An automated-flow microreactor system for quick optimization and production: application of 10- and 100-gram order productions of a matrix metalloproteinase inhibitor using a Sonogashira coupling reaction

Sugimoto, Atsushi; Fukuyama, Takahide; Rahman, Md. Taifur; Ryu, Ilhyong

doi:10.1016/j.tetlet.2009.08.089

Cited by 46 publications

(35 citation statements)

References 19 publications

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“…Sugimoto et al recently built a system that automatically screened residence time and temperatures of a Sonogashira cross-coupling ( Figure 38). 115 After intermediate offline HPLC analysis, new conditions were implemented using the information gained on an intuitive basis.…”

Section: Reaction Screening and Optimizationmentioning

confidence: 99%

9.03 Organic Synthesis in Small Scale Continuous Flow: Flow Chemistry

Born

O'neal

Jensen

2014

Comprehensive Organic Synthesis II

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Section: Reaction Screening and Optimizationmentioning

confidence: 99%

9.03 Organic Synthesis in Small Scale Continuous Flow: Flow Chemistry

Born

O'neal

Jensen

2014

Comprehensive Organic Synthesis II

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“…9 In another homogenous flow approach Sugimoto applied a loop reactor (1000 μm i.d., 10 m length) mixing the alkyl halide and the alkyne in DMF and using PdCl 2 (PPh 3 ) 2 (1 mol %), CuBr (2 mol %), and diisopropylethylamine as a base at 120 °C. 10 The application of heterogeneous catalysis in conjunction with microreactor technology can facilitate a cleaner/green and scalable flow methodology for coupling reactions. As the most simple solution microtubular ("loop") reactors were coated with thin catalytic metal inner surface (Pd or Pd− Cu alloy) and applied in high pressure and high-temperature water (HPHT− H 2 O) in flow.…”

Section: Introductionmentioning

confidence: 99%

Rapid catalyst evaluation for Sonogashira coupling in continuous flow

Borcsek¹,

Bene²,

Szirbik³

et al. 2012

Arkivoc

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Selection of the most appropriate catalyst for Pd-catalyzed Sonogashira coupling often requires time and resources. We applied a continuous flow device for rapid catalyst screening of 4 heterogeneous catalysts over 6 Sonogashira coupling reactions together with longevity estimation. The screening procedure requires only 8 hours. For coupling the alkynes with 4-iodo-anisole Fibrecat types of catalysts showed the highest performance, while when 4-bromoanisole was applied as an aromatic halide PdCl 2 (PPh 3 ) 2 DVB gave superior results. For phenylacetylene and ethynyl-cyclohexene the coupling of the bromo derivative resulted in relatively low conversion as well as selectivity for most of the polymer-bound catalysts. Applying the cheap catalyst 10 % Pd/C the coupling reaction could only be achieved with the rather reactive 4-iodo-anisole although with moderate conversion.

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“…Flow microreactors have several advantages over conventional batch reactors, which include efficient mixing, rapid heat and mass transfer, and operational safety inherent to a tiny reaction space. Work in our laboratory over a decade has focused on the use of microreactors for practical organic synthesis [ 22 ], which includes catalytic reactions [23][24][25][26], radical reactions [27 -29], carbonylation reactions [30][31][32], and photoirradiation reactions [33][34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

Benchtop factory for cross-coupling reactions by circulatory catalyst flow using low-viscosity ionic liquid as reaction medium and catalyst support

Fukuyama

Ryu

2012

Green Processing and Synthesis

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This article describes the development of a circulatory catalyst flow system for Pd-catalyzed cross-coupling reactions, such as the Mizoroki-Heck reaction and the Sonogashira reaction, in which low-viscosity ionic liquids such as [bmim]NTf 2 and [emim]NTf 2 were used as a recyclable reaction medium and a catalyst support. A benchtop production system consisting of a flow reactor (micromixer plus residence time unit), a dual extraction unit with two T-shaped micromixers, and a catalyst/ solvent pumping back system has been designed and tested for a 100 g scale synthesis using the Mizoroki-Heck reaction, which indeed worked well. Using a similar continuous-flow equipment, 103 g of the key intermediate of the matrix metalloproteinase inhibitor was synthesized by Cu-free Sonogashira reaction with [emim]NTf 2 as a solvent, in which the system was run for 5.5 h. The attributes of facile separation and recycling of both the catalyst and the ionic liquid reaction medium impart certain characteristics of heterogeneous catalysis to this continuousflow system.

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An automated-flow microreactor system for quick optimization and production: application of 10- and 100-gram order productions of a matrix metalloproteinase inhibitor using a Sonogashira coupling reaction

Cited by 46 publications

References 19 publications

9.03 Organic Synthesis in Small Scale Continuous Flow: Flow Chemistry

9.03 Organic Synthesis in Small Scale Continuous Flow: Flow Chemistry

Rapid catalyst evaluation for Sonogashira coupling in continuous flow

Benchtop factory for cross-coupling reactions by circulatory catalyst flow using low-viscosity ionic liquid as reaction medium and catalyst support

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