rapid reaction optimisation and scale-up in continuous ... · temperature (°c) flow rate...

www.chemtrix.com

Rapid Reaction Optimisation and Scale-Up

in Continuous Flow Reactors

Paul Watts

Department of Chemistry, The University of Hull, Hull, HU6 7RX.

Chemtrix BV, Burgemeester Lemmensstraat 358, Geleen, The Netherlands.

CPAC Rome Workshop 2010, 22-24 March 2010

Temperature (°C)

Flow Rate

(µLmin-1)

Indole

(%)

90 1 60.7

95 1 81.3

105 1 85.7

105 0.5 93.3

115 0.5 98.9

• Indole Synthesis

• Reaction conditions:

• 0.1M Phenylhydrazine, cyclohexanone, methanesulphonic acid in DMF

• Heat

Rapid Optimisation of Reaction Conditions

Tetrahedron, 2010, in press

MANUALOPERATION

SLOW

MESSY

Labtrix®: Micro Reactor Development Platform

• Labtrix® developed with the researcher in mind to enable:

– Continuous flow process optimisation (R&D) → Reaction optimisation

– Generation of data that can readily be transferred through scale-up stages to attain production volumes

Labtrix® Features: Micro Reactors

• Standard reactors enable various reaction configurations to be investigated

– 2, 3 and multi-component reactions

– Reactor Dimensions: 2.2 cm x 4.5 cm x 0.1 mm

– Channel Dimensions: 300 µm (wide) x 60 µm (deep) → various lengths

• Channel Volumes: 1, 5 and 10 µl

• In-situ quench terminates reactions within the reactor (1.5 µl)

• Customisation

→ Custom manufactured reactors can also be fabricated for use within Labtrix®

Labtrix® Features: Reactant Delivery

• Reactants are delivered to the micro reactor using 5 syringe pump drivers

• Separate pump for each reactant

• Continuous flow pumps afford constant re-filling of the syringes enabling the use

of a quench solution to terminate reactions within the reactor

– Stable, reproducible flow

– Large volume delivery using small, accurate syringes (1 ml)

• Glass, gas-tight luer lock syringes

– Teflon coated plungers

– Solvent and reactant resistant

• PEEK luer connections to micro reactor

– No dead volume

– Broad spectrum chemical compatibility

Labtrix® Features: Reactor Holder*

• Glass reactors are housed within a holder which enables rapid fluid connection

• Interconnects made using PEEK finger-tight fittings

• Constant pressure (25 Bar) using a BPR (6 µl dead volume):

– Reactants are maintained as a liquid phase

– Insufficient pressure → automatic shutdown (no over heating)

• Using a Peltier device:

– Reaction temperature (-15 to 200 °C)

→ 0.9 ° C sec-1

– Thermal probe measures reactor temperature

→ to an accuracy of 0.1 °C

– Temperature programs can be employed

– Automatic sample diversion to waste if condition is not met

* Patented

• Pressurised to 25 bar and direction of flow maintained using PEEK check valves

– All common organic solvents are liquid up to 200 °C

– System capable of tolerating a wide range of viscosities

• All materials in contact with liquid flow are Perlast, PEEK or PTFE

Labtrix® Features: Solvent Compatibility

Pressure Required @ 200 °C

Solvent Polarity Index Boiling Point (°C) Viscosity (cP) (psi) (Bar)

DI H2O 9.0 100 1.00 178.5 12.3

EtOH 5.2 78 1.20 151.1 10.4

MeOH 5.1 35 0.60 185.0 12.8

Acetone 5.1 56 0.32 207.6 14.3

MeCN 5.8 82 0.37 143.8 9.9

EtOAc 4.4 77 0.45 154.3 10.6

Hexane 0.0 69 0.33 173.7 12.0

DMSO 7.2 189 2.00 18.8 1.3

DMF 6.4 155 0.92 40.1 2.8

Toluene 2.4 111 0.59 89.2 6.2

THF 4.0 65 0.55 180.1 12.4

Diethyl ether 2.8 35 0.32 271.1 18.7

CHCl3 4.1 61 0.57 193.8 13.4

DCM 3.1 41 0.44 255.7 17.6

Labtrix® Features: Automation

• Computer control of reactor temperature, flow rates and dispensed volumes:

– Automated equilibration

– Diversion of output stream from waste to collection vial

– Operate unattended

• Data logging

– Archiving of reaction conditions used

– Graphical view of reaction conditions

Chemtrix Feasibility Study 1: 1,2-Azole Synthesis

• Heterocyclic compounds such as 1,2-azoles demonstrate biological activity, as

such their synthesis is of interest to pharma-, agro- and fine chemical industries

– Analgesic, anti-microbial, anti-bacterial, anti-fungal and anti-inflammatory activities

• Synthetic routes include 1,3-dipolar cycloadditions and the reaction of acetylenic

ketones or chalcones with hydrazines.

• The condensation of 1,3-diketones with hydrazine derivatives remains the most popular route to 1,2-azoles

– Polar protic solvents are favoured → MeOH, EtOH and iso-propanol

– Unsymmetrical 1,3-diketones affording regioisomers

Disadvantages:

• Often harsh reaction conditions and long reaction times are employed

– Low yielding and often requires an acid catalyst

Continuous Flow Evaluation:

• Reaction times 30 to 300 sec

• Temperature: 25 to 200 °C (8 temperatures)

• Pressure: 25 Bar over the whole temperature range

• Solvents screened: MeOH, EtOH, THF

• Reactant stoichiometry: 1:1.1 (excess hydrazine derivative)

• Reactant concentration: 0.1 M and 0.11 M respectively

• Quench agent: Acetone

– ‘mop-up’ unreacted hydrazine derivative → terminate the reaction within the reactor


NHRNH2


Optimal conditions:

• Micro reactor: 180 sec, 125 °C, 100% conversion

• Batch stirred reactor 1 h, 125 °C cf. 93.6 % conversion

Investigation:

• Number of reactions: 200 (n = 5)

• Time taken to generate samples: 27 h

• Volume of reactants employed: 5.97 ml (94.3 mg 1,3-diketone)

• Limiting factor: Analytical evaluation of the samples and data processing (4 days)

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

0 50 100 150 200

Co

nv

ers

ion

(%

)

Temperature (oC)

(300s)

(180 s)

(150 s)

(60 s)

(30 s)

Production Technology

Scale-up:

• Re-optimised at each stage

• Costly and time consuming

Scale-out:

• Numbering-up/replication

• Cost effective and flexible

• Requires reproducibility within single reactors

Medium-Scaleproduction

Large-Scale

Production

Lab-Scale

Scale-out

Pilot Plant Large-Scale

Production

Lab-Scale

Chemtrix Feasibility Study 2: Aza-Michael Addition

• Development project to illustrate the practicalities of internal parallelisation

• Single reaction channel vs. Multiple reaction channels:

– Increased productivity without increasing reactor footprint

• 2.2 cm (wide) x 3.0 cm (long) x 0.1 cm (deep)

• Internal vs. External parallelisation

– Single input feeds, simplifies interconnection strategy

• Aza-Michael addition used as a model reaction:

Rationale:

– Long reaction times

– Exothermic → reaction is reversible at elevated temperatures

‘Internal Parallelisation’

3.0 cm

2.2 cm

‘Reaction Optimisation’(Single Channel)

3.0 cm2.2 cm

1

‘External Parallelisation’(Multiple Single Channel Reactors)

Partners: Lionix BV and TNO Science & Industry BV

Chemtrix Feasibility Study 2: Single Channel

Reactor:

• Channel dimensions 350 µm (wide) x 60 µm (deep) x 3.58 cm (long)

– Internal volume = 0.59 µl

Reaction Conditions: 1.0 M reactants in MeCN at 25 °C

• RT = 7.08 s (5 µl min-1) afforded the optimum conversion (95.2 %)

• Quantified using internal standardisation

Peak Area Run ID Anisole 4-(Diethylamino)butan-2-one Ratio Conversion (%)

1 5062260 1350645 0.267 95.3

2 3737603 997608 0.267 95.33 4467481 1193128 0.267 95.4

4 6697704 1775737 0.265 94.7

5 5423418 1449400 0.267 95.5

Average 0.267 95.2% RSD 0.320 0.32


Chemtrix Feasibility Study 2: 8 Channel Reactor

Reactor:

• Channel dimensions 350 µm (wide) x 60 µm (deep) x 3.58 cm (long)

– Internal volume = 4.72 µl

Reaction Conditions: 1.0 M reactants in MeCN at 25 °C

• RT = 7.08 s (40 µl min-1) afforded the optimum conversion (96.4 %)

• Quantified using internal standardisation

Peak Area

Run ID Anisole 4-(Diethylamino)butan-2-one Ratio Conversion (%)

1 12149238 3262116 0.269 95.9

2 11627649 3147729 0.271 96.7

3 12097683 3268153 0.270 96.5

4 9727519 2645885 0.272 96.8

5 10883218 2926689 0.269 96.0

Average 0.269 96.4% RSD 0.78 0.42



Single Channel Reactor:

• Internal volume = 0.59 µl

• Outer dimensions = 3.0 cm x 2.2 cm

• Residence time = 7.08 sec

• 95.2 % conversion

– 0.32 % RSD (n = 10)

• Throughput = 2.0 mg h-1

Parallel Reactor (8-channels):

• Internal volume = 4.72 µl

• Outer dimensions = 3.0 cm x 2.2 cm

• Residence time = 7.08 sec

• 96.4 % conversion

– 0.42 % RSD (n = 10)

• Throughput = 16.6 mg h-1

Internal numbering-up:

• No additional optimisation required

• No increase in reactor footprint or feed lines

• No increase in system complexity

• Still controlled using a single pump, employing only 2 inputs and 1 output

• Eight-fold increase in reaction throughput


External numbering-up effect:

• Modular system

• Reactors can be readily removed/installed → flexible production capacity

• Thermostatted 25 to 120 °C

– Using re-circulating silicone oil

– Six-independently heated zones reactor-1

• Sequential reactions with different thermal requirements

• Reproducible reaction conditions obtained in each reactor



Protrix ® Technology• Utilising the same reactors as Labtrix, system throughput is increased by

parallel reactor operation

• The ‘plug and play’ approach enables the user

access to higher throughputs with:

• No increase in system complexity

• No additional optimisation required

• The holder enables:

• Temperatures: - 40 to 200 oC

• Pressure: 25 bar

• Reactors: 1 to 32 reactors per holder

• Up to four holders operated in parallel

• Reactors: Flow splitter enables multiple

reactions to be run in parallel

Protrix ® Reactor Holder

• Holder enables 1 to 32 reactors to be employed in parallel

• Maintained under pressure to enable heating (25 bar)

Reactant Delivery:

• Single input per reactant and product stream

Heating/Cooling:

• -40 to 200 oC using a re-circulating heating system

No. of

Reactors

No. of

Holders

Reactor Volume

(ml)

Product

Conc.

(%)

Reaction Time

(min)

Productivity

(g h-1)

128 4 5.1 ml 10 1 61.4*

(538.2 kg annum-1)

Heating fluid

Reactant

input

Plantrix ® Meso Reactors

• Glass reactors 15 cm x 15 cm:

– Contain six layers (2 reactor layers, 2 heat transfer layers and a top/bottom

plate)

– Reaction channels of 1 mm (wide) x 0.7 mm (deep) x 10.5 m (long)

Reactant Inlets/Outlets Heating Fluid Inlets/Outlets

• Reactor can be used for multi-input and operated at 35 bar

• Temperatures of -40 to 200°C

• Pre-heater and cooler modules are also available to increase/decrease

reactant temperature ahead of reaction zone or upon collection• Customizable reactors available to maximize productivity

Plantrix ® Scale Up

• Holder is constructed from stainless steel and PEEK

– All wetted parts are chemically resistant and metal-free

• Separate inputs for reactants and heating fluid

– Remove contamination risk when exchanging reactors

• Reactors can be stacked to increase productivity (x 10)

– Scale a process from 0.13 kg h-1 to 1.3 kg h-1 with no change of operating conditions

• Further increases can be made by employing multiple holders– i.e. Ten holders = 13.0 kg h-1 (11.4 tonne annum-1)

• We offer a total solution for the pharmaceutical and fine chemical industry in the

field of micro reactor technology (MRT)

• Design, fabricate and supply micro- and meso-reactors

• Perform chemical evaluations, train and consult

• Engineer scalable micro reactor equipment

• Delivering ‘plug and play’ modules and systems based on a scale-up (numbering-

up) concept utilising either standard or customised micro reactors

Products:

Chemtrix Summary

Laboratory System: Labtrix®-S Large-scale Production: Plantrix®-MSmall-scale Production: Protrix®-S

• Researchers

• Dr. Charlotte Wiles

• Dr. Bongkot Ngamsom

• Dr. Joe Dragavon

• Dr. Vicki Hammond

• Dr. Gareth Wild

• Dr. Tamsila Nayyar

• Dr. Julian Hooper

• Dr. Linda Woodcock

• Dr. Haider Al-Lawati

• Dr. Nikzad Nikbin

• Dr. Ping He

• Dr. Victoria Ryabova

• Dr. Vinod George

• Dr. Leanne Marle

• Mairead Kelly

• Ben Wahab• Francesco de Leonardis

• Collaborators

• Hull colleagues

• Prof. J. A. Littlechild

• TNO

• TUe

• Funding

• EPSRC

• Sanofi-Aventis

• LioniX

• Astra Zeneca

• EU FP6

• EU FP7

• Yorkshire Concept

Research Workers and Collaborators

rapid reaction optimisation and scale-up in continuous ... · temperature (°c) flow rate...

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