(09 May 30 June 2018) Syrris Advanced technology for chemists & - - PowerPoint PPT Presentation

(09 May – 30 June 2018)

• Syrris – Advanced technology for chemists &

chemical engineers

• Dolomite – Cutting-edge products for

microfluidics

• Glass Solutions – High-quality precision

scientific glassware

• Particle Works – Precision engineered nano-

and micro- materials

• Dolomite Bio – Innovative products for high

throughput single cell research

Syrris creates automated products for R&D chemists and is a world leader in flow chemistry... Dolomite develops the most advanced technology microfluidic products Dolomite Bio creates innovative products for high throughput single cell research. Glass Solutions is a world leader in precision manufacturing of glass components... Particle Works creates high- performance nano and micro materials with precise control

• ver particle size, shape and

architecture.

• Founded in 2001 to address the challenges

faced by the pharmaceutical industry.

• Syrris is the longest established flow

chemistry company.

• Our customers include all of the top 20

pharmaceutical companies and most leading academic institutions

• Headquartered in Royston (UK), with over 100

people globally over 8 offices. Driven by “Productizing Science”

Atlas Classic

Round bottom flask and vial system 1ml to 1L Parallel chemistry

Orb

Manual jacketed reactor system 100ml to 10L Rapid vessel change

Atlas HD

Automated jacketed reactor system 50ml to 5L Modular design allows for future upgrades

Atlas Pressure

Pressure reactor systems 200 Bar (SS) or 3 Bar (Glass) Modular systems available with automation

ChemiSens

The most sensitive reaction calorimeter on the market Provides true heat flow data in real-time

Orb Pilot

Pilot-scale manual jacketed reactor system 10L to 50L on the same frame Drain and change vessels in under an hour

• Asia is a revolutionary range of advanced

flow chemistry products from Syrris. It has been designed by chemists for chemists to enable the widest variety of chemical reactions and ultimate ease of use.

• The proprietary technology allows manually

controlled or fully automated experiments. Asia offers maximum chemical resistance with an extensive range of temperatures, pressures, and reaction times on scales from mg to kg. Asia celebrated its unique design as a winner of the R&D 100 Award for innovative technology.

• Atlas HD is the new reactor platform

following the hugely successful Atlas Classic system from Syrris

• Atlas Classic system has been a flagship

product for Syrris with over 700 installations globally

• Atlas HD is fully backwards compatible with

Atlas Classic making upgrading trivial.

• Atlas Classic does offer some unique

benefits:

Ability to control round bottom flasks Ability to control high pressure stainless steel reactors (200 Bar)

New jacketed reactor system from Syrris

Atlas HD has an intuitive

• touch screen,

delivering unmatched capability to define and monitor reaction conditions in real time Follow the progress of your reaction with the

• real time graphing function to show your key

reaction parameters in up to 5 user-defined graphs The Atlas HD base contains

• preconfigured

temperature control (PID) settings to ensure

• ptimal thermal performance for all vessel

sizes and reactor contents Ultimate control at your fingertips

All important process parameters are displayed simultaneously and are easily adjusted. Display plotted data of reaction parameters in real time.

Atlas HD is configured to work with market leading circulators (Huber/Julabo). Base Unit has been finely tuned to offer optimal temperature performance. User defines reaction parameters, Atlas HD selects

• ptimal temperature (PID) settings for the process

The Atlas HD can accommodate

• vessels

from 50 mL to 5 L in a single footprint, freeing up valuable lab space Changing vessels can be accomplished in

• minutes with the Oil Drain Unit and tool-

free clamping system The tool

• free clamp supports the vessel even

when the clamp is undone to ensure safe vessel changes Vacuum

• jacketed options available for all

volumes Supreme flexibility from 50 mL to 5 L

• Simply connect all hardware to either the base

unit or PC directly then drag-and-drop hardware icons to configure your system

• Create, run and modify experimental recipes

quickly and intuitively, including alarms and safety cut-offs

• Real time graphing (set point and actual data)

makes following your reactions trivial

• Automatic data logging ensures all data is

captured continuously in one .csv file

• Virtually any manufacturers apparatus (if

controlled by RS232) can be controlled and sensed Easy to use advanced control solution

• Converts your reaction logs into graphical

data with a drag-and-drop interface

• A simple to use wizard makes importing data

incredibly simple

• Process multiple .csv files at once, enabling

comparision from batch to batch

• For calorimetry applications built-in maths

functions allow automatic calculation of reaction enthalpy and overall process enthalpy etc. with automatic corrections depending on calibration Prepare publication quality graphs in minutes

• Atlas HD can support numerous applications

all on the same platform, including:

Volumetric and Gravimetric Dosing pH monitoring and control Temperature Dependant Dosing Parallel synthesis Reaction Calorimetry Sonocrystallization Pressure Systems

• Additional functionality can be added at any

time, increasing functionality when your needs change Tailor Atlas HD to your application

Skip applications

• Offers automated or manual dosing using 2

independent channels offering flow rates up to 200 mL/min

• Several modes of operation; from simple

additions to advanced flow profiles:

Dual dosing: Independent operation of each syringe Continuous flow: Both channels work together for one stable flow pH control: Dose acid/base to keep pH within a defined range (up to 70 °C) Temperature dependent dosing: Dose within defined temperature window to avoid exo/endotherms Autosampling: Automated aspiration of up to 6 samples at user defined intervals.

Versatile Dosing and Sampling system

10 reagents to 1 reactor 5 reagents to 1 reactor (x 2) 1 reagents to 10 reactor 1 reagents to 5 reactor (x 2)

• Offers automated or manual dosing using 2

independent channels offering flow rates up to 200 mL/min

• Several modes of operation; from simple

additions to advanced flow profiles:

Dual dosing: Independent operation of each syringe Continuous flow: Both channels work together for one stable flow pH control: Dose acid/base to keep pH within a defined range (up to 70 °C) Temperature dependent dosing: Dose within defined temperature window to avoid exo/endotherms Autosampling: Automated aspiration of up to 6 samples at user defined intervals.

Versatile Dosing and Sampling system

• Acid/base concentrations required for dosing

were established through iterative

• experiments. This ensures limited overshoot

during the pH control process.

• To an unbuffered solution of water, single

portions of acid and base were added, and the pump was allowed to control to pH 7.

• Following the addition of acid/base, the Atlas

Pump quickly returned the solution to the desired pH value. Automated pH Control

NaOH added

pH Temperature Cumulative Volume H2SO4 Cumulative Volume NaOH

H2SO4 added

• To mimic an exothermic reaction, using an

Atlas Syringe Pump, NaOH (aq) was dosed into an Atlas HD batch reactor containing H2SO4

(aq).

• The circulator was set to control the reactor

temperature to 20 °C.

• The pump was set to automatically dose

NaOH (aq) into the reactor, pausing when the temperature exceeds 23 °C, and resuming when the temperature falls back below 20.1 °C.

• Effective temperature dependent dosing is

demonstrated, limiting the effect of the exothermic acid/base neutralisation. Temperature Dependent Dosing

Reactor Temperature Circulator Temperature Cumulative Volume NaOH

Based on market

• leading Atlas HD with all its

benefits Designed to be used by regular chemists, not

• nly safety specialists

Comprehensive Atlas software suite allows

• quick generation reaction power/enthalpy

plots Easily connect virtually any RS

• 232 device to

work with your system (dosing setups, MFC) Full automation of processes with built in

• safety shutdown mechanisms

The simplest RC to use on the market

• To offer “calorimetry for the ordinary

chemist” as well as for process safety (in turn to make reaction calorimetry more accessible to many more people)

• To not get in the way of chemistry
• To not require a specialist
• To be extremely quick and reliable
• To be used with other monitoring techniques

(pH, turbidity, IR, FBRM)

• To be extremely good value

The idea behind the Atlas Calorimeter

Works in two isothermal modes (with same equipment): Power Compensation Calorimetry

• Quick and efficient, doesn’t require calibration

runs, limited maximum reaction power Heat Flow Calorimetry

• Traditional technique, perfect for investigation
• f unknown processes (high exotherms)
• Requires pre- and post- run calibration steps

TIN Tr Tr

Differences from standard Atlas System

• Additional fast response temperature probe

Reactor and jacket temperature

• Insulated oil connectors

Minimizing heat fluctuations

• Power supply with calibration heater

Enable calibration steps in HFC and perform PCC

• PC software upgrade

Seamlessly perform calorimetry experiments

Atlas HD automated reactor system Powerful automated reactor platform, seamlessly used as standard jacketed reactor when calorimetry measurements aren’t required. Vacuum jacketed vessels are necessary to maintain isothermal conditions. Atlas Calorimetry bundle Includes all necessary modules to turn Atlas HD into a reaction calorimeter:

• RS232 enabled power supply and calibration

heater

• Quick response RTDs for precise temperature

control

• Additional insulation for oil connectors

Atlas 1 PC Software with Calorimetry upgrade Create experiment recipes for standalone

• perations. The calorimetry step is designed as a

wizard, to set all important parameters before the

• setup. It will automatically include calibration steps.

Atlas Reporting software Used for post experiment analysis. Compensates for enthalpy of addition, and allows for generation of reaction power and enthalpy in single click.

Atlas 1 PC software

• Advanced software for advanced control of Atlas
• Calorimetry wizard for easy set-up – define all

parameters and safety limits in few minutes

• Control wide array of hardware (dosing setups, pH

and turbidity probes etc.) Atlas Reporting Software

• Plot power and enthalpy data with a few clicks
• Automatically correct for enthalpy of addition

Atlas PC Software Suite with Calorimetry upgrade

Example Thermogram: Hydrolysis of Acetic Anhydride

Run Ac2O used (g) Measured enthalpy (KJ) Measured enthalpy (KJ/mol) 1 33.05 19.2 59.25 2 33.05 19.93 61.5 3 33.12 20.98 64.61 Measured enthalpy (KJ/mol) Average 61.8

• Std. Dev.

2.69 Literature Value 58.6

Excellent control: Sophisticated PID control and powerful circulators result in accurate isothermal performance. Accurate: Vacuum jacketed vessels, automated calibration and sensitive RTDs give extremely high accuracy results. Walk away operation: Automated gravimetric or volumetric reagents additions are all made easy. Easy analysis: Easy to use software allows graphs of power and enthalpy to be plotted with only a few clicks. Quick: Everything clicks together quickly and easily without the need for tools. Vessels can be changed in under 1 minute. Flexible: The same equipment and software can be used for HFC or PCC, allowing the chemist to pick the best method for the reaction, or simply used as standard jacketed reactor for everyday use.

• Fully independent control over each reactor

with process data logging

• The Atlas HD systems can be identical or

completely different, offering the same flexibility as stand-alone Atlas HD systems

• Atlas Parallel software allows for multiple

instances of Atlas software to be opened, assigning each instance to one reactor.

• Data for each reactor is saved independently

in its own .csv file Control up to 4 Atlas HD systems from 1 PC

Crystallisation process consists of two major events:

• Nucleation
• Crystal Growth

Following the progress of a crystallisation process can allow chemists to tailor the properties of the crystals to suit their needs

• Syrris offers two approaches:

Monitor: Using Syrris Turbidity Node and Probe Control: Using Sonocrystallization technique

Fine control of your crystallizations

• Turbidity has been used to measure

crystallisations for decades

• Works by measuring back-scattered light by

suspended solids in a liquid Turbidity Monitoring

Crystallisation of Adipic Acid

20 40 60 80 100 120 00:05 00:10 00:15 00:20 00:25 Time (minutes) Power (watts) \ Turbidity (%) 54 56 58 60 62 64 66 Temperature (°C) Turbidity probe:Turbidity percentage Power supply: actual power Reaction temperature:Temperature celsius

Dissolution of Adipic Acid

20 40 60 80 100 120 00:00:00 00:05:00 00:10:00 00:15:00 Time (minutes) Turbidity (%) 54 56 58 60 62 64 66 Temperature(°C) Turbidity probe:Turbidity percentage Reaction temperature:Temperature celsius

• Powerful tool for calculating metastable zone of a system

and monitoring the subsequent crystallisation

• Atlas can use turbidity signal to control other reaction

parameters (e.g. stop dosing when turbidity exceeds X %)

• Reduced induction time
• Decreased Metastable Zone Width (MSZW)
• Increased crystal growth rate
• Reduced agglomeration
• Tailored crystal size distribution
• Polymorph control

To overcome the issues associated with ultrasound probes (short lifetime due to cavitation/poor ultrasound energy distribution), Syrris offer the Atlas Sonolab. Benefits of ultrasound-mediated crystallizations

• Using proprietary ultrasound technology, the

Sonolab allows fully automated control of:

Particle size Shape Crystallinity Polymorphism

• The Sonolab consists of an ultrasound flow cell

and ultrasound generator

• Unique flow cell designed to give uniform

ultrasound radiation throughout, offering the highest levels of reproducibility/repeatability. Total crystallization control

• Syrris offer two types of pressure vessel:
• Atlas Sodium Pressure System (200 Bar)
• Atlas Potassium Pressure System (3 Bar)
• Designed for applications such as hydrogenations,

carbonylations, catalyst screening etc. where elevated pressures are required.

• Both systems are based on the Atlas Classic System,

and are available with or without automation

Control manually or via PC for total reaction

• control

Vessel range:

• 100, 160, 300 and 450 mL

reactors available in SS, Hastelloy, titanium etc. Safety is assured with a pressure burst disc

• and temperature cutouts

Pressure Control Module allows for precise

• pressure control and the Gas Selection

Module allows selection of up to 3 gases. Automating pressure reactions made easy

• Tool-free pressure vessel changes allow

vessels to be interchanged in minutes

• Vessel sizes available: 100 mL, 250 mL, 500 mL,

1 L, 2 L or 3L

• Accurately control temperature between -80

°C and +200 °C

• To ensure safety, the Atlas 3 Bar system

comes equipped with a pressure burst disc and pressure relief valve.

• A safety enclosure is also provided for extra

peace of mind. 3 Bar pressure up to 3 Litres

Continue to Orb

Designed with simplicity and flexibility in mind, Orb is the jacketed reactor system combining high performance and excellent value. A revolution in bench top reactors

• No matter if you are using 100ml or 10L

reactors , the simple click –lock system adjusts to ensure that you always have the perfect working height

• All components and stirrer motor move

together on the unique slide rail support

• No other adjustment required.

Simple click-lock system

• Conveniently positioned handle to lift and

swivel the stirrer motor for easy access to the reactor

• No further adjustment required once the

system is first installed, even when changing reactor sizes Single handle to lift and swivel

• Rapid action clamping mechanism
• The unique patented clamp design allows
• pening without the risk of the glassware

falling

• Torque limited closure eliminates the risk of

damage through overtightening Engineered for ease of use

• Choice of 27 different reaction vessels 100 ml

to 10 L, there is one for every application

• Simple to operate , reconfigured to your needs

in seconds

• Robust heavy duty construction , engineered

for years of service , day after day. All the reactors you need in one compact footprint

Continue to Orb Pilot

Syrris has taken more that a

• 15 years to refine

its lab scale products. The knowledge and experience gained by its

• engineers and scientists has been redirected

to develop scale-up systems for both Batch and Flow chemistry The same ethos of creative design, superior

• engineering and high performance has been

carried forward into these new products Products that you can trust

• Orb Pilot is the most flexible and easy to use

batch reactor at this scale

• Offering market leading performance at

affordable prices

High performance stirring Excellent thermal properties User friendly and clever features built in Wide variety of options and upgrades

Orb Pilot is the ultimate scale-up batch reactor

High performance mixing is assured with a wide variety of impellor designs and powerful stirrer motors. Easy-fit Baffles are also offered in a selection of profiles to maximise the efficiency

stirring without baffles stirring with baffles

Orb Pilot reactors all feature a special oil inlet design which evenly distributes incoming oil around the base of the vessel ensuring uniform temperature around 360O High performance, smooth bore, 20mm ID hoses ensure maximum oil flow.

• Orb Pilot’s unique self-adjusting frame

makes switching between vessels sizes a trivial exercise.

• You can rapidly change between 10 L, 20 L,

30 L and 50 L reactors in a matter of minutes

• Vacuum jacket vessels are available for ultra-

low or high temperature applications Multiple working volumes in one footprint

The combinations of easy-lift-and -swing motor mount, self adjusting frame and predefined clamp positions, make vessel changes very simple even for a novice user.

• Stirrer options include industry standard

A310 Hydrofoil impellors

• Sizes and positions are optimised for the

down-flow design ensuring the best possible mixing. Industry standard designs and geometries

Continue to Chemisens

• The unique design and measurement

principle can provide data for processes where other systems struggle

• The True Heat Flow principle allows precise

and repeatable experiments at reflux, high pressure or during phase change with unrivalled sensitivity, accuracy and precision

• Ideal choice for process development,

kinetic studies, low-energy processes and reaction safety data generation The most sophisticated reaction calorimetry system available

• Idea conceived and turned into product by

Swedish researchers in polymer science in late 1980s

• Syrris acquired the Chemisens company in

2015 to continue their ideas

• Polymerizations are very challenging to

measure using calorimeters – due to high changes in viscosity and/or phase changes

• The unique design corrects for those

phenomena, resulting in the most sensitive and sophisticated reaction calorimetry system available – not only for polymerizations! Design philosophy

• Traditional methods suffer from shifting

baseline – as a result of dosing/phase change – the data is always interpreted

• Unique design of the reactor fights this – the

heat exchange area – the base of the reactor - is always constant. It contains array of heat flow sensors, and Peltier element for temperature control

• This principle enables the biggest feature of

the system - stable zero baseline, even at reflux operation. True Heat Flow – the key for accurate measurements

• Different filling volumes
• Reactor contents
• Changes in viscosity
• Changes in stirrer speed

Stable zero baseline. No guessing. No interpreting. Precise and accurate real-time kinetic data All data can be logged (50 parameters, every 2 seconds) No calibration required – The heat transfer area is always the same Ingenious design allows to run experiments unaffected by:

Thermograms of generic semi-batch reactions with CPA and HFC calorimeter. Thanks to this advantageous design, CPA measurements are very sensitive (± 0.01 W), and offers unrivalled performance accuracy, precision and sensitivity wise.

• Bench Unit

Reactor with stirrer and reference thermostat

• System Controller

Processes all signals, connects to operator PC

• PC

ChemiCall V2 software suite CCReport V2 data manipulation software COMLI communication protocol

• Dosing controller (Optional)

Interface to connect various supporting devices Pumps, balances, sensors (pressure, pH etc.), valves Reflux condenser & reflux split kit

The standard system consists of:

• Volume of 250 mL, useful volume 10-180 mL
• Lid fittings compatible with Swagelok system,

dosing ports available in base as well

• Stirring 50-2000 rpm (10 Ncm)
• Temp ranges: -50 to +200 °C (

HighSens: -20 to +150 °C

• 20 bar reactor available in SS316, HC276 and

Tantalum

• 100 bar available in SS316 and HC276

The heart of the system

The zero baseline allows for easy and precise

• peration at reflux. The reflux condenser measures

heat dissipated using heat balance principle, and the signal is directly calculated in real-time in PC software.

Continue to Flow

• Flow chemistry is the process of performing

chemical reactions in a continuous tube or pipe.

• Reagents are pumped together at a mixing

junction and the flow continues down a temperature controlled tube or pipe.

• The ratio of the reactants are controlled by

their concentrations and relative flow rates. The rapid mixing and large surface area to volume ratio provides excellent reproducibility and control of a chemical process.

A B C

Skip flow principles

• 1. Residence Time
• 2. Mixing
• 3. Temperature
• 4. Pressure

Residence time is the time that every fraction of the reaction volume spends in the reactor, and is equivalent to reaction time in batch chemistry. Two ways of controlling the residence time:

• Vary the reactor volume.
• Vary the flow rates.

To control the molar ratio:

• Vary the flow rates ratio

Residence Time= Reactor Volume Total Flow Rate

Example: 2 reagents flowing into a 1 ml glass microreactor at 0.25 ml/min flow rate each.

• What is the residence time?

To change the residence time to 8 min.

• What are the two options?

Combined flow rate = 0.25 + 0.25 = 0.5 ml/min Residence time = 1/0.5 = 2 min

• Total Flow Rate Needed: 0.125ml/min (Each reagent with 0.0625 ml/min)

OR

• Increase the reactor volume to 4 ml.

Residence Time= Reactor Volume Total Flow Rate

In batch chemistry, mixing is turbulent In flow chemistry, the mixing can be turbulent or laminar Small tube diameter results in laminar flow conditions (Reynolds number Re<2500)

Radial diffusion

• In turbulent flow conditions, static mixers are

used to increase mass transfer

• In laminar flow conditions, mixing occurs by

diffusion Diffusion time is proportional to distance squared, therefore over short distances, diffusion is fast and reproducible

Reservoir Pump Reservoir Pump

Very high

• surface area to volume ratio

Fast heat transfer:

• better temperature control

Reactions cool down or heat up extremely rapidly

• (faster than a microwave)

Small volume therefore flow reactors can be easily

• pressurised

By pressurising, flow reactors can operate at

• temperatures above the typical boiling point of

reactions

This enables easy superheating of reactions e.g. 100ºC to 150ºC above reflux temperatures at atmospheric pressure

100°C Tr Tr 100°C

Back pressure due to flow This increases with higher flow rate, narrower channels or more viscous liquid Back pressure intentionally applied This is typically applied by a pressure regulator near the exit of the system Reactions with gas – either adding gas into a reaction

• r gas evolving reactions

Avoiding cavitation – volatile material boiling Superheating – taking material above its reflux temperature

Monophasic liquid-liquid reactions Biphasic liquid-liquid reactions Solid-liquid reactions Liquid-Gas Solid-Gas

Batch Flow

• Reaction of CaCl2 and Na2CO3 to synthesize CaCO3 in batch and flow
• Exactly the same scale, concentration, temperature and reaction time
• Quality and reproducibility clearly much higher in flow than batch

85

Homogeneous catalysis

• Suzuki reaction
• Heck reaction
• Grubbs ring forming

Multicomponent reactions

• Passerini 3CR
• Biginelli 3CR
• Ugi 4CR

Deprotection chemistry

• BOC deprotection
• MOM deprotection and

intra epoxide opening

• Ester saponification

Ring formations

• Grubbs ring forming
• Ugi followed by ring

closure to benzimidazole

• Diels Alder
• 1,3,4 Oxadiazole

formation

• Fischer indole synthesis
• 1,3 Thiazole formation
• Pyrazole formation

Oxidations and reductions

• Borohydride reduction
• Borane reduction of a

heterocycle

• Reductive amination
• Dess Martin alcohol
• xidation

General Synthesis

• Aldol reaction
• Biphasic Schotten-Baumann
• HBTU amide coupling
• Elimination of an alcohol to alkene
• Esterification of an alcohol
• Wittig reaction
• Nucleophilic aromatic substitution
• SN1 reaction
• Mitsunobu reaction
• N-Alkylation

Nanoparticles

• Gold , Nickel, Silver, Iron (biosensors)

• Faster reactions
• Safer reactions
• Faster reaction optimisation
• Reaction conditions not possible in batch
• Reactions are usually more selective
• Easier scale-up
• Simpler work-up
• Easy integration of reaction analysis

The key benefits of flow chemistry are:

• It is much easier to pressurize flow reactors
• Higher pressures enable higher temperatures
• Higher temperatures result in faster reaction rates

• Poor selectivity comes from variations in

temperature, concentration and addition /stirring rates

• Due to a high surface area:volume ratio and

diffusion mixing, flow chemistry offers a much better parameters control.

Minimal concentration gradient Excellent temperature control

Potential energy Reaction coordinate

A C E

• If a 10L batch reactor explodes, this has

serious consequences The same 10L can be passed through a 10ml flow reactor, ensuring that only 10ml is reacting at any time For a fast reaction e.g. 1 min reaction this

• nly takes an overnight run

In this case the risk is 1/1000!!!

• Reaction time - Vary total flow rate
• Reaction temperature - Low thermal mass
• The ratio of reagents - Vary flow rate ratio
• Concentration - Vary solvent stream

One reaction is flushed out by the next (separated by a solvent) therefore only one reactor is used.

• Do you have a scale limit – COSHH (Control
• f substances hazardous to health), glassware

etc.

• Do you have a temp. limit – TSu, DSC,

cyrogenics, microwave

• Do you require controlled addition –

exotherm’s, mixing, etc.

• Do you have selectivity issues – can you

control your stoichiometry

• Do you generate reactive intermediates or

hazardous by-products

• Do you have safety issues – see any of the

above

Syringe Pump

Pumps are potentially the most important part of a flow chemistry system. Without confidence in pumping accuracy and performance many of the advantages of flow chemistry are lost.

Pressure

The ability to apply pressure to a flow chemistry reaction is a major benefit of using the

• technique. Pressure allows

superheating of the reaction mixture to increase reaction rates and can also control reactions that evolve gas or where gas is added as a reactant.

Product Collector

Flow chemistry allows material to be collected without the restriction of reactor size. Small amounts can be collected for reaction

• ptimization and larger

quantities for scale up applications.

Microreactor

Flow chemistry reactors need to cover the greatest range of reaction conditions. Reactors should be flexible in volume, provide excellent mixing/heat transfer and

• ffer good visibility where

possible.

• Asia is a revolutionary range of advanced

flow chemistry products from Syrris. It has been designed by chemists for chemists to enable the widest variety of chemical reactions and ultimate ease of use.

• The proprietary technology allows manually

controlled or fully automated experiments.

• Asia offers maximum chemical resistance

with an extensive range of temperatures, pressures, and reaction times on scales from mg to kg.

• Asia celebrated its unique design as a winner
• f the R&D 100 Award for innovative

technology.

• Reactor temperature: -100°C to +250°C
• Liquid phase reactor volumes: 62.5μl, 250μl, 1ml,

4ml, 16ml

• Solid phase reactor volumes: 0.7ml, 2.4ml, 5.6ml,

12ml

• Pressure: 0 to 20bar (300psi)
• Flow rate: 1μl/min to 10ml/min per pump channel
• Residence times: 1 second to multi hour
• Wetted materials: Glass, PTFE and PCTFE (stainless

steel and hastelloy possible)

• Mixing: Rapid diffusion mixing
• Production volumes: micrograms to kilograms

Specifications

• The Asia Starter Systems are ideal for chemists

eager to begin using flow chemistry as well as academics interested in introducing flow chemistry to their group.

• The easy-to-use and affordable system contain all

essential flow system parts: an Asia Syringe Pump, an Asia Chip Climate Controller, a glass microreactor, and an Asia Pressure Controller.

• The systems are future-proof and can be seamlessly

upgraded with additional features and modules as the user experience with flow chemistry grows.

• The Asia Premium Flow Chemistry Systems
• ffer a full range of Asia modules and enables

standard flow chemistry operations as well as advanced use.

• Ideal for chemists who are interested in the

utmost functionality and access to the widest range of chemical space.

• The Asia Premium Flow Chemistry Systems

enables standard flow chemistry operations such as reaction optimization, scale-up, etc., as well as advanced flow chemistry such as electrochemistry, multi-step reactions, cryogenic reactions, etc.

Skip applications

Nitration of pyrazoles at AstraZeneca “In the case of a hazardous reaction, the risk of an incident is minimised as the accumulation of potentially dangerous intermediates is avoided.”

Continuous DIBAL-H reduction of a methyl ester in flow.

• Garner´s Aldehyde: Chiral starting material for natural

product synthesis – used in over 100 natural product synthesis (very expensive)

• Reaction requires immediate quenching of the DIBAL

reagent to prevent further reduction.

• Batch: difficult to control direct transformation.

Continuous Flow-Processing of Organometallic Reagents , Duncan Browne, Steve V. Ley OPRD, 2015.

DIBAL – H

common reducing agent Difficult to handle: air moisture sensitive, pyrophoric.

ester

1° step - reduction 2° step - oxidation

• Create the core intermediate: a-halo ketones can

be synthesized from N-protected amino acids

• The resulting a-halo ketones are chiral building

blocks for the synthesis of HIV protease inhibitors (most of the approved inhibitors contain the chiral amino alcohol in the central core)

• Authors set out to develop a multi-step a-halo

ketone synthesis

Synthesis of a-halo ketones

• The most direct route involves a 3 step process
• Activation of the amino acid (8) to the

mixed anhydride (9)

• Condensation of the mixed anhydride

(9) and diazomethane (CH2N2) to form the a-diazo ketone (10)

• Hydrohalogenation of the diazo ketone

to the a-halo ketone Challenges in developing process

acid mixed anhydride Acid chloride diazomethane a-diazo ketone a-halo ketone Hydrohalogenation

• Commercially available Tube in Tube allows gas

reactions to be performed in flow

• Semi permeable membrane which allows gas to be

delivered into a liquid flowing stream (developed in

• S. Ley laboratory)
• Aim was to generate CH2N2 in-situ
• Achieved by passing Diazald/KOH mixture

through inner tube

• CH2N2 is formed in inner tube and passes

through the membrane into the outer tube where it dissolves in THF

Generating Diazomethane in-situ

Optimized generation of CH2N2 was 53% measured by reacting output with benzoic acid - Aq. Waste passed to acetic acid to remove any residue CH2N2

Diazomethane in acid (will methylate )

• Step 1 performed in Asia 4ml Reaction loop with 6.7min

residence time

• Step 2 allowed direct in-situ generation of CH2N2 to

react with aldehyde

• Step 3 – initially performed in batch but then easily

adapted to flow using a tube reactor at 0oC Acid chloride Acid a-diazo ketone mixed anhydride Diazomethane Acid a-halo ketone Hydrohalogenation

The risks associated with the activation of magnesium are circumvented by a new on-column initiation procedure. Solutions with a precise titration were obtained. Telescoped flow or batch reactions allow access to a diverse set of functional groups.

• Magnesium particle size of 20-230 mesh was

selected

• 1 M solution of DIBAL-H in toluene followed

by 2 M solution of TMSCl and 1-bromo-2- chloroethane in THF/Tolune to activated the Mg.

• 0.5 M bromobenzene in 0.5 LiCl in THF was

found to give optimal conditions and greatest range of Grignard solubilities.

• Grignard was titrated with salicylaldehyde

phenyl hydrazine. The calculated concentration of the organozinc reagent was 0.34M. Magensium Activation

Once the preparation of the Grignard reagents had been optimized, the scope and limitations of this methodology were studied. The outcoming

• rganomagnesium solutions were mixed in line with

the corresponding electrophile in flow to obtain the final compounds in high yields in less than 30 min total reaction time

Unique activation of reagents enabling selectivity and transformations not possible by

• ther techniques

A reduction in the quantities of toxic and hazardous oxidizing/reducing reagents used. Ideal for creating reactive intermediates

• Ideal for multi-step synthesis

Rapid oxidations and reductions (even up to 6 electron oxidation) Oxidative synthesis of drug metabolites

• Syrris has developed a flow electrochemistry

system known as the FLUX module as part of the Asia product family

• The FLUX module controls the current or the

voltage applied to the electrodes, locates the cell on the front of the module

• Can work in constant Voltage or constant

Current mode

Cell and holder Asia FLUX control module

Control module Working electrode Counter electrode Electrical connector Gasket with channels (serpentine flow path)

Temperature control module

• The flow cell consists of pairs of electrodes

separated by a gasket.

• Cell can be divided to isolate anode from

cathode.

• Cell volume 225ml.
• Electrode materials include SS, Pt, C, Mg, Cu.

Electrochemistry Flow Cell