flow chemistry is ideally suited for this scope, as the integration of in-line analysis is simple; experimental parameters such as temperature, pressure, and flow rate can be easily controlled and fine-regulated; and automation of reaction screening can be accomplished with software assistance. This review article aims to illustrate how the combination of flow synthesizers and design of experiments can be profitable to speed up the development and optimization of more efficient, safer, and reproducible protocols for modern synthetic methods and manufacturing processes.

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Section: Central Composite Designmentioning

confidence: 99%

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

Gioiello¹,

Filipponi²,

Mostarda³

et al. 2016

J Flow Chem

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“…DoE has been utilised by Lonza Ltd as part of a standard methodology for optimising industrial reaction scale up, 161 as well as being used to optimise the de-protection of the amine protecting p-methoxyphenyl group in an automated microreactor platform. 162 There are now a number of more advanced optimisation methodologies are routinely used in flow chemistry and microfluidic applications, such as central composite 163 and full factorial design. 164 Of the several optimisation techniques available, potentially the most useful for flow applications are designs based on a class of figures known as simplexes.…”

Section: Introductionmentioning

confidence: 99%

Design and additive manufacture for flow chemistry

et al. 2013

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“…The number of applications of continuous flow systems in synthetic organic chemistry is rapidly increasing [1][2][3][4][5][6][7][8][9][10][11][12]. This trend is stimulated by the vision that fine chemical and pharmaceutical processes could strongly benefit of microreactor technology leading to increased selectivity and efficiency of reactions and consequently higher yields [13,14].…”

Section: Introductionmentioning

confidence: 99%

Continuous flow azide formation: Optimization and scale-up

Delville

Nieuwland²,

Janssen

et al. 2011

Chemical Engineering Journal

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a b s t r a c tThe intrinsically small volumes and highly controlled reaction conditions render continuous flow microreactors ideal systems for the synthesis of potentially explosive compounds such as organic azides. In this article, we report the formation of benzyl azide from benzylamine using imidazole-1-sulfonyl azide hydrochloride as diazotransfer reagent. In a small scale (semi-automated) continuous flow setup the diazotransfer reaction was optimized using minimal amounts of reagents; less than 400 mg of benzylamine was required to perform 60 optimization reactions. The optimal reaction conditions were indentified to be room temperature, 600 s of residence time and an imidazole-1-sulfonyl hydrochloride to benzylamine stoichiometric ratio of 3 to 4. Furthermore, we successfully scaled up the reaction with a factor of 200 to gram scale using one single continuous flow reactor.

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Optimizing the Deprotection of the Amine Protecting p-Methoxyphenyl Group in an Automated Microreactor Platform

Cited by 36 publications

References 19 publications

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

Design and additive manufacture for flow chemistry

Continuous flow azide formation: Optimization and scale-up

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