Thales nano reactor overview jan 2013

Accessing new chemical space with flow chemistry

Heather Graehl, MS, MBA Director of Sales North America

Agenda •  Company Background •  Intro to Flow Chemistry •  H-Cube Pro Overview •  Reaction Examples •  Gas Module for H-Cube Pro •  Phoenix Module for H-Cube Pro

Who are we?

•  ThalesNano is a technology company that gives chemists tools to perform novel, previously inaccessible chemistry safer, faster, and simpler.

•  Market leader: 800 customer install base on 6 conDnents. •  10 years old-‐most established flow reactor company. •  33 employees with own chemistry team.

•  Headquarters in Budapest •  R&D Top 100 Award Winner.

Customers (>800 worldwide)

§  20 out of 20 top pharmaceutical §  Top 3 agrochemical companies §  Petrochemical emerging

Number of Publications on ThalesNano Instruments

0 2 4 6 8

10 12 14 16 18 20

2005

2006

2007

2008

2009

2010

2011

142 in 7 years

What is flow chemistry?

What is flow chemistry?

Performing a reaction continuously by pumping fluid through a coil or fixed bed reactor.

Coil/Glass Chip Homogeneous: Liquid-Liquid

Column Homogeneous: Liquid-Liquid (inert column) Heterogeneous: Liquid-Solid Heterogeneous: Liquid-Solid-Gas

Heating Control

Lower reaction volume. Closer and uniform temperature control

Outcome:

Safer chemistry. Lower possibility of exotherm.

Batch

Flow

Larger solvent volume. Lower temperature control.

Outcome:

More difficult reaction control. Possibility of exotherm.

Heating Control

Lithium Bromide Exchange

Batch

Flow

•  Batch experiment shows temperature increase of 40°C. •  Flow shows little increase in temperature.

Ref: Thomas Schwalbe and Gregor Wille, CPC Systems

Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Batch vs. Flow

Better surface interaction Controlled residence time Elimination of the products

Flow Method

H-Cube Pro™

Catalyst System - CatCart®

• Benefits •  Safety •  No filtration necessary •  Enhanced phase mixing

• Over 100 heterogeneous and Immobilized homogeneous catalysts

10% Pd/C, PtO2, Rh, Ru on C, Al2O3 Raney Ni, Raney Co Pearlmans, Lindlars Catalyst Wilkinson's RhCl(TPP)3 Tetrakis(TPP)palladium Pd(II)EnCat BINAP 30

• Different sizes • 30x4mm • 70x4mm (longer residence time or scale up)

• Ability to pack your own CatCarts • CatCart Packer (with vacuum) • CatCart Closer (no vacuum)

Other Advantages

•  Fast Optimization §  Analytical sample after 5 min to change parameters

•  Safety §  Generate H2 on demand, no tanks §  CatCart system ideal pyrophoric catalysts

•  Automation •  Selectivity

§  Residence time on catalyst controlled, not possible batch

•  Speed §  Better mass transfer, high temp, high pressure §  Optimize for single pass 100% conversion for under

10min reactions

Industry Perspective

The innovation gap

Closing the Innovation Gap

•  Companies are actively looking at new techniques to: §  Decrease reaction times → Faster to market §  Cut down on number steps→Lower cost §  Increase yields→Less purification downstream §  Reduce solvent/waste → Cost savings §  Re-examine industry wide untouchable

chemistries→novel molecules→competitive edge

•  Flow chemistry is one of these techniques being investigated.

Survey Conducted

Small scale: §  Making processes safer §  Accessing new chemistry

§  Speed in synthesis and analysis

§  AutomaDon

Large scale: §  Making processes safer §  Reproducibility-‐less batch to batch variaDon

§  SelecDvity

Why move to flow?

Survey Conducted

What chemistries are of interest?

Difficult to perform chemistries

•  Low temperature exothermic reactions •  Reactions with gases •  Very slow reactions or unaccessible chemistry •  Reactions with selectivity issues

Approx. 30% of reactions!

Catalysis reactor: Modular: H-Cube Pro

H-Cube Pro H2 Generation 150°C, 100 bar Hydrogenation Selective C-C coupling

Gas Module 12 Extra gases 100 bar

Phoenix Module 450°C Novel heterocycles

Automated injection & collection. Optimization

H-Cube Midi H2 Generation 150°C, 100 bar Scale Up

H-Cube Pro

H-Cube Pro Overview

•  HPLC pumps continuous stream of solvent •  Hydrogen generated from water electrolysis •  Sample heated and passed through catalyst •  Up to 150°C and 100 bar (almost 1500 psi!)

In Situ H2 Production No more H2 Tanks or costly bomb rooms Safe hydrogenations up to 1450 PSI!!

Hydrogen generator cells §  Solid Polymer Electrolyte

High-pressure regulating valves

Water separator, flow detector, bubble detector

New on H-Cube Pro: •  Double H2 production •  Full H2 mode at any pressure up to 100bar!

H-Cube Pro Overview

Hydrogenation Reactions

Reactions without H2

§ Nitro Reduction § Nitrile reduction § Heterocycle Saturation § Double bond saturation § Protecting Group hydrogenolysis § Reductive Alkylation § Hydrogenolysis of dehydropyrimidones § Imine Reduction § Desulfurization

No Modules § Suzuki Reaction § Heck Reaction § Catalysis (homogeneous or heterogeneous)

With Adding Modules § Carbonylation § Oxidation § Diels Alder § Rearrangements § Supercritical fluids

H-Cube Pro - Higher temperature capability

Lower temperature capability-more selective

T (oC) p (bar) Flow rate (ml/min) Conversion (%) B Selectivity (%)

20 1, controlled 1 37 99 20 1, controlled 2 65 93 20 1, controlled 3 87 77

Solvent Conc. Temp. (°C) Pressure (bar)

Flow Rate (mL/min)

Product Distribution (%, GC-MS)

A B C EtOH 0.1 M 10 10 1 0 100 0

H-Cube

H-Cube Pro

Simple Validation Reactions (out of 5,000)

10% Pd/C, RT, 1 bar Yield: 86 - 89%

Raney Ni, 70°C, 50 bar, 2M NH3 in MeOH, Yield: >85%

Simple Validation Reactions (out of 5,000)

10% Pd/C, 60˚C, 1 bar Yield: >90%

Batch reaction of {3-[(2-carbazol-9-yl-acetylamino)-methyl]-benzyl}-carbamic acid benzyl ester Reagent: H2, catalyst: 10% Pd/C, EtOH, 1 atm, Yield: 76 % Conn, M. Morgan; Deslongchamps, Ghislain; Mendoza, Javier de; Rebek, Julius; JACSAT; J. Am. Chem. Soc.; EN; 115; 9; 1993; 3548-3557.

Raney Ni, 80˚C, 80 bar Yield: 90%

Batch reference: Reagent: HCOONH4, catalyst: 10% Pd/C, solvent: MeOH, Reaction time: 30 min, 1 atm. Yield: 78 % Kaczmarek, Lukasz; Balicki, Roman; JPCCEM; J. Prakt. Chem/Chem-Ztg.; EN; 336; 8; 1994; 695-697

H-Cube® Reaction Examples

Batch: 200°C, 200 bar, 48 hours

Batch: 150°C, 80 bar, 3 days

Chemoselective hydrogenations

Selective reduction in presence of benzyl protected O or N 5% Pt/C, 75°C, 70 bar, 0,01M, ethanol,no byproduct Yield: 75%

Batch reference: Reagent: aq. NaBH4, Solvent: THF; 0°C, Yield: 76,1 % Nelson, Michael E.; Priestley, Nigel D.; JACSAT; J. Am.

Chem. Soc.; EN; 124; 12; 2002; 2894-2902

Route A: Raney Ni, abs. EtOH, 0,01 M, 70 bar, 25°C. Yield: 80%

Route B: Raney Ni, abs. EtOH, 0,01 M, 70 bar, 100°C. Yield: 85%

No batch reference

Hydrogenations in a simplified manner

Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17s Results: 100% conversion, 97% yield


Conditions: Au/TiO2, 70 bar, 30°C, residence time 17s Results: 100% conversion, 100% yield

H-Cube® - Chemoselective hydrogenations

Ürge, L.et al. submitted for publication

Selective hydrogenation of the double-bond

Selective hydrogenation to afford oxime

Selective hydrogenation of the double-bond


Conditions: 10% Pd/C, 70 bar, 0°C, residence time 16s Results: 100% conversion, 100% yield

Conditions: 1% Pt/C, 70 bar, 30°C, residence time 11-17s Results: 100% conversion, 100% yield


Ürge, L.et al. submitted for publication

H-Cube® - Chemoselective hydrogenations

Nitro group reduction in the presence of a halogen

Nitro group reduction in the presence of Cbz-group

Nitro group reduction without retro-Henry as a

side-reaction


Conditions:

Raney Ni

Full H2 mode

T = 40°C

v = 1 mL/min

c = 0,012M (25 mL, MeCN)

Result: Yield: 95%

Kappe, O.C. et al. J. Comb. Chem., 2005, 7, 641-43

H-Cube® - Dethionation

Conditions:

10% Pd/C

p = 40 bar

T = 50°C

v = 0.5 mL/min

c = 10 mg/mL (MeOH)

Result: Quantitative reaction (was used in the following reaction step without further purification

Porco, J.A. et al. Angew. Chem. Int. Ed., 2009, 48 (8), 1494-1497

H-Cube® - Formyl group reduction

Deuteration

Substrate Product Deuterium content(%)

Isolated yield / %

99 99

97 98

93 97

96 98

96 99

Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374

Conversion: 90-95% (TLC) Purity: 70% (LC-MS) without work-up

Batch parameters: K3PO4, TBA-Br, Pd(OAc)2, DMF, 2 hours, 130 °C Reference: (Zim, Danilo; Monteiro, Adriano L.; Dupont, Jairton; Tetrahedron Lett.; EN; 41; 43; 2000; 8199-8202)

Suzuki-Miyaura C-C cross coupling:

Sample reactions

Br

N O 2 B

O H O H

N O 2 CatCart TM 70*4 mm Pd EnCat TM BINAP 30, 2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min

+

Selective Suzuki coupling (Cl, Cl)

The condiDons were:

1 equivalent of 2,6-‐dichloroquinoxaline with 1.2 equivalent of o-‐Tolylboronic acid

ConcentraDon set to 0.02M

Solvent: Methanol

Base: NaOH

AnalyDcs: GC-‐MS

Flow rate (ml/min)

Pressure Temperature Catalyst Base

Result (bar) (oC) LC-‐MS, 220nm

0.8 20 100 Fibrecat 1007

(70mm) 3 ekv

Conversion: 82% SelecDvity: 48%

0.3 20 100 Fibrecat 1007

(70mm) 3 ekv


0.8 20 100 Fibrecat 1035

2.5 ekv Conversion: 16%

(30mm) SelecDvity: 100%

0.8 20 100 Fibrecat 1029

(30mm) 2.5 ekv


0.8 20 100 Fibrecat 1048

(30mm) 2.5 ekv


0.8 20 100 10% Pd/C



0.5 20 50 Fibrecat 1048

2.5 ekv Conversion:17%

(30mm) SelecDvity: ~100%

0.5 20 100 Fibrecat 1048


(30mm) SelecDvity: ~100%

0.2 20 100 Fibrecat 1007



0.2 20 100 Fibrecat 1007



0.2 20 100 Fibrecat 1029



Purity (LCMS): 63%

Batch parameters: Pd(OAc)2, PPh3, TEA, DMF, 3 days, 110°C, yield: 70% Reference: J. Chem. Soc. Dalton Trans., 1998, 1461-1468 J. Chem. Soc. Dalton Trans., 1998, 1461-1468

Heck C-C cross coupling:

Sample reactions

CatCartTM: Pd (PPh3)4, TBAF, 2-propanol, 0.05M, 100oC, 1 bar, 0.2 ml/min.

Conversion: complete Purity (crude azide product): 95-100% (TLC)

Batch reference: (Saxon, Eliana; Luckansky, Sarah J.; Hang, Howard C.; Yu, Chong; Lee, Sandy C.; Bertoyyi, Carolyn R.; J. Am. Chem. Soc. EN; 124; 5`; 2002; 14893-14902) Parameters: NaN3, DMF, 12 hours, 20 °C; Yield: 91%

In-situ organic azide synthesis:

Sample reactions

Faster Optimization

Monitor reaction progress after 5 minutes!

Temperature can be changed during the reaction

50 reaction conditions can be validated in a day.

Example for fast optimization

•  Batch reactions gave results after 4 hours!

H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446

Hydrogenation of diphenylacetylene, one day optimization, %f(T)

•  [RuCl2(mTPPMS)2]/Molselect DEAE

•  p(H2) = 30 bar, [S] = 0.1 M •  Solvent: toluene/ethanol 1/1 •  24 experiments, total operation time

is one day H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446

Hydrogenation of diphenylacetylene, one day optimization, %f(pressure) [RuCl2(mTPPMS)2]/Molselect DEAE

T = 50 oC, [S] = 0.1 M Solvent: toluene/ethanol 1/1

26 experiments, total operation time is one day

H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446

Prof. Oliver Kappe, University of Graz, B. Desai, D. Dallinger, C. O. Kappe, Tetrahedron, 2006, 62, 4651-4664.

University of Graz-Prof. Oliver Kappe

Catalysis reactor: Modular: H-Cube Pro

H-Cube Pro H2 Generation 150°C, 100 bar Hydrogenation Selective C-C coupling

Gas Module 12 Extra gases 100 bar

Phoenix Module 450°C Novel heterocycles

Automated injection & collection. Optimization

H-Cube Midi H2 Generation 150°C, 100 bar Scale Up

H-Cube Pro Modules

Expanding Chemistry Capability of H-Cube and

H-Cube Pro

Gas Module

Gas Module

•  Versa7le: Compressed Air, O2, CO, C2H4, SynGas, CH4, C2H6, He, N2, N2O, NO, Ar.

•  Fast: ReacDons with other gases complete in less than 10 minutes

•  Powerful: Up to 100 bar capability.

•  Robust: All high quality stainless steel parts.

•  Simple: 3 bubon stand-‐alone control or via simple touch screen control on H-‐Cube Pro™.

Use of Gas Module Attached to the H-Cube Pro™

Gas Module HPLC pump H-Cube Pro™

Filter included Check valve included

Alcohol oxidation: Optimization

Pressure Temp. (oC) CatCart Conversion Selectivity

40 25 1 % Au/TiO2 0 – 40 65 1 % Au/TiO2 6.5 >85 40 25 1 % Au

/Fe2O3 0 – 40 65 1 % Au

/Fe2O3 12.7 0 40 25 5 % Ru

/Al2O3 2.8 ~100 40 65 5 % Ru

/Al2O3 3.6 ~100 100 65 5 % Ru

/Al2O3 2.7 ~100 100 100 5 % Ru

/Al2O3 8.5 ~100 100 140 5 % Ru

/Al2O3 15.5 ~100 100 65 1 % Au/TiO2 5.6 84 100 100 1 % Au/TiO2 47.2 93 100 140 1 % Au

/TiO2 ~100 93 100 65 1 % Au

/Fe2O3 4 0 100 100 1 % Au

/Fe2O3 31 7 100 • Area% of desired product in GC-MS / (100 – Area% of reactant in GC-MS)

General conditions: H-Cube Pro with Gas Module, 50 mL/min oxygen gas, 1 mL/min liquid flow rate (0.05M in acetone, 20 mL sample volume), CatCart: 70mm., 1 % Au/TiO2 (cartridge: 70mm, THS 01639),

Batch ref.: Oxygen; perruthenate modified mesoporous silicate MCM-41 in toluene T=80°C; 24 h; Bleloch, Andrew; et al. Chemical Communications, 1999 , 8,1907 - 1908

Very fast addition of alcohol to gold surface. Alkoxide formation.

Aromatization of heterocycles

Reaction parameters were tested: -  H-Cube Pro with and without GasModule -  Oxidizing agent: Hydrogen-peroxide and Oxygen -  Catalyst: MnO2, Amerlyst 36, Au/TiO2 -  Solvent: Acetone/H2O2, Acetone -  Temperature 60-150oC, pressure 20-50 bar, flow rate 1 ml/min, concentration: 0.05 mmol/ml

Oxidizing agent Solvent Catalyst

Temperature (oC)

Pressure (bar) Conversion Comment

MnO2 Acetone MnO2 60 20 82% Blockage afer 10 minutes

H2O2 Acetone -‐ H2O2

(4-‐1) Au/TiO2 70 20 68% afer 1 run 78% afer 2 run

H2O2 Acetone -‐ H2O2

(4-‐1) Au/TiO2 100 30 68% afer 1 run 98% afer 2 run

The catalyst was reacDvated with H2O2 between the runs.

O2 (10 ml/min) Acetone Au/TiO2 75 11 8%

O2 (10 ml/min) Acetone Au/TiO2 150 11 95%

Afer 10 minutes the conversion was dropped to

50%

O2 (50 ml/min) Acetone Au/TiO2 150 20 > 98%

Ø  Conditions: 100oC, 30 bar, CO gas, 0.5 ml/min liquid flow rate, 0.01 M in THF Ø  Catalyst: Polymer supported Pd(PPh3)4 Ø  Reaction was repeated Ø  Different gas flow rates were tested

Results

Aminocarbonylation

ReacDon HC-‐Pro with gas module (CO flow rate)

10 ml/min

30 ml/min

30 ml/min

30 ml/min

60 ml/min

60 ml/min

60 ml/min

60 ml/min

Conversion % 60 65 62 66 79 79 79 82

Reproducible Conversion for Each Flow Rate

Phoenix Module

Phoenix Flow Reactor High Temperature Synthesis

Powerful & New Parameter Space Up to 450°C, 100 bar

Versatile: Cartridges for Heterogeneous and loops homogeneous capabilities.

Fast: Reactions in seconds or minutes.

Chemical Resistance: Stainless steel, Hastelloy, and teflon options

Innovative: Validated procedure to generate novel bicyclic compounds

Scale Up: Different size CatCarts, MidiCart, Loops

Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.

Catalyst Cartridges (Heterogenous Rxns)

Type Volume Max. T/p (100 bar unDl it is indicated otherwise)

Comment

H-‐Cube Pro Type CatCarts 30 mm 0.38 mL 250°C Packed by

ThalesNano 70 mm 0.76 mL 250°C Packed by

ThalesNano Metal-‐Metal Sealing High T CatCarts

125 mm (1/4 SS id 3 mm) 0.9 mL 450 °C User can fill 125 mm (1/4 SS id 3.8 mm) 1.3 mL 450 °C User can fill 125 mm (1/2 SS id 9.4mm) 9 mL 450 °C User can fill, filters

are needed 250 mm (1/4 SS id 3mm) 1.8 mL 450 °C User can fill, filters

are needed 250 mm (1/4 SS id 3.8 mm) 2.6 mL 450 °C User can fill, filters

are needed 250 mm (1/2 SS id 9.4mm) 18 mL 450 °C User can fill, filters

are needed H-‐Cube Midi Type MidiCarts

MidiCart 7.6 mL 150 °C Packed by ThalesNano

Loop-Reactor Options (homogenous rxns)

•  Control Residence/Rxn Time by Length/Volume of Coil.

•  Materials and Sizes §  Stainless steel (1 – 16 mL) – up to

450oC and 100bar •  Coil (1/16” 4-16 ml) •  Short coil (1/16” 1-4ml) •  Static mixer (3/8”, 32ml) •  Acidity limit

§  Hastelloy (4 – 16 ml) – up to 450oC and 100bar

•  Less sensitive to acid though more expensive than stainless steel

§  PTFE coil (4 – 16 ml) – up to 150oC or 20bar

•  Easy to recoil •  Versatile

Places dedicated for connection of Phoenix

2.

1.

1.) reaction in the Phoenix Flow Reactor, followed by a reaction in the H-Cube Pro 2.) reaction in the H-Cube Pro, followed by a reaction in the Phoenix Flow Reactor

i.) if inert CatCart is placed into the H-Cube Pro: reaction in the Phoenix Flow Reactor only ii.) engineering: forget about the H-Cube Pro CatCart place

To Heat Exchanger

Back from Heat Exchanger

To Heat Exchanger Back from Heat Exchanger

Heat exchanger and release valve (140 bar)

Heterocyclic rings of the future, J. Med. Chem., 2009, 52 (9), pp 2952–2963.

• 3000 potential bicyclic systems unmade • Many potential drug like scaffolds Why? • Chemists lack the tools to expand into new chemistry space to access these new compounds. • Time • Knowledge

The quest for novel heterocycles

57

Our focus: 2 main cyclization routes

• Gould-Jacobs-reaction

• Meldrum’s acid variation

Curran, T.T. in Named reactions in Heterocyclic Chemistry; Li, J.-J., Corey, E. J. Eds. Wiley Interscience: New York, 2005, pp423-436

Gould-Jacobs Cyclization

•  Standard benzannulation reaction •  Good source of:

•  Quinolines •  Pyridopyrimidones •  Naphthyridines

•  Important structural drug motifs

Disadvantages: • Harsh conditions • High b.p. solvents • Selectivity • Solubility

Condensation

Cyclization

Saponification Decarboxylation

methylenemalonic ester

W. A. Jacobs, J. Am. Chem. Soc.; 1939; 61(10); 2890-2895

59

• Gould-Jacobs-reaction §  Replacement of diphenyl ether with THF

Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted for publishing)

Cyclization conditions: a: 360 °C, 130 bar, 1.1 min b: 300 °C, 100 bar, 1.5 min c: 350 °C, 100 bar, 0.75 min

Pyridopyrimidinone Quinoline

No THF polymerization!

Batch conditions: 2 hours

Pyrolysis of Meldrums Acid

ketene

•  Meldrum’s acid is more acidic than malonic ester=easier synthesis of adduct •  Decomposition needs no purification •  Lower temperature reactions

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Process exploration

• Meldrum’s acidic route to pyridopyrimidones and to hydroxyquinolines

Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted for publishing)

Cyclization conditions: a: 300 °C, 160 bar, 0.6 min b: 300 °C, 100 bar, 0.6 min c: 360 °C, 100 bar, 1 min d: 350 °C, 130 bar, 4 min e: 300 °C, 100 bar, 1.5 min

The nature of the substituents is critical because they increase or decrease the nucleophilicity of the ring: Electron donating groups increase yields, Electron withdrawing groups decrease yields.

62

• Extension to the synthesis of naphthol and phenyl-substituted salicylic acid-derivatives

• Formal mechanism:

Lengyel L., Nagy T. Zs., Sipos G., Jones R., Dormán Gy., Ürge L., Darvas F., Tetrahedron Lett., (accepted)

63

Thermal cyclisation of amino-flavon

• Solution Phase Flow Thermolysis method

50% Yield 95% NMR purity

In collaboration with the Patonay Group from Debrecen University

Going supercritical: 350°C<T>500°C

Razzaq, T.;, Glasnov, T.N.; Kappe, O. C., Continuous-Flow Microreactor Chemistry under High-Temperature/Pressure Conditions, Eur. J. Org. Chem., 2009, 9, 1321-1325

Transesterification

Esterification

Conditions:

p = 180 bar T = 350°C v = 0.5 mL/min c = 0.05 M (MeOH)

85% yield

Remark: little or no reaction below 200°C

Conditions:

p = 120 bar T = 300°C v = 1.0 mL/min c = 0.33 M (EtOH)

87% yield

Remark: 3 passes little or no reaction below 200°C

Under supercritical conditions

MeOH and EtOH act as an acidic

catalyst

Esterification in supercritical methanol

- Suppression of side reactions by increasing the pressure and flow rate - MeOH: Tcr = 239.4°C, pcr = 80.8 bar - Concentration: 0.05M

Temp. (°C) Pressure (bar) Residence 7me (sec) Calc. yield (%)* 300 150 30 15 425 117 18 9 450 118 7,2 38 450 118 12 25 450 109 12 27 460 140 9 55 460 144 9 54 460 135 9 59 436 137 9 74 460 137 9 76 481 137 9 76 496 137 6,9 76 483 137 5 80 483 137 3,3 80 475 137 2,6 74 475 137 2,9 79

- Isolated yield 60%, NMR 98%

* By calibration curve, loop size 1.5 mL

Rapid optimization

Thank you for your attention

Thales nano reactor overview jan 2013

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