Synthetr

onTM

Flow Reactor Technology

SynthetronTM

©2012 KinetiChem, Inc. Irvine, CA Jeffrey C. Raber, Ph.D.

Flow chemistry offers significant advantages

Current flow reactor technology does not meet all

possible reaction needs:

Precipitate and plugging concerns

Shortened diffusion path is not enough

Simple, rapid scale-up is most desired

Smaller plant footprint desirable

The Synthetron™ platform was conceived to over-come these limitations

Formation of

thin flowing

films of

reagents

1. Line Contacting

The Synthetron incorporates two innovations

US Patents 7,125,527 & 7,534,404

Forced Uniform

Molecular

Interdiffusion

2. FUMI

Disruption of molecular clusters enables more molecules to

be immediately available for reaction participation

Molecular clusters, groups of the same molecules together

in solution, slow down and impede potential reaction

rates

The Synthetron incorporates two innovations

Molecular Clusters in Solutions

Ideal flow reaction

The Synthetron incorporates two innovations

Formation of

thin flowing

films of

reagents

1. Line Contacting

Forced Uniform

Molecular

Interdiffusion

2. FUMI

Synthetron S3 Reactor

Synthetron S3T1 Reactor

Easy to clean

Easy to assemble and inspect

Easy to re-machine the surfaces

Broad material capabilities

Can mix and match materials

Flexibility of creating the right tool for the job

Options for making disks out of unique materials

PLASTICS METALS CERAMICS

PEEK® Hastelloy® SiC*

1 Watt/M - K 22 Watt/M - K 100 Watt/M - K

*not currently implemented

Flexible and Scalable Technology Platform

Wide Range of Flow Rates are Possible

From 0.5 mL/min up to 400 mL/min on same device

Current Capabilities of Kilos-Per-Hour

Demonstrated with a 2.5” disk diameter

Scalability is based on increasing disk diameter

As disk diameter increases, reactive surface area

increases as a square function.

4 Kg/hr @ 2.5” disk diameter = 16 Kg/hr @ 5”!

High Flow Rates = Production Capabilities

Broad Flow Rate Ranges Demonstrated

0.5 Kg/hr up to 8.0 Kg/hr in SAME DEVICE!

Tremendous Throughput

0.5 Kg/hr = 4Kg in 8 hour shift

8 Kg/hr = 64 Kg in 8 hour shift

KILO LAB IN A FUME HOOD!

Space and Time Savings

Energy Efficient

High Flow Rates = New Options

Handling of precipitate formations

Particle Size Controls

Tremendous Throughput

Multiple Kg’s per hour possible with a reaction

volume of 0.2 mL

Enabling New Directions

New Applications

New Chemical Possibilities

The Frequency Factor Impact

Impacting a “SLOW” Reaction - ODS

Reactivity complementary to HDS – zero-levels not achieved

Oxidation occurs through peroxo-acid

Catalytic amounts of acid are required

Requires an aqueous oxidant to act on a substrate in the

organic phase

Translates into hours stirring at elevated temperatures!

How to improve and adapt this reaction to the Synthetron™

platform?

Otsuki, S. et al Energy & Fuels 2000, 14, 1232-1239

Kong, L. et al Catal. Lett. 2004, 92, 163-167

García-Gutiérrez, J. L. et al Appl. Catal A: General 2006, 305, 15-20

Optimize Conditions with DOE

• Resolution IV experiment - Included 1 fold-over for a total of 29 trials

- 5 replicates of center point included

Parameter Low High

FR (mL/min) 0.3 2.0

gap size (µm) 25 150

RPM 740 6300

org:aq 1 10

% formic acid 2.5 5

temperature (˚C) 10 70

Shear Rate (sec-1)

16000 840000

Residence Time (sec)

1 53

• Bottom line: Discovered conditions that lead to ~60% removal

with a residence time of 80 seconds at only 10 C

• The same reaction with vigorous “traditional” stirring took

over 8 hours to reach the same extent conversion at 70 C

Further Optimization Efforts

Higher flow rates were found to be effective

Residence Time is NOT an independent parameter

Recirculation = further ODS

Could use multiple reactors in-line as well

0

10

20

30

40

50

1 2 3

Pass Number

Percen

t d

eu

lfu

riz

ati

on

Seies 1

Series 2

Series 2 = smaller gap @

much higher shear rates

with lower oxidant ratios

Reaction Examples

Traditional methods provided product in only 57%

yield and required difficult purification

How to improve and adapt this reaction to the

Synthetron™ platform?

Reaction Examples

First Approach Second Approach

Feed 1 = Aniline/LHMDS Feed 1 = Nitroarene/Aniline

Feed 2 = Nitroarene Feed 2 = LHMDS

First Flow Rate = 60% First Flow Rate = 94%

Faster Flow Rate = 62% Faster Flow Rate = 96%

Reaction Examples

Batch Synthetron

Add aniline to flask and cool to 0℃

Dropwise addition of LHMDS

Maintain 0℃, slowly add Nitroarene

Warm to r.t. over 12 hours

Equilibrate reactor at 25℃

Pump reagents as needed

Produce at 22.6 g/min or 1.36Kg/hr

57% Crude Yield 96% Crude Yield

Chromatography, Recrystallize recrystallization or direct use

Reaction Examples: Organometallics

2.0M, r.t. Process Temp = 0°C 2.0M, r.t.

Batch Synthetron

30% Yield 98% Yield

Multiple side products 2 Kg/hr

Reaction Examples: Organometallics

Batch CPC CLS-

microreactor Synthetron

76% Yield 90% Yield 98% Yield

50 g/hr 1.5 Kg/hr

Reaction Examples: Gas-Liquid Efficiencies

Synthetron Process:

96.2% Purity @ 292 g/hr (unoptimized)

2.7% Biphenyl, 90% Isolated Yield

Only 1.75 equivalents of gas utilized!

Reaction Examples: Precipitates

Complete Conversion of N-Boc-Phe

2880 g/h

Observed very small and fine particles

Others are studying particle formation

Reaction Examples: Halogen/Lithium Exchange

Batch Synthetron

97% Yield 98% Yield

Variable results at scale 2.7 Kg/hr

Feed reagent concentrations of 2.0M, lithium products were quenched

with TMSCl and analyzed by GC.

Tet. Lett., 2010, 51, p. 4793.

Reaction Examples: Halogen/Lithium Exchange

Batch Synthetron

85% Yield 92% Yield

Selectivity: 10 : 1 Selectivity: 104 : 1

Variable results at scale 3.5 Kg/hr

Feed reagent concentrations of 2.0M, lithium products were quenched

with TMSCl and analyzed by GC.

Reaction Examples: Halogen/Lithium Exchange

Synthetron Process:

94% Conv., 2466 g/hr

400g produced in ~ 10 min reaction time.

A 50g batch process required ~40 min of

reagent addition time!

Tet. Lett., 2010, 51, p. 4793.

Reaction Examples: Halogen/Lithium Exchange

Synthetron Process:

93% Conv., 1569 g/hr

Overall combined flow rate = 400 mL/min

Highly flexible synthetic platform for the

creation of diverse fine chemical building blocks

Reaction Examples: Halogen/Lithium Exchange

Synthetron Process:

96% Conv., 2135 g/hr

Overall flow rate of 250 mL/min

Both solutions at 1.0M

Comparisons

CPC CLS-microreactor Synthetron

100% Yield 97% Yield

177 g/hr 8602 g/hr

1.36 mol/hr† 44.8 mol/hr*

†Using Ethanol, www.cpc-

net.com/reactions/CPC01054.html

*Unoptimized Results, THP-Ether yield based

on crude 1H NMR

O

PhCH2OH+ +

O O Ph

Neat3 mol%HCl (conc.)

CPC CLS-microreactor Synthetron

80% Yield 98% Yield

24 g/hr 2250 g/hr

0.237 mol/hr† 15.08 mol/hr*

†Using Propylamine, www.cpc-

net.com/reactions/CPC01017.html

*Unoptimized Results, Yield based on crude

1H NMR

Comparisons

NH2

O

O O+ N

H

O

Toluene

Capabilities

OH

O

O O+ O

ONeat,

DMAP

(10 mol%) 96% 8.25 Kg/hr

98% 2.85 Kg/hr

ONH2

+NNeat

O

NC CN+

CN

CN

90% 5.24 Kg/hr

EtOH

• Line contacting

• Forced Uniform

Molecular

Interdiffusion

1. High Throughput

• Gas/Liquid

reactions

• Precipitates

2. Flexible

• Take apart and clean

• Re-surface

• A forgiving reactor

3. Easy to use