Enabling Your Synthesis with Flow Chemistry

Heather Graehl, MS, MBADirector of Sales North AmericaThalesNano North America

Who are we?

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

• Based Budapest, Hungary• 33 employees with own chemistry team.• 12 years old-most established flow reactor company.• R&D Top 100 Award Winner.

•Flow Chemistry Market Leader•Over 800 customers worldwide

Customers

What is flow

chemistry?

Performing a reaction continuously, typically on small scale, through either a coil or fixed bed reactor.

OR

PumpReactor Collection

What is flow chemistry?

• In a microfluidic device with a constant flow rate, the concentration of the reactant decays exponentially with distance along the reactor.

• Thus time in a flask reactor equates with distance in a flow reactor

X

A

dX/dt > 0

dA/dt < 0

Kinetics in Flow Reactors

Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)

Improved Mixing Compared to Batch

Improved mixing can lead to improved reaction times, especially with fixed bed reactors

Improved Mixing = Faster Rxn Time

• Microreactors have higher surface-to-volume ratio than macroreactors, heat transfer occurs rapidly in a flow microreactor, enabling precise temperature control.

Yoshida, Green and Sustainable Chemical Synthesis Using FlowMicroreactors, ChemSusChem, 2010

Enhanced Temperature Control

Lower reaction volume. Closer and uniformtemperature control

Outcome:

Safer chemistry. Lower possibility of exotherm.

Batch

Flow

Larger solvent volume. Lower temperature control.

Outcome:

More difficult reaction control. Possibility of exotherm.

Enhanced Temperature Control

Batch Heated Rxns• Safety concerns, especially in scale

up• Microwave technology is fastest

way of heating solvent in batch

Flow Chemistry Heated Rxns• Flow mimics microwave’s rapid

heat transfer• Solvent is not limited to dipole• Higher pressures and

temperatures possible• High pressures allow use of low

boiling point solvents for easy workup

• Safety improvement as small amount is reacted, continuously

Enhanced Temperature Control

Exothermic Chemistry – LiBr Exchange

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

Ref: Thomas Schwalbe and Gregor Wille, CPC Systems

Enhanced Temperature Control

Reactants

Products

By-products

Traditional Batch Method

Gas inlet

Reactants

Products

By-products

Better surface interactionControlled residence timeElimination of the products

Flow Method

H-Cube Pro™

Selectivity – Residence Time Control

Catalyst screening

Parameter scanning: effect of residence time to the conversion and selectivity

0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 2,2

85

90

95

100

105

110

Conversion Selectivity

%

Flow rate / mLmin-1

1% Pt/C (V) catalyst at 0,02 concentration of 4-bromo-nitrobenzene

Catalyst Flow rate / mL/min

Residence time / sec

Conc. / mol/dm3

Conv. / %

Sel. / %

IrO2 2 9 0,2 52 69

Re2O7 2 9 0,2 53 73

(10%Rh 1% Pd)/C

2 9 0,2 79 60

RuO2

(activated)2 9 0,2 100 100

1 18 0,2 100 99

0,5 36 0,2 100 98

Ru black 2 9 0,2 100 83

1% Pt/C doped with Vanadium

2 9 0,2 100 96

1 18 0,2 100 93

0,5 36 0,2 100 84

Conditions: 70 bar, EtOH, 25°C

Increase and decrease of residence time on the catalyst cannot be performed in batch

Selective Aromatic Nitro Reduction

150°C, 100 bar (1450 psi)

H2, CO, O2, CO/H2, C2H4, CO2.

Reactions in minutes.

Minimal work-up.

-70 - +80C

O3, Li, -N3, -NO2

Safe and simple to use.

Multistep synthesis.

2 step independant T control.

450°C, 100 bar (1450 psi)

New chemistry capabilities.

Chemistry in seconds.

Milligram-kilo scale

Solve Dead-end chemistry.

H-Cube & Gas Module:

Reagent gases

Phoenix Flow Reactor:

Endothermic chemistry IceCube:

Exothermic Chemistry

Reactor Line

H-Cube Midi Scale Up Flow Hydrogenation

Parameters:- p= 1-100 bar- T=10-150°C- v=0.1-3 ml/min-c=0.01-0.1 M-H2 production = up to 60ml/min-CatCarts = 30x4mm or 70x4mm

Parameters:- p= 1-100 bar- T=RT-150°C- v=5-25 ml/min-c=0.05-0.25 M-H2 production = up to 125ml/min-CatCarts = 90x9.5mm

Milligram to Gram Scale

Half Kilogram Scale

H-Cube Midi – For Scale Up

• HPLC pumps continuous stream of solvent • Hydrogen generated from water electrolysis• Sample heated and passed through catalyst• Up to 150°C and 100 bar. (1 bar=14.5 psi)

NH

O2N

NH

NH2

H-Cube Midi Overview

System overview of the H-Cube Midi™

• 500 g product/24 hours• Standard lab compatible • Temperature: RT-150°C • Pressure: 1 bar- 100 bar• Flow Rate: 3 -25 mL/min• In-situ hydrogen generation•Built-in pump with software control• Two-step heating• Easy control using the touch screen

Pump

Mixer Unit

Touch Screen Panel

Outlet Bubble Detector

System Pressure Sensor

System Pressure Valve

Outlet Valve Switch Inlet Valve Switch

Inlet Pressure Sensor

Inlet Bubble Detector

Heating Unit With MidiCart™

Heat Exchanger Preheating Unit

H-Cube Midi

4 Hydrogen generator cells Solid Polymer Electrolyte

High-pressure regulating valves

Water separator, flow detector, bubble detectors

In Situ Hydrogen Generation

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

•Over 100 heterogeneous andImmobilized homogeneous catalysts

10% Pd/C, PtO2, Rh, Ru on C, Al2O3

Raney Ni, Raney CoPearlmans, Lindlars CatalystWilkinson's RhCl(TPP)3

Tetrakis(TPP)palladiumPd(II)EnCat BINAP 30

•Different sizes•30x4mm•70x4mm•90x9.5mm

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

Catalyst System - CatCart

10% Pd/C, RT, 1 barYield: 86 - 89%Alternate reductionsKetone: Pt/CAromatic: Ru/O2

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

Simple Validation Reactions

10% Pd/C, 60˚C, 1 barYield: >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 barYield: 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

Simple Validation Reactions

N

O

OEt

Ar

NH

O

OEt

Ar

Acetic Acid

20% Pd(OH)2/C, 70 bar, 70oC

70% Yield, 5g

RuO2, 100 C

100 bar, 1 mL/min

99% Conversion

Batch: 200°C, 200 bar, 48 hours

Batch: 150°C, 80 bar, 3 days

Difficult 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

Selective Hydrogenations

NO2 NO2

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

O2N

O2N

NHO

Conditions: 1% Pt/C, 70 bar, 30°C, residence time 17sResults: 100% conversion, 100% yield

Conditions: Au/TiO2, 70 bar, 30°C, residence time 17sResults: 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

Selective Hydrogenations

OO2N

Cl

OH2N

Cl

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

HN

OOO

OO2N HN

OOO

OH2N

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

O2N NO2

OHH2N NH2

OH

Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17sResults: 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

Selective Hydrogenations

Analysis by GC-MSAt the same substrate: catalyst ratio 0.125 mol substrate was reduced

N

N

NH

HN

Reaction parameters

Batch in house H-Cube Midi™

CatalystC (M)

Flow rate (mL/min)T (°C)

p (bar)Conversion(%)

Selectivity(%)

360 mg RaNi0.05 (60 cm3)

-3020

10095

After 120 min 0.003 mol compound was reduced

15.02 g RaNiEtOH0.2

12.53020

10095

After 1.2 min 0.003 mol compound was reduced

Co

nversio

n (%

)

Flow rate (mL/min)

C = 0.20 M c = 0.25 M c = 0.30 M c = 0.35 M c = 0.40 M

Quinoxaline reduction

Optimization on H-Cube Midi

Problem: Cyclopropylcarbinol cleavage with Pd/C

H-Cube®-screening suggested better catalysts: Pt/C, Raney nickel, Pd/CaCO3....

Selective hydrogenation of alkenes in the presence of cyclopropylcarbinols Transfer to batch conditions: Scalable Synthesis of Pashminol

OH

1

catalyticheterogeneous

hydrogenation

OH

2

OH

Pashminol™+

run cartridge T / p cyclopropane cleavage to 2

substrate 1

product Pashminol

a 10% Pd/C 25 °C / 1 bar 5 3 73

b 5% Pd/Al2O3 25 °C / 1 bar 15 17 53

c 5% Pt/C 25 °C / 1 bar 0 1 84

d Raney nickel 80 °C / 1 bar 1 2 87

e 5% Pd/CaCO3 25 °C / 1 bar 1 1 83

Table: H-Cube® hydrogenation of 1. GC-conversion. Selected examples.

Hydrogenation Challenge

Ar

F

F

Cl Ar

F

F

H Ar

F

H

H Ar

H

H

H

A B C D

Flow rate

(mL/min)

Pressure (bar)Temperature (oC)

Bubdet Catalyst Amount A (%)

Amount B (%)

Amount C (%)

Amount D (%)

1 20 (∆p:5 bar) 110 50 10% Pd/C 26.7% 61.5% - 7%1 20 (∆p:3 bar) 110 50 1% Pd/C 61,90% 29,40% - 2,50%1 20 (∆p:13

bar)110 50 5% Rh/C 78.9% 5.1% - 9.2%

1 20 (∆p:10 bar)

110 50 5% Pd/C 26.7% 60.9% - 6.7%

1 20 (∆p:5 bar) 110 50 5% Pd/C(S) 25% 63.4% - 6.6%

Solvay Objective: Match similar selectivity of 60% but without additives of

CsF, S, K2CO3 and PPh3

Selective Dehydrochlorination

Flow rate(ml/min)

Pressure(bar)

Temp(oC)

Catalyst H2 amount Result

2 12(∆p:8) 120 1% Au/TiO2 80(48%) Conversion: 48%Selectivity: 99%(Z-isomer: 81%)

1 12(∆p:5) 120 1% Au/TiO2 68(51%) Conversion: 99%Selectivity: 99%(Z-isomer: 84%)

2 12(∆p:5) 120 1%Pt/C(V) 80(48%) Conversion: 63%Selectivity: 99%(Z-isomer: 62%)

1 12(∆p:7) 120 1%Pt/C(V) 68(51%) Conversion: 99%Selectivity: 99%(Z-isomer: 64%)

Ar

Ar NO2

Ar

Ar NH2

Selective Nitro Reduction: Sanofi

N

OH

OHHO

OH

● Genzyme needed 1.2 kg of Zavesca for an internal study, which was priced at 47K USD per 100 g.

N

OH

OHHO

OH

HN

OH

OHHO

OH

H2 / Pd(OH)2 on C

O

H

Saved~ 500K as opposed to purchasing it. It assayed with higher purity than previous commercial lots. Kilo scale.

Genzyme Chemistry

Cooper, C., Nivororozhkin, V., Process Development of a Potent Glucosylceramide Synthase Inhibitor, OPRD, 2012

Powerful: Up to 450°C

Versatile: Heterogeneous and homogeneous capabilities.

Fast: Reactions in seconds or minutes.

Innovative: Validated procedure to generate novel bicyclic compounds Simple: 3 button stand-alone control or via simple touch screen control on H-Cube Pro™.

Phoenix Flow Reactor

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

• Standard benzannulation reaction

• Good source of:

• Quinolines

• Pyridopyrimidones

• Naphthyridines

→ Important structural drug motifs

Disadvantages:

•Harsh conditions

•High b.p. solvents

•Selectivity

•Solubility

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

NH2

RO2C CO2R

OR''R'

+NH

R'

CO2RRO2C

Heat, -R''OH

R = alkylR' = alkyl, aryl, or HR" = alkyl or H

Heat

N R'

CO2R

OH

N R'

CO2H

OH

OH- Heat

methylenemalonic ester

CyclizationSaponification Decarboxylation

Condenzation

N R'

OH

High Temp Chemistry – In Batch

•Replacement of diphenyl ether (b.p: 259°C) with THF (b.p.: 66 °C)

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

Y

CO2Et

OEtX NH2

R

R'

X NH Y

R

CO2EtR'Batch Flow

1a-c 2a-c

3a-c

a: R=H, R'=H, X=N, Y=CO2Etb: R=H, R'=H, X=N, Y=CNc: R=H, R'=H, X=CH, Y=CN

+THF

3a (70%) 3b (75%) 3c (73%)

N

N

O

CO2EtN

N

O

CN

N

CN

OH

Gould Jacobs Reaction - Overview

5 novel bicyclic scaffolds generated-fully characterized.

Many more to follow

New Scaffold Generation

• Choice of stainless steel, teflon, or Hastelloy

• Different length coils to vary residence time

• Easy to recoil

Phoenix Homogeneous Reactions

• Use same H-Cube Pro or Midi CatCarts

• Phoenix metal-metal Catcarts for >250°C reactions

Phoenix metal-metal CatCarts (125mm/250mm)

H-Cube Pro CatCarts (30 or 70mm)

Phoenix Heterogeneous Reactions

HN

N

R

O

R

HO

HN

OR

HN R

Phoenix

T3P, 300C80 bar, THF

Ring closure on aryl NH : key step• Mitsunobu reaction or traditional heating with T3P did not

furnish the bicyclic heterocycle.• Reaction proceeded smoothly in Phoenix reactor at 300oC with

65% yield despite requirement for the cis amide conformer in transition state.

Mitsunobu Reaction not Possible in Batch

NHNH2

O

NH

+AcOH/2-propanol (3:1) (0.5 M)

200°C, 75 bar, 5.0 mL min-1

96 %

cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003

In AcOH/2-propanol (3:1) (0.5M)150 °C, 60 bars,

1.0 mL min-1 (4 min res. time) 88% isolated yield

Continuous Flow Results (4 mL or 16 mL Coil)

Scale-up 200 °C, 75 bars,

5.0 mL min-1 (~3 min res. time) 96% isolated yield

25 g indole/hour

Fischer-Indole Synthesis – Scale Out

High EnergyReactions

Safe: Low reaction volume, excellent temperature control, SW controlled – including many safety control points

Simple to use: easy to set up, default reactor structures, proper system construction

Powerful: -70°C to +80°C

Versatile chemistry: Ozonolysis, nitration, lithiation, azide chemistry, diazotization

Versatile reactors: Teflon loops for 2 reactors with 1/16” and 1/8” loops

High Chemical resistance: Teflon wetted parts

Multistep reactions: 2 reaction zones in 1 systemModular: Option for Ozone Module or more pumps

Size: Stackable to reduce footprint

IceCube

First Reaction Zone Second Reaction Zone

Water inlet and outlet

Reactor Plate•Aluminum stackable plates•Teflon tubing for ease in addressing blockage•Easy to coil for desired pre-cooling and desired residence time after mixing•Different mixers types available

AB

D

-70-+80ºC -30-+80ºC

CFirst Reaction Zone Second Reaction Zone

Reaction Zones

A

BC

AB

C

D

Pre-cooler/Mixer Reactor

-70-+80ºC

-70-+80ºC -30-+80ºC

Applications: Azide, Lithiation, ozonolysis, nitration, Swern oxidation

Azide, nitration, Swern oxidation

Ideal for reactive intermediates or quenching

Single or Multi-Step Reactions

What is ozonolysis?

• Ozonolysis is a technique that cleaves double and

triple C-C bonds to form a C-O bond.

• Currently neglected oxidation technique• Highly exothermic, ozonide accumulation is dangerous

R1

R3 R4

R2

R4

R2R1

R3

O O

O

OR

H

OR

OH

R

OH

O3

Ozonide

Carboxylic Acid(oxidative work-up)

Aldehyde/Ketone(simple quenching)

Alcohol(reductive work-up)

R3

R1 R2

R4

OR

OH

OR

H

OHR

Workup Determines Product

Synthesis of Indolizidine 215F

Other major drug syntheses featuring ozonolysis includes:

(+)-ArtemisininD,L-Camptothecin L-IsoxazolylalanineProstaglandin endoperoxides.

Van Ornum, S.G., Champeau, R., Pariza, R., Chem. Rev. 2006, 106, 2990-3001

Ozonolysis in Industry

Why ozonolysis is neglected?

• Highly exothermic reaction, high risk of explosion • Normally requires low temperature: -78°C.• In addition, the batchwise accumulation of ozonide is

associated again with risk of explosion• There are alternative oxidizing agents/systems:

• Sodium Periodate – Osmium Tetroxide (NaIO4-OsO4)

• Ru(VIII)O4 + NaIO4

• Jones oxidation (CrO3, H2SO4)• Swern oxidation

• Most of the listed agents are toxic, difficult, and/or expensive to use.

• Highly effective oxidation• In line quenching of ozonide – SAFETY• Efficient cooling for exotherm control - SAFETY• The reactions typically go cleanly in high yield and

conversion with little by products• Gas is used as a reagent, so work up is less labor

intensive• Can be used in non-aqueous condition• Ozonolysis is fast and atom efficient• Ease in Scale Up

Why Ozonolysis in Flow?

M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett.,

Flow Ozonolysis of Styrenes

Batch reaction:Max. -60°C to avoid side reaction

In Flow:

Even at -10°C without side product formation

0.45 M in DCM, 0.96 mL/min

0.45 M alcohol, 0.14 M DMSO in DCM0.94 mL/min

3.6 M in MeOH, 0.76 mL/min

* After purification

When compared to batch conditions, IceCube can still control reactions at warmer temperatures due to better mixing and more efficient heat transfer.

Application Note 1: Swern Oxidation

Entry Vflow (ml/min)

A - B - C

T (°C) τ (1. loop, min)

τ (2. loop,

min)

Isolated Yield (%)

1 0.4 0 2.12 3.33 912 0.9 0 0.94 1.48 913 0.6 0 1.42 2.22 854 0.9 10 0.94 1.48 855 1.5 10 0.56 0.88 866 1.5 15 0.56 0.88 987 1.2 15 0.71 1.11 848 1.8 15 0.47 0.74 86

NH2 N N+ Cl-NaNO2

HCl

O-

NaOH

N N

OH

AnilineHCl sol. Pump A

Pump BNaNO2 sol.

Pump C

Phenol NaOH sol. • Most aromatic diazonium salts

are not stable at temperaturesabove 5°C• Produces between 65 and 150 kJ/mole and is usually run industrially at sub-ambient temperatures• Diazonium salts decompose exothermically, producing between160 and 180 kJ/mole. • Many diazonium salts are shock-sensitive

Dioazitization and Azo Coupling

OH OH

NO2

NO2

O2N

Phenol

Pump A Pump BTemperature

(oC)Loop size

(ml)Conversion

(%) Selectivity (%)Solution

Flow rate (ml/min) Solution

Flow rate (ml/min)

ccHNO3 0.41g Ph/15ml

ccH2SO4 0.4 5 - 10 7 1000 (different products)

1.48g NH4NO3/15ml ccH2SO4 0.7

1g Ph/15ml ccH2SO4 0.5 5 - 10 13 100 100

1.48g NH4NO3/15ml ccH2SO4 0.5

1g Ph/15ml ccH2SO4 0.5 5 - 10 13 50 80 (20% dinitro)

70% ccH2SO4 30% ccHNO3 0.6

1g Ph/15ml ccH2SO4 0.5 5 - 10 13 (3 bar) 100 100

70% ccH2SO4 30% ccHNO3 0.6

1g Ph/15ml ccH2SO4 0.5 5 - 10 13 (1 bar) 80

70 (30% dinitro and nitro)

Nitration of Aromatic Alcohols

• Lithiation experiments

• Halogenations/Fluorination experiments

• Epoxidation experiments, asymmetric

• Very low temperature experiments, where batch

conditions required liquid nitrogen temperature or

below

Coming soon…

Our chemistry team is full of flow chemistry and catalysis experts

We aim to solve your challenging chemistry in flow!

Phoenix Flow Reactor - High temperature and pressure reactor for novel heterocycle and compound synthesis (up to 450C)

H-Cube Pro and Gas Module - for gas reagent chemistry from hydrogenation to oxidation

IceCube - for low temperature and high energy reactions

Free chemistry services on Thalesnano flow platforms for up to a week. No strings attached.

Ship us your compound or visit our labs in Budapest, Hungary. CDAs and NDAs are approved quickly.

Free Chemistry Services

We can visit your site for chemistry demos and seminars. Impress your colleagues and bring flow chemistry to your lab.

Phoenix Flow Reactor - High temperature and pressure reactor for novel heterocycle and compound synthesis (up to 450C)

H-Cube Pro and Gas Module - for gas reagent chemistry from hydrogenation to oxidation

H-Cube Midi – scale up H-Cube for 10-500g/day hydrogenations

IceCube - for low temperature and high energy reactions

Heather Graehl, MS, MBADirector of Sales North America

Based in sunny San Diegoheather.graehl@thalesnano.com

Onsite Demos & Seminars Available

THANK YOU FOR YOUR ATTENTION!!

ANY QUESTIONS?