Microwave Synthesis

1

Dr. Mauro Iannelli

2

Milestone

3

• Established in 1989• Organized in six operating units

– Company headquarter based in Bergamo, Italy– Manufacture and R&D facility based in Leutkirch,

Germany– Milestone Inc, Connecticut USA– Milestone General K.K. in Japan– Milestone Korea– Milestone China

• A network of ca. 50 exclusive and non-exclusive distributors worldwide

Milestone

4

Over 30 European and US patents

Milestone Foundation

5

Microwave-Assisted Synthesis

Introduction and General Overview

6

Microwaves

Infrared Radio wavesMicrowaves

300 MHz30 GHz2450 MHz

c

HH

Electric field: Magnetic field: Wavelength (12,2 cm for 2450 MHz)H

7

Energetics

M. Nüchter, B. Ondruschka, W. Bonrath and A. Gumb, G r e e n C h e m . , 2 0 0 4 , 6 , 1 2 8

Microwaves promote kinetic acceleration

8

Advantages of Microwaves

• Reduced reaction time(superheating, closed vessels)

• Reduced side reactions

• Increased yields

• Improved control on reaction

• Improved reproducibility

9

Temperature profilesMicrowaves

Tem

pera

ture

Time

Conv. Heating Reflux

Conv. Heating Autoclave

10

Temperature profiles

Tem

pera

ture

Time

Microwaves

Conv. Heating Reflux

Conv. Heating Autoclave

11

Microwave Instruments

Images adapted from: C.O. Kappe, A. Stadler: Microwaves in Organic and Medicinal Chemistry, Wiley, 2005

Multimode Instruments

wave guide Mono-Mode Instruments

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• Same Field homogeneity

• Same Chemical performances

• Different Reaction scale

• Different Application versatility

Mono-Mode Vs. Multimode

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Mono-Mode Vs. Multimode

14

Mono-Mode

SEM Image

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Multimode

SEM Image

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Mono-Mode Vs. Multimode.

…nearly identical results could be achieved using single-mode andmultimode instruments if an appropriate control of the temperature ismaintained...

…the combination of mono-mode and multimode instrumentation wasdemonstrated to be a valuable tool for the chemist to quickly optimizereactions and subsequent scale up in parallel

J. Alcazar, G. Diels,B. Schoentjesc, Johnson & Johnson Pharmaceutical Research and Development,

QSAR Comb. Sci. 2004, 23

Reproducibility across Microwave Instruments:First Example of Genuine Parallel Scale up ofCompounds under Microwave Irradiation

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First Hybrid PlatformMultiSYNTH

Mono and Multi Mode System

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Mono-Mode Configuration

• Low Minimum Processable Volume (250 l)• High Energy Density• No Standing Waves• Easy Reaction Optimization

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2 3

1234

Fiber opticInfraredVibrating and Shaking-StirrerAir cooling

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Multimode Configuration

1234

Fiber opticInfraredShaking-StirrerAir coolingCarousel Rotation5

5

1

2

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• Easy Scale-Up (parallel fashion)• Parallel Optimization• Open Vessel Reactions (up to 1 L)

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Microwave Labstation for Synthesis

MicroSYNTH

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State-of-the-Art Microwave Technology

Inherent Safety

High FieldHomogeneity

Easy-to-UseControl Terminal

Full Documentation

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Technical Specifications

T640 Terminal withEasyCONTROL software

Control

Open vessel (reflux)Single closed vesselMultiple closed vesselsHigh temperature vessels

Operation

Compressed airCooling

Built-in magnetic stirrerStirring

1600 W (installed, 2magnetrons)Microwave Power

Multi-mode (pyramid shapedmode diffuser)Microwave Technology

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T640 Terminal

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T640 Terminal

• Industrial grade touch-screen controller• 6,5” screen with 65.000 colors• VGA resolution 640 x 480 for sharp process

graphics• 1 USB port for printer, 2 PS2 ports for mouse

and keyboard, 3 RS 232 ports for externaldevices

• Methods and runs saved on a removableWindows™-formatted flash-card

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EasyCONTROL software

26Open System

ClosedSystem

Scale-Up

ParallelScreening and

Scale-Up

Closed System

Application Versatility

Fusion, Sintering

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QV-50 Setup

S. Harusawa et al., Chemical and Pharmaceutical Bulletin, 55 (8), 2007, 1245

Optic FiberThermometer

Pressure Sensor

Quartz VesselPEEK Shield

45 ml40 bar250°C

Cooling Port

28

247

262

250 (27 bar)

213

250 (38 bar)

248

244

204

230

201

bp (40 bar)

4680MEK

2082Acetonitrile

3378Ethanol

4277Ethyl Acetate

4765THF

3869Hexane

3465Methanol

36100Water

4656Acetone

4240DCM

Tbp (1 bar)Solvent

QV-50 Setup

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Organic Chemistry

Oxidation (Mild Conditions)

NHNN

HNN

NCl

OH

NHNN

HNN

NCl

O

OHMnO2 / H2O

180 °C

reflux

Conditions

64 %50 minMW

10 %100 hConventional

YieldTimeSystem

V. Santagada et al., Tetrahedron Letters, 44, 2003, 1149

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Q20 Rotor

991003d

81993c

94993b

931003a

Yield(%)

Conversion(%)

Amine 1Compound

J. Alcázar, G. Diels, B. Schoentjes, QSAR & Combinatorial Science, 23, 2004

600 ml 40 bar 250°C

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High Pressure Rotor

X. J. Bi, L. T. Higham, J. L. Scott, C. R. Strauss, Australian Journal of Chemistry, 59, 2006, 883

High Temperature Water Hydrolytic Cleavage

100 ml TFM vessel100 bar250°C

10 X 100 mlTFM vessel

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Inorganic Chemistry

Adapted from: C.-K. Kim, J.-H. Lee, et al., Materials Research Bullettin 36,. 2001, 2241-2250

Hydrothermal Synthesis of Co-ferrites powders

CoCl2·6H2O FeCl3·6H2O

MW Irradiation

NH3(aq)+ CoFe2O4

2(CuK, Degree)

b)

a)

Conv. Heating

a)120 °C, b)180 °C

b)

a)

2(CuK, Degree)

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Synthesis using fractionalproduct distillation

Open System Setup

T. Razzaq, C. O. Kappe, Tetrahedron Letters, 48, 2007, 2513

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Medicinal Chemistry

J. Schmitz, E. Heller, and U. Holzgrabe, Monatshefte fűr Chemie 138, 2007, 171

Allosteric Modulators of Muscarinic Receptors

Cl

Cl

ON

N+

N+

NO

Cl

Cl

Cl

Cl

ON

N

Br Br

(E,E)-1-10-(1,3-Propanediyl)bis[4-[[(2,6-dichlorobenzyloxy)imino] methyl]pyridinium] dibromideDUO3

CH3CN85 °C

MW: 800 W, 3 h, 54 %Δ: 144 h, 53 %

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High Temperature Applications

MultiFAST

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MultiFAST Rotor

• Ceramic muffle with 4-place rotating carousel• Silicon carbide crucibles holders• Standard metal crucibles (Pt or Ni)• IR contact-less temperature control in all crucibles

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Fast Heating Rate

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Sintering of TiO2 Nanoparticles

Normal sintering MW sintering

Solar Energy Materials & Solar cells 91 (2007) 6-61

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Microwaves + UV Light

V. Cirkva, M. Hajek, J. Photochem.Photobiol. A – Chem. 1999, 123, 21–23.

Addition of THF to Perfluorohexylethylene

Yield

40


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Scaling-Up Microwave Synthesis

Parallel Approach

Reactions in multiple vessels

Batch Approach

Large Batch ?

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Scaling-Up Microwave Synthesis

Continuous Flow Approach

Improved control of reaction conditions

More efficient mass and heat transfer

Exothermic reaction can be minimized,creating safer and more selective processes

Easy management of poorly stable intermediates

Higher flexibility

Higher safety for reactions under pressure

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Output (g/h) =Flow rate (ml/min) x Conc (mol/ml) x MW (g/mol) xYield (%) x 0,0006

From Batch to Flow

Batch: Reaction Time, Scale (Yield%)Flow: Residence Time, Output (Productivity)

Residence time (RT)RT = Reactor volume (ml) / Total Flow Rate (ml/min)

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Back Pressure Valve

Cooling Chamber

ChillerPump

MechanicalStirrer

Tubular MWReactor

FlowSYNTHContinuous-Flow Microwave Reactor

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Technical Specifications

Up to 6 L/hProductivity

2-15 minResidence time

12-100 ml/minFlow rate

Mechanical stirrer withmagnetic driven motorMixing

Stainless steel cooling jacketwith rotating PTFE coilCooling

30 bar (435 psig) with presetback pressure valveMaximum pressure

200°CMaximum temperature

250 ml (180 ml with paddlestirrer)Reactor Volume

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• TFM liner 250 ml volume (Chemical Resistant)

• Fibre Glass reinforced PEEK safety shield(Pressure Resistant)

• TFM bottom sealing with double O-ring

Components of the Reactor

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Mixing Paddle

• Stainless Steel shaft

• PTFE cooling coil

• 3 Weflon® paddle stirrers

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High-Pressure Pump

• Stainless steel headwith check valves

• PTFE membrane• Programmable speed

control• Adjustable piston run

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EasyWAVE Software

• Automatic real-time monitoring and feedback control of temperature,pressure, time, power, stirring and pump speed

• Multiple access levels with passwords

• Methods and process reports can be stored and exported

• Full documentation for quality assurance

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Application Example

Methylation Using DMC

W.-C. Shieh, S. Dell, O. Repic (Novartis Pharma), Organic Letters, 2001

NN

O

O

O O

O

NO

OO

O

NO

O

cat

H

ContinuousFlow

Batch

Conditions

97 %12 minMW

90 %16 hConventional

YieldTimeSystem

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Process Chemistry

Suzuki reaction

M. D. Bowman, J. L. Holcomb, C. M. Kormos, N. E. Leadbeater, V. A. Williams, Organic Process Research &Development, 12, 41-57, 2008

140°C

Temperature

40 ml/min

Flow rate

83 %5 min1:1.3

YieldResidence

TimeRatio

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Limitations

1. High viscosity2. Heterogeneous reaction mixtures3. Catalysts4. Precipitations during the reactions

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Large Batch Scale-Up

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1 vessel Up to 3.5 L

6 vessels

Up to 77 vessels

Up to 200 bar

UltraCLAVE

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Alkoxycarbonylation

MW, Pd(OAc)2

DBU, EtOH

I O

O

+ CO

1 mmol scale, 0.1 mol% Pd, 10 bar CO (excess CO used):

2 mmol scale, 0.1 mol% Pd, 1 bar CO (1.1 eq):

8 vessels of 32 mmol, total quantity 256 mmol, 0.1 mol% Pd, 17 bar CO (1.4 eq):

100 mmol scale, 0.1 mol% Pd, 17.2 bar CO (1.1 eq):

1 mol scale, 0.1 mol% Pd, 34 bar CO (excess CO used):

1 mol scale, 0.1 mol% Pd, 27 bar CO (1.1 eq):

91% isolated yield [Reference 5]



86 % isolated yield [Reference 10]

79% isolated yield

80% isolated yield

heat to 125 °C and hold for 30 min

MW, Pd(OAc)2

DBU, EtOH

I O

O

+ CO

1 mmol scale, 0.1 mol% Pd, 10 bar CO (excess CO used):

2 mmol scale, 0.1 mol% Pd, 1 bar CO (1.1 eq):

8 vessels of 32 mmol, total quantity 256 mmol, 0.1 mol% Pd, 17 bar CO (1.4 eq):

100 mmol scale, 0.1 mol% Pd, 17.2 bar CO (1.1 eq):

1 mol scale, 0.1 mol% Pd, 34 bar CO (excess CO used):

1 mol scale, 0.1 mol% Pd, 27 bar CO (1.1 eq):




86 % isolated yield [Reference 10]

79% isolated yield

80% isolated yield

heat to 125 °C and hold for 30 min

M. Iannelli, F. Bergamelli, C. M. Kormos, S. Paravisi, N. E. Leadbeater, Org. Proc. Res. Dev., 2009, In Press.

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Alkoxycarbonylation

MW, Pd(OAc)2

DBU, EtOH

I O

O

+ CO

R R

I COMe

I I

I

OMe

I

OMe

I

99 % 99 % 99 %

97 % 94 % 91 %

M. Iannelli, F. Bergamelli, C. M. Kormos, S. Paravisi, N. E. Leadbeater, Org. Proc. Res. Dev., 2009, In Press.

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“In 10-15 years, we will see a microwavereactor in every academic and industriallaboratory.They will be the Bunsen burners of the 21stcentury.”

A.K. Bose and coll., Chemtech, 1997, 27, 18.

Conclusions

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Milestone’s Commitment

l LHelping Chemists

Research Process

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Thanks for your attention!

www.milestonesrl.com

[email protected]

ChinaChinaLabtechLabtech

www.milestonesrl.com

mailto:[email protected]

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Documents

Microwave Synthesis