Dr.

Mauro Iannelli
1

Milestone

Milestone
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 nonexclusive distributors worldwide

Milestone Foundation
Over 30 European and US patents

Microwave-Assisted Synthesis
Introduction and General Overview

Microwaves
Infrared

Microwaves

Radio waves

2450 MHz
30 GHz

300 MHz

H
Electric field
H : Magnetic field

: Wavelength (12,2 cm for 2450 MHz)

Energetics

Microwaves promote kinetic acceleration

7

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

Advantages of Microwaves
Reduced reaction time
(superheating, closed vessels)

Reduced side reactions

Increased yields
Improved control on reaction
Improved reproducibility
8

Temperature profiles
Microwaves
Conv. Heating Reflux

Temperature

Conv. Heating Autoclave

Time

Temperature profiles
Microwaves
Conv. Heating Reflux

Temperature

Conv. Heating Autoclave

Time

10

Microwave Instruments
Multimode Instruments

wave guide

11

Mono-Mode Instruments

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

Mono-Mode Vs. Multimode

Same Chemical performances

Same Field homogeneity
Different Reaction scale
Different Application versatility

12

Mono-Mode Vs. Multimode

13

Mono-Mode

SEM Image
14

Multimode

SEM Image
15

Mono-Mode Vs. Multimode

.
Reproducibility across Microwave
Instruments:
First Example of Genuine Parallel Scale up of
Compounds under Microwave Irradiation
J. Alcazar, G. Diels,B. Schoentjesc, Johnson & Johnson Pharmaceutical Research and Development,
QSAR Comb. Sci. 2004, 23

nearly identical results could be achieved using single-mode and

multimode instruments if an appropriate control of the temperature is
maintained...
the combination of mono-mode and multimode instrumentation was
demonstrated to be a valuable tool for the chemist to quickly optimize
reactions and subsequent scale up in parallel

16

First Hybrid Platform

MultiSYNTH
Mono and Multi Mode System

17

Mono-Mode Configuration
4
2

1
3

Fiber optic
2 Infrared
3 Vibrating and Shaking-Stirrer
4 Air cooling

Low Minimum Processable Volume (250 l)

High Energy Density
No Standing Waves
Easy Reaction Optimization

18

Multimode Configuration
1
1
4

2
3

3
2

4
5

Fiber optic
Infrared
Shaking-Stirrer
Air cooling
Carousel Rotation

Easy Scale-Up (parallel fashion)

Parallel Optimization
Open Vessel Reactions (up to 1 L)

19

MicroSYNTH
Microwave Labstation for Synthesis

20

State-of-the-Art Microwave Technology

High Field
Homogeneity

Easy-to-Use
Control Terminal

Full Documentation

Inherent Safety

21

Technical Specifications
Microwave Technology

Multi-mode (pyramid shaped

mode diffuser)

Microwave Power

1600 W (installed, 2
magnetrons)

Stirring

Built-in magnetic stirrer

Cooling

Compressed air

Operation

Open vessel (reflux)

Single closed vessel
Multiple closed vessels
High temperature vessels

Control

22

T640 Terminal with

EasyCONTROL software

T640 Terminal

23

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 external
devices
Methods and runs saved on a removable
Windows-formatted flash-card

24

EasyCONTROL software

25

Application Versatility

Fusion, Sintering

Closed
System
Scale-Up

Parallel
Screening and
Scale-Up

Closed System
Open System
26

QV-50 Setup
Optic Fiber
Thermometer

Quartz Vessel
PEEK Shield

45 ml
40 bar
250C
Pressure Sensor

Cooling Port

27

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

QV-50 Setup
bp (1 bar)

bp (40 bar)

DCM

40

201

42

Acetone

56

230

46

Methanol

65

204

34

THF

65

244

47

Hexane

69

248

38

Ethyl Acetate

77

250 (38 bar)

42

Ethanol

78

213

33

Acetonitrile

82

250 (27 bar)

20

MEK

80

262

46

Water

100

247

36

Solvent

28

Organic Chemistry
Oxidation (Mild Conditions)
Cl
N
N

Cl
N

OH
N N
HN
NH

OH N N
HN
NH

System

Conditions

Time

Yield

Conventional

reflux

100 h

10 %

MW

180 C

50 min

64 %

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

29

MnO2 / H2O

Q20 Rotor

Conversion
(%)

Yield
(%)

3a

100

93

3b

99

94

3c

99

81

3d

100

99

Compound

Amine 1

600 ml 40 bar 250C

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

30

High Pressure Rotor

10 X 100 ml
TFM vessel

100 ml TFM vessel

100 bar
250C

High Temperature Water Hydrolytic Cleavage

31

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

Inorganic Chemistry
Hydrothermal Synthesis of Co-ferrites powders
CoCl26H2O + FeCl36H2O
Conv. Heating

NH3(aq)
a)120 C, b)180 C

CoFe2O4

MW Irradiation
b)
b)

a)
a)

2(CuK, Degree)

32

2(CuK, Degree)

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

Open System Setup

Synthesis using fractional

product distillation

33

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

Medicinal Chemistry
Allosteric Modulators of Muscarinic Receptors
Cl
O

Cl

CH3CN
85 C

Br

Br

Cl

Cl
O

Cl

Cl

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

DUO3
MW: 800 W, 3 h, 54 %
: 144 h, 53 %

34

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

High Temperature Applications

MultiFAST
35

MultiFAST Rotor

36

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

Fast Heating Rate

37

Sintering of TiO2 Nanoparticles

Normal sintering

38

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

MW sintering

Microwaves + UV Light

Addition of THF to Perfluorohexylethylene

Yield

39

V. Cirkva, M. Hajek, J. Photochem.Photobiol. A Chem. 1999, 123, 2123.

Microwaves + UV Light

40

Microwaves + UV Light

41

Scaling-Up Microwave Synthesis

Parallel Approach
Reactions in multiple vessels

Batch Approach
Large Batch ?

42

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

44

FlowSYNTH
Continuous-Flow Microwave Reactor
Back Pressure Valve

Mechanical
Stirrer
Cooling Chamber

Tubular MW
Reactor

Pump

45

Chiller

Technical Specifications

46

Reactor Volume

250 ml (180 ml with paddle

stirrer)

Maximum temperature

200C

Maximum pressure

30 bar (435 psig) with preset

back pressure valve

Cooling

Stainless steel cooling jacket

with rotating PTFE coil

Mixing

Mechanical stirrer with

magnetic driven motor

Flow rate

12-100 ml/min

Residence time

2-15 min

Productivity

Up to 6 L/h

Components of the Reactor

TFM liner 250 ml volume (Chemical Resistant)
Fibre Glass reinforced PEEK safety shield
(Pressure Resistant)
TFM bottom sealing with double O-ring

47

Mixing Paddle

Stainless Steel shaft

PTFE cooling coil
3 Weflon paddle stirrers

48

High-Pressure Pump

Stainless steel head

with check valves
PTFE membrane
Programmable speed
control
Adjustable piston run

49

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
50

Application Example
Methylation Using DMC
O

O
O

O H

O
O

N
O

N
N
cat

51

System

Conditions

Time

Yield

Conventional

Batch

16 h

90 %

MW

Continuous
Flow

12 min

97 %

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

Process Chemistry

Suzuki reaction

52

Ratio

Temperature

Flow rate

Residence
Time

Yield

1:1.3

140C

40 ml/min

5 min

83 %

M. D. Bowman, J. L. Holcomb, C. M. Kormos, N. E. Leadbeater, V. A. Williams, Organic Process Research &

Development, 12, 41-57, 2008

Limitations
1.
2.
3.
4.

53

High viscosity
Heterogeneous reaction mixtures
Catalysts
Precipitations during the reactions

Large Batch Scale-Up

54

UltraCLAVE
1 vessel Up to 3.5 L

6 vessels

Up to 200 bar
Up to 77 vessels
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O
I

MW, Pd(OAc)2

CO

Alkoxycarbonylation
DBU, EtOH

heat to 125 C and hold for 30 min

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

O
91% isolated yield [Reference 5]
O
84% isolated yield [Reference 6]

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

81% isolated yield [Reference 8]

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

I
MW, Pd(OAc)2
DBU, EtOH

heat to 125 C and hold for 30 min

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

86 % isolated yield [Reference 10]

1 mmol
scale,Pd,
0.1 34
mol%
bar CO (excess
CO used):
91% isolated
1 mol scale,
0.1 mol%
barPd,
CO10(excess
CO used):
79% isolated
yieldyield [Reference
2 mmol scale, 0.1 mol% Pd, 1 bar CO (1.1 eq):

84% isolated yield [Reference

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

81% isolated yield [Reference

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

86 % isolated yield [Reference

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

56

80% isolated yield

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

79% isolated yield

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

80% isolated yield

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

Alkoxycarbonylation
O
I

MW, Pd(OAc)2

CO
DBU, EtOH

OMe

OMe

COMe

99 %

57

91 %

94 %

97 %

99 %

99 %

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

Conclusions
In 10-15 years, we will see a microwave
reactor in every academic and industrial
laboratory.
They will be the Bunsen burners of the 21st
century.
A.K. Bose and coll., Chemtech, 1997, 27, 18.

58

Milestones Commitment

Helping Chemists
l
Research

59

L
Process

Thanks for your attention!

China
Labtech

www.milestonesrl.com
synthesis@milestonesrl.com
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