Application notes

    The following application notes show the range of synthesis that are possible with the Vapourtec system.

    Application Note 56 – Photodecarboxylative addition of phenylacetic acid to N-methyl phthalimide

    Reaction-Scheme

    This application note illustrates the use of the Vapourtec UV-150 photochemical reactor for the photodecarboxylative benzylation of N-methyl phthalimide. The transformation has been systematically optimized in terms of reagent concentration and residence time. The optimized procedure was subsequently performed on large-scale, achieving a productivity of 1.34 g (88%) of product per hour (or 32.16 g per day). The reactor enabled continuous photochemistry in an easy-to-use, safe and efficient manner.

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    Application Note 55 – Selective hydrogenation with Stoli Catalysts reactor

    Selective-Hydrogenation-of-Cinnamaldehyde

    Vapourtec have teamed up with Innovate UK award winning catalyst manufacturer Stoli Catalysts Ltd to demonstrate a new range of catalyst-coated tube reactors for continuous flow selective hydrogenation.

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    Application Note 54 – Selective hydrogenation of O-benzyl vanillin using hydrogen gas and a palladium on charcoal slurry

    Selective-Hydrogenation

    As part of our ongoing work with slurries, the powerful combination of the Vapourtec E-series and SF-10 has made it possible to quickly achieve the selective hydrogenation.

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    Application Note 53 – Sodium Hydride as a Slurry in Continuous Flow

    Sodium-hydride-Reaction

    As part of our ongoing series of application notes on pumping slurries of reagents we have turned our attention to sodium hydride, one of the most versatile heterogeneous strong bases.

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    Application Note 52 – Rapid Mixing Reactor for Amide Formation under Biphasic Flow Reaction Conditions

    Biphasic-Schotten-Baummann-conditions

    In this application, Dr Claudio Battilocchio of the Ley group, University of Cambridge, has used Vapourtec’s 20 ml Rapid Mixing Reactors to perform an amide synthesis under biphasic flow reaction conditions.

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    Application Note 51 – Palladium on Charcoal Slurries in Continuous Flow Hydrogenation

    Slurry-Reactor

    Using a Vapourtec E-Series with V-3 peristaltic pumps it has been possible to handle solids in flow, to perform a continuous flow hydrogenation of 4-(2-fluoro-4-nitrophenyl)morpholine to the Linezolid intermediate 3-fluoro-4-(4-morpholinyl)aniline, using ammonium formate, and a heterogeneous palladium on charcoal slurry.

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    Application Note 50 – Rapid Mixing Reactor for Biphasic Reaction Scale-up

    BleachOxReaction.jpg

    In this application note the Vapourtec High Flow pump module and an R-series equipped with a Vapourtec large diameter Reactor for Rapid Mixing has been used to perform a scale-up of biphasic Stevens oxidation. The Reactor for Rapid Mixing enabled yields of greater than 99% to be reached with a 58 second residence time at just 50 °C, achieving a throughput of 4.5 kg/day.

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    Application Note 49 – Suzuki Coupling with SiliaCat DPP-Pd Heterogeneous Catalyst

    suzuki-coupling

    In this application, a Vapourtec R-Series has been used to achieve rapid reaction times and high conversion of a Suzuki coupling, using a commercially available supported palladium catalyst. With a reaction time of just 1 min 15 seconds, it was possible to achieve yields of over 80%, at greater than 95% purity following a simple chromatographic separation. This application demonstrates how the Vapourtec R-Series can be used as a tool for the synthetic flow chemist, or for a development chemist beginning the scale up process.

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    Application Note 48 – Photochemical synthesis of Cubanes

    Application-Note-48-Photochemical-Synthesis-of-a-Cubane

    This application note demonstrates the preparation of cage compound 2 from an advanced diene precursor 1, which can be prepared from cyclopentanone. After optimization, this key photochemical [2+2] photocycloaddition was successfully scaled up to multigram scale, and the cycloadduct was transformed to 1,4-cubane dicarboxylate 3.

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    Application Note 47 – [2+2] Photocycloaddition with wavelength specific low pressure mercury lamps

    Application-Note-47-Photocycoladdition-using-low-pressure-mercury-lamps

    This application note uses the photochemical reaction explored in application note 36, the photocycloaddition of maleimide and 1-hexyne, to explore the performance of Vapourtec’s new low pressure mercury lamps. For this reaction the low pressure lamps are used in place of the
    medium pressure lamp with filters. Three low pressure mercury lamps are tested, each with a specific and very narrow wavelength emission band.

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    Application Note 46 – Photochemical hydrogenation with TiO2 packed column

    Application-Note-46-Photochemical-Reduction-By-Immobilised-Photocatalyst

    This application note expands on the work described in application notes 41 and 42 describing a
    photochemical hydrogenation using an immobilized photo catalyst. Using an immobilized catalyst
    allows the reactants to be free of a titanium dioxide slurry/suspension. Instead the TiO2 is packed
    into a column type reactor. The versatility the of Vapourtec’s systems is demonstrated and a new
    UV illumination system for column reactors is presented.

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    Application Note 45 – Selective oxidation using 50% aqueous hydrogen peroxide

    Application-note-45-oxidation-using-hydrogen-peroxide

    This new application note demonstrates the oxidation of thioanisole using hydrogen peroxide in continuous flow. It highlights the use of 50 wt% aqueous hydrogen peroxide which can be pumped neat with Vapourtec systems. Both cooled and heated conditions are explored for this exothermic reaction.  The reaction temperature was controlled using a Vapourtec cooling module for the sub-ambient conditions.  To explore the highest possible throughput, mildly heated conditions were also explored.

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    Application Note 44 – Direct, [2+2] photocycloaddition using LED light

    Application Note 44 – Direct, [2+2] photocycloaddition using LED light

    This application note demonstrates the potential throughput capabilities of the UV-150, using an uncatalysed, intramolecular photochemical [2+2] cycloaddition. Further, it showcases the efficiency of the Vapourtec LED gen 2 light source, showing that a single, relatively small reactor together with low power LED can achieve a noteworthy throughput.

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    Application Note 43 – Singlet oxygen reaction in continuous flow, an example of an ene reaction.

    Application Note 43 – Singlet oxygen reaction in continuous flow, an example of an ene reaction.

    This application note demonstrates the use of singlet oxygen in flow. A range of parameters are investigated that determine the conversion and throughput. The ene like reaction of singlet oxygen with citronellol is used as a model. The versatility of the V-3 pump is showcased by the simultaneously pumping of both the reagent solution and gaseous oxygen. The bi-phasic gas / liquid mixture enters the reactor in Taylor flow. On exiting the UV-150 photochemical reactor the bi-phasic flow is no longer seen as the majority of the gas is consumed in the reactor. Further, by using a variable backpressure regulator, reaction parameters are controlled individually and optimized. Significant advantage is shown over traditional batch singlet oxygen reactions in which some reaction parameters are difficult to control.

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    Application Note 42 – Photochemical hydrogenation of a range of Nitro compounds

    Application Note 42 – Photochemical hydrogenation of a range of Nitro compounds

    This application note builds upon the previous application note 41’s exploration into green photochemical reductions.  The range of aromatic nitro compounds is extended, including the hydrogenation of a Linezolid intermediate (Pfizer brand name Zyvox), and demonstrating excellent adaptability for the varying chemical properties. Vapourtec’s efficient and precise generation 2 LED (Gen-2) is the sole light source used, allowing accurate and uniform 365 nm irradiation while providing impressive throughput. The optimized condition for each reduction is quickly achieved; residence time, concentration and reaction temperature are modified to maximize throughput while concurrently achieving close to 100% conversion to desired product.  The aim of this work was to showcase the capability of the Vapourtec’s E-Series when used in combination with the UV-150 photochemical

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    Application Note 41 –  Photochemical hydrogenation of 3-nitroacetophenone

    application-note-41-abstract

    *See Mahdavi et. al. for suggested reaction mechanisms

    This application note demonstrates a green photochemical route to the reduction of Nitro compounds. The powerful combination of Vapourtec’s V-3 pump and the UV-150 Photochemical reactor is utilised to deliver the photo catalyst as a slurry and provide precise control over the continuous flow photochemical reaction, even with the short reaction times of less than 1 minute. The TiO2 photo catalyst is safe, cheap and simply removed by filtration. There is also a fascinating comparison of the performance of three different 365 nm light sources; filtered mercury lamp, LED Gen-1 and LED Gen-2. The Gen-2 LED achieves comparable throughput of the mercury lamp while consuming <50% of the power.

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    Application Note 40 – Preparation of Silver Nanoparticles under Continuous Flow Conditions

    This application note illustrates the use of the Vapourtec E-Series to synthesise nanoparticles under continuous flow conditions. Two classes of silver nanoparticles are reported. The properties of metal nanoparticles are highly dependent on size and morphology, so ensuring consistency is paramount. Flow chemistry brings the advantages of precise control over experimental conditions (temperature, pressure, and residence time) and essentially limitless scale. As such, it is often the method of choice for production of nanoparticles.

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    Application Note 39 – Synthesis of Artemisinin using E-Series and UV-150 reactor

    application-note-39

    This application note demonstrates the use of the UV-150 photochemical reactor and E-Series system in the continuous synthesis of Artemisinin via the photooxidation of dihydroartemisinic acid. This application note shows how the easy-Photochem system can deliver not only the substrate but also oxygen in a safe, efficient continuous manner with the UV-150 effectively generating the singlet oxygen required for the reaction. This self-contained unit, coupled to an additional room temperature reactor is shown to synthesise the anti-malarial medicine artemisinin in comparable yields to previously published methods.

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    Application Note 38 – α-Photodecarboxylation of Phthaloyl Glycine

    application-note-38

    This application note illustrates the use of the Vapourtec UV-150 photochemical reactor for the conversion of phthaloyl glycine to N-methylphthalimide. The transformation has been systematically optimized in terms of reagent concentration and residence time. The optimized procedure was subsequently performed on large-scale, achieving a productivity of 1.15 g of product per hour (or 27.6 g per day). The reactor enabled continuous photochemistry in an easy-to-use, safe and efficient manner.

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    Application Note 37 – Photochemical Transformation of Methyl Coumalate

    application-note-37

    This application note illustrates the advantages of the UV-150 in performing continuous photochemistry against a published batch photochemical method demonstrating precise irradiation time, temperature control and wavelength selectivity . The 4π electrocyclisation of methyl coumalate shows an eight fold decrease in reaction times, an eight fold decrease in the amount of solvent used, a thirty fold decrease in the energy consumed by the lamp and switches to a greener solvent using acetonitrile compared to dichloromethane.

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    Application Note 36: [2+2] Photocycloaddition of Maleimide and 1-Hexyne

    app_note36

    This application note illustrates the use of the Vapourtec UV-150 photochemical reactor which allows
    access to continuous photochemistry in an easy-to-use, safe and efficient manner.

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    Application Note 35 – Reaction of Grignard Reagents using the E-Series

    app_note35

    This application note illustrates the use of the Vapourtec E-Series system to run reactions such as Grignard reactions under continuous flow conditions for extended periods with no pump issues.

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    Application Note 34 – Reaction of Organolithium Reagents using the E-Series

    app_note34

    This application note illustrates the use of the Vapourtec E-Series system to run organometallic reagents such as n-Butyl lithium under continuous flow conditions.

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    Application Note 33 : Chromium Arene Synthesis

    app_note33

    This application note demonstrates the preparation of arene chromium tricarbonyl complexes using continuous-flow processing: (η6C6H5CH3)Cr(CO)3 as an example.

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    Application Note 32: High Pressure and Temperature Process Scale S N Ar Reaction under Solvent Free Conditions using Liquefied Dimethylamine.

    app_note32

    This application note illustrates the use of the Vapourtec R-Series system to run reactions under solvent free (neat) conditions and it’s ability to pump liquefied gases at high temperatures and pressures. This expands on work carried out in Application note 29 (where a game changing throughput of material from a bench top system was demonstrated).

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    Application Note 31: Process Scale Uncatalysed Amination of 2-Chloropyridine (SNAr) under Solvent Free (Neat, 10.6M) Conditions

    app_note31

    This application note illustrates the use of the Vapourtec R-Series system to run reactions under solvent free (neat) conditions. It expands the work previously highlighted in Application note 29 in which a novel stratagem for throughput of material was demonstrated using a bench top system. By harnessing the higher temperatures and pressures available on the Vapourtec R-Series and again running the reaction solvent free it is possible to perform direct uncatalyzed amination of 2-chloropyridine on potentially larger scales than previously thoughti.

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    Application Note 30: Oxidation using a Gas/Liquid Membrane Reactor

    app_note30

    This application note illustrates the use of the Vapourtec R-Series system with gas-liquid “tube-in-tube” reactor to perform in flow an oxidation previously shown in batch in the publication
    “Transition-Metal free approach to efficient aerobic oxidation of alcohols to aldehydes and ketones under mild conditions”

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    Application Note 29: Process Scale SNAr Reaction under Solvent Free (Neat) Conditions

    app_note29

    This application note illustrates the use of the Vapourtec R-Series system to run reactions under solvent free (neat) conditions. This expands on work previously carried out in Application note 4 where it was shown that by using the the Vapourtec R-series facility of placing four reactors in series the mass transfer of the reaction could be dramatically increased. By taking this a step further and demonstrating the ability of running reactions of this type solvent free, this application note shows a game changing increase in the amount of material that can be generated.

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    Application Note 28: Continuous O-Methylation of Carboxylic Acids with Trimethylsilyldiazomethane

    app_note28

    This application note illustrates the use of the Vapourtec R-Series system to pump highly reactive, hazardous reagents in a safe and stable continuous reaction. Here we describe the continuous O-methylation of a carboxylic group with trimethylsilyldiazomethane (TMSCHN 2 ) pumping directly through the R-series acid resistant pump heads.

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    Application Note 27 : Decarboxylative Cross-Couplings with a Soluble Catalyst System

    app_note27

    This Application Note illustrates how the R-Series flow chemistry system can be used to develop a transfer of novel decarboxylative cross-coupling reactions from batch to flow.

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    Application Note 26: Continuous Fluorination Reaction with Diethyl Amino Sulfur Trifluoride (DAST)

    app_note26

    This application note illustrates the use of the Vapourtec R-Series system to pump highly reactive, moisture sensitive reagents in a safe and stable continuous reaction. Here we describe the continuous fluorination of a carbonyl group with diethylaminosulfurtrifloride (DAST) pumping directly through the R-Series acid resistant pump heads.

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    Application Note 24: Solvent Free Synthesis of an Imidazolium based Ionic Liquid under Continuous Flow Conditions

    app_note25

    This example illustrates the use of the Vapourtec R-series to safely control the highly
    exothermic synthesis of the first generation ionic liquid [bmim]Br as well as handling
    the highly viscous product.

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    Application Note 23 –  SNAr with dimethylamine

    app_note23

    This example illustrates the use of the Vapourtec R-Series system to react
    dissolved gases under pressure without the use of scale limiting pressure
    reactors (e.g. Parr ‘bombs’). The SnAr displacement of an aryl fluoride with
    dimethylamine is described.

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    Application Note 22-  Continuous Reduction of N-Boc Protected Amines to N-Me Amines

    app_note22

    This example illustrates the use of the Vapourtec R-Series system to carry out reactions with moisture sensitive, highly reactive reagents under flow conditions. It demonstrates how the proper drying procedure allows the Vapourtec R2 pump to handle this highly water sensitive reagent.

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    Application Note 21-  Michael Addition with Nitromethane

    app_note21

    This example illustrates the use of the Vapourtec R-Series flow chemistry platform to safely process an extremely energetic, reactive intermediate.

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    Application Note 20 – Ethoxycarbonylation of Unprotected Iodoindole with CO Gas

    app_note20

    This example illustrates the use of the new Vapourtec tube in tube gas reactor combined with the Vapourtec R-Series system to react reagent gases under pressure without the use of scale limiting pressure reactors (e.g. Parr ‘bombs’). Here we describe the catalytic ethoxycarbonylation of unprotected iodoindole with CO gas.

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    Application Note 19 – Ethoxycarbonylation of Iodotoluene with CO Gas

    app_note19

    This example illustrates the use of the new Vapourtec tube in tube gas reactor combined with the Vapourtec R-Series system to react reagent gases under pressure without the use of scale limiting pressure reactors (e.g. Parr ‘bombs’). Here we describe the catalytic ethoxycarbonylation of iodotoluene with CO gas.

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    Application Note 18 – Aromatic Nitration with fuming nitric acid

    app_note18

    This Application Note illustrates how a Vapourtec acid resistant R Series flow chemistry system (with acid resistant pumps, sensors, connectors, tubing and back pressure regulator) was used to pump highly corrosive, fuming nitric acid and determine optimal flow-through conditions suitable for a scale-up nitration of an aromatic starting material, all in a period of 3 days.

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    Application Note 17 – Simplified Aromatic Nitro Reduction with Iron Granules

    app_note17

    This study demonstrates a flow based approach to reduction of an aromatic nitro compounds using a column of iron granules as the catalyst.

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    Application Note 16 : Bromination of Alkenes with NBS under continuous flow

    app_note16

    This application note illustrates ease of scale-up and ease of control of a reaction that in batch would require careful incremental addition of reagents.

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    Application Note 15 – Bromination of Ketones

    app_note15

    α-Bromination of ketones is an important reaction in organic synthesis as the resulting α-Bromo-ketones are widely used in organic synthesis as valuable reaction intermediates used in the synthesis of variety of biologically active compounds. Various bromination procedures for carbonyl compounds have been developed, in which the most commonly used protocol involved the use of molecular bromine.

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    Application Note 14: Phase Transfer Catalysis Alkylation of 2-Oxo-cyclopentanecarboxylic acid ethyl ester under biphasic conditions using phase transfer catalysis

    app_note14

    This example illustrates how a continuous flow tubing reactor can be used to carry out biphasic reactions.
    It demonstrates Phase Transfer Catalyzed (PTC) alkylation of β-Keto ester under segmented flow conditions using the Vapourtec flow system along with the flow Commander software enabling fast screening of reaction conditions.

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    Application Note 13: Suzuki Coupling with a Heterogeneous Pd Catalyst

    app_note13

    This example illustrates use of a heterogeneous catalyst to perform a Suzuki coupling with high conversion and short residence times.

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    Application Note 12 : Trimethylaluminium mediated (Weinreb) amide bond formation

    app_note12

    This application note illustrates how a reaction which would be subject to thermal runaways and possible explosions in batch mode can be carried out safely using a continuous flow approach.

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    Application Note 11: Array Synthesis using Loop Injection and a Tubing Reactor Combined with a Scavenger Column

    app_note11

    This Application Note illustrates how the R-2+ pump/injector and R-4 flow reactor modules can be used in combination with a tubing reactor and a PACT scavenger column to perform sequential array synthesis employing simultaneous loop injection. Excess starting material 2{n} is used to drive the SNAr reaction with the aryl fluoride 1 to completion by incubation in the tubing reactor. The remaining amine is then scavenged prior to collection of the product 3{n}.

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    Application Note 10: Heterocycle Formation in Flow: 4,5-Disubstituted Oxazoles

    app_note10

    This Application Note illustrates how the R-2 pump/injector and R-4 flow reactor modules can be used to prepare oxazoles utilising a combination of a tubing reactor and polymer-assisted continuous flow-through (PACT) reactors1. Reagents are introduced into the flow stream via sample
    loops attached to the injection valves.

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    Application Note 9: Amide Formation using ‘Catch and Release’

    app_note09

    This Application Note illustrates how the R-2 pump/injector and R-4 flow reactor modules can be used to prepare amides uilising polymer-assisted continuous flow-through (PACT) chemistry1.

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    Application Note 7: Flow-Through Ester Hydrolysis under Superheated Conditions

    app_note07

    This Application Note illustrates how the R-2 pump/injector and R-4 flow reactor modules can be readily used to perform flow-through chemistry under superheated conditions.

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    Application Note 6: Transfer Hydrogenation using a Monolithic Nanoparticular Pd[0] PACT Reactor Cartridge

    app_note06

    This Application Note illustrates how the R-2 pump/injector and R-4 flow reactor modules can be used in combination with a reactor column to perform Polymer Assisted Continuous flow-Through (PACT) chemistry.

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    Application Note 5: Heck C-C Coupling using a Monolithic Nanoparticular Pd[0] PACT Reactor Cartridge

    app_note05

    This Application Note illustrates how the R-2 pump/injector and R-4 flow reactor modules can be used in combination with reactor columns to perform Polymer Assisted Continuous flow-Through (PACT) chemistry.

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    Application Note 4: Example: Scale-up SNAr using 4 Reactor Channels in Series

    app_note04

    The flow reactor was configured using a combination of the R-2 Pump Module and R-4 Reactor Module as shown in Scheme 1. Four Tubing Reactors (10 mL each) were installed and connected together in series. A 40 psi BPR was fitted in-line between the reactor outflow and the collection Valve.

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    Application Note 3: Example: Scale-up SNAr using Single 12 mL Tubing Reactor

    app_note03

    The flow reactor was configured using a R-4 Flow Reactor Module and 2 Knauer A120 high pressure pumps as shown in Figure 1. The pumps were connected to a 12 mL tubing reactor via a T-piece. Each pump was connected to the T-piece through a 100psi BPR. A ‘T’ pressure release safety valve fitted with a 250 psi BPR was fitted between the T-piece and the tubing
    reactor. The outflow from the tubing reactor was directed into either a 100 mL Duran waste collection bottle or into a 5L Duran product collection bottle filled with 4L of water, which was placed on a magnetic stirrer and stirred at approximately 600 rpm. A manual 2-position 3 way valve from used to direct the outflow to either ‘waste’ or collect. A 40psi BPR was connected in-line between the tubing reactor outflow and the selection valve.

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    Application Note 2 – Optimisation of Step 1 in the Synthesis of Linezolid using a ‘Dual-Core™’ Tubing Reactor

    app_note02

    This Application Note illustrates how the smaller volume tubing reactor (810 mL) within a Dual-CoreTM element was used to determine optimal flow-through conditions suitable for the scale-up synthesis of the intermediate 3 required for the preparation of UpJohn’s oxazolidinone antibiotic linezolid (Zyvox®).

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    Application Note 1: Example: Reaction Profiling using a ‘Dual-Core™’ Tubing Reactor

    app_note01

    This Application Note illustrates, using an SNAr reaction as a simple example, how a continuous flow tubing reactor containing a dual core can be used for reaction profiling, using the smaller capacity reactor to minimise sample wastage, to obtain optimal reaction conditions that may be directly scaled-up in the larger reactor.

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