FlowCAT -continuous flow reactor system for … Singh flowcat... · FlowCAT -continuous flow...

FlowCAT - continuous flow reactor system for hydrogenation

screening and small scale production

HEL LimitedLondon, England

HEL IncNJ, USA

HEL IndiaMumbai

HEL Italia Milan

HEL China Beijing

Dr Jasbir Singh(Jsingh@helgroup.com)

HEL Ltd, England

2nd Symposium on Continuous Flow Reactor Technology for Industrial Applications,

3-4 October, 2010Paris

Terminology in catalytic reactions

� Homogeneous catalysis

� Heterogeneous catalysis

� Fixed bed or Plug Flow (continuous) and stirred/Batch reactors

better chemistry - faster

Fixed Bed is special case of continuous flow type.

Terminology in catalytic reactions

� Homogeneous catalysis

� Heterogeneous catalysis

� Fixed bed or Plug Flow (continuous) and stirred/Batch reactors

better chemistry - faster

Fixed Bed is special case of continuous flow type.

Crude Mathematical equivalence of flow and batch reactors

Batch Time Residence Time = Volume/flow rateBatch Time Residence Time = Volume/flow rate

Equivalence – time in batch reactor equates to position down plug flow.Changing flow rate changes residence time: corresponds to batch time.

better chemistry - faster

Closer Mathematical equivalence of Reactors

PFR (plug flow)

Many CSTRs in seriesCo-Current feeds

better chemistry - faster

Vertical orientation (top-to-bottom)

Lab-scale flow Systems – Screening and Prep-scale

Screening •Catalyst in small cartridge, very high catalyst loading• Conversion limited by hydrogen solubility (at high conc.)• Typical throughput 1+ g/day

H-cube (Thales-nono) well established in this field. Limited to

hydrogenations and to screening applications only.

Prep-scale • Traditional “tubular” reactor• “Trickle flow” mode demonstrated• High conversion far exceeding solubility limit• Typical throughput 100+g/day

No fully automated product established up to now.

better chemistry - faster

FlowCAT Package

•Developed to bridge screening and prep-scale needs•Not limited to hydrogenations• Fully software controlled• Does not require high pressure expert for operation

better chemistry - faster

Trialled at length by Pfizer for hydrogenation applications. Some results to follow.

flowCAT Feed Section

N2

H2

MFC

HPLC

Pump

Manual valve

Catalyst / glass packing

FilterTr

better chemistry - faster

P

Reactor

Heater

Tj

Filter

flowCAT Product Sampling and Collection

Pressure

controlNeedle

valve

GAS

VENT

better chemistry - faster

SampleSeperation

vessel

Liquid

product

FlowCAT Typical Specification

• Standard lengths: 15cm (6”)

• Two standard int. diameters: ½” (12mm) or ¼” (6mm)

• Volumes : 2.8ml, 12ml (in hot zone, approx).

• Standard ovens: heated lengths 10 cm

• 100bar/300C standard (higher temperature/pressureoptions)

better chemistry - faster

options)

•One liquid and one gas feed standard, other combinationspossible.

Not limited to hydrogenations

Not limited to heterogeneous catalytic reactions

Flow Capacity of Tubular Reactors

Very wide range of flows are possible, subject to pump range and pressure drop across reactor.

Gas and liquid flow rate determines:

• the “pattern” of flow • Gas/liquid mixing and contact with catalyst • Gas/liquid mixing and contact with catalyst • Conversion•Ease of scale up

Flows rates widely selected to favour that “trickle bed” mode.

better chemistry - faster

Trickle Bed Flow Regime

Most common mode of operation for tubular fixed bed reactors

� Fixed bed of inert and catalyst pellets, former occupying large volume (50% or more)

� Co-current downward flow of gas and liquid

� Leads to gas dispersed, liquid continuous phases around solids

General Plot for

flowCATtypical

General Plot for flow regimeprediction

Hydrogen plusNitrobenzene/solvent

G/L vol. ratio 20 (100max, gas at NTP)Hydrogen excess typically 1.83 x stoich.

C6H5NO2 + 3H2 C6H5NH2 + 2H2OHydrogenation of (4%) nitrobenzene to aniline

flowCAT performance Testing

better chemistry - faster

0.25” internal dia.Temperature 30 deg C

1% Pd/C mixed with glass beads4ml packed volume (30% voids)

Catalyst mass 0.1g (0.2 and 0.4g alternates)

Product (Aniline), analysed by GC

Trickle Bed Flow – Lab ReactorsDiagram below shows likely position of bench scale flow reactors

flowCAT

better chemistry - faster

flowCATrange

Reported data range

0.15

0.2

0.25

0.3

0.35

Gas

co

nsu

mp

tio

n (

mm

ol/m

in)

Hydrogen consumption with pressure Hydrogenation of nitrotoluene to aniline

0

0.05

0.1

0 10 20 30 40 50 60 70 80 90 100

Gas

co

nsu

mp

tio

n (

mm

ol/m

in)

Pressure (bar)

H2 Saturation

0.5 ml/min Liquid flow

Hydrogen 1.83 x stoichiometric( = 20 n ml/min)

Catalyst loading 0.1gBed volume 4ml (30% void)

0.3

0.4

0.5

0.6

Gas

co

nsu

mp

tio

n (

mm

ol/m

in)

Hydrogen consumption with at different substrate flows Hydrogenation of nitrotoluene to aniline

0

0.1

0.2

0 20 40 60 80 100

Gas

co

nsu

mp

tio

n (

mm

ol/m

in)

Pressure (bar)

H2 Saturation

0.5 ml/min

1 ml/min

2 ml/min

Hydrogen 1.83 x stoichiometric(= 20 to 80 n ml/min)Catalyst loading 0.1g

Bed volume 4ml (30% void)

0.4

0.5

0.6

0.7F

ract

ion

al C

on

vers

ion

Fractional conversion with pressure Hydrogenation of nitrotoluene to aniline

0

0.1

0.2

0.3

0 10 20 30 40 50 60 70 80 90

Fra

ctio

nal

Co

nve

rsio

n

Pressure (bar)

0.5 ml/min

Liquid flow = 0.5ml/minuite(residence time approx 2.4 mins)Hydrogen 1.83 x stoichiometric

( = 20 n ml/min)Catalyst loading 0.1g

Bed volume 4ml (30% void)

0.2

0.25

0.3

0.35

0.4

0.45

0.5F

ract

ion

al

con

ve

rsio

n

0.92

Hydrogen flow as

fraction of

stoichiometric

Conversion at different gas flows Hydrogenation of nitrotoluene to aniline

0

0.05

0.1

0.15

0 10 20 30 40 50 60 70 80 90

Fra

ctio

na

l co

nv

ers

ion

Pressure (bar)

1.83

4.58

Liquid flow 1ml/minuteCatalyst loading 0.1g

Bed volume 4ml (30% void)

Comparison with Stirred Reactor Data

better chemistry - faster

Auto-MATE4 x 100-300ml HP reactors

AUTOLAB 1000ml HP glass reactor

HP Chemscan8 x 16ml reactors

Up

take

(l)

1.4

1.2

1.0

0.8

0.6

HYDROGENATION 100ml stirred HP autoHYDROGENATION 100ml stirred HP auto--MATEMATE

10 bara

3.4 bara

Catalyst loading approx 1/100th of flow reactor

100 Psi 50 Psi 75 Psi 125 Psi 150 PsiTime (mins)

80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0

Up

take

(l)

0.6

0.4

0.2

0.0

50ml 4% nitrobenzene in decanol, 0.35g Pd/C catalyst – parallel hydrogenations at 40°C, 1500 rpm

Typical residence time in flow tests

80

100

120

140

160

180

200

Rea

ctio

n t

ime

(min

s)Time to 100% conversion in stirred reactors (5 to 500ml)

40 °C60 °C

Data from three sizes of stirred reactors

0

20

40

60

80

0 2 4 6 8 10 12 14

Catalyst concentration (g/l)

Rea

ctio

n t

ime

(min

s)

4% nitrobenzene Pd/C catalyst, 6.9 bar

Residence time in flow tests

Catalyst conc in flow tests

Hydrogenation Screening?

H-cube • Hydrogen generation in situ – safety advantage• Low flow only, limited to screening at low conc orsmall scale compound prep (eg med chem)

flowCAT • Needs hydrogen supply – less safe potentially•Low flow version feasible, cartridge designs being tested•Already in use for prep-scale work Can flowCAT be adapted for screening?

.

better chemistry - faster

Conversion limited by H2 solubility which increases with pressure

Screening with H-cube: Conversion Limited by hydrogen solubility

10% Rh/CPhCHO0.35 M

PhCH2OH

EtOH, 80°C

(courtesy J Hawkins, Pfizer Inc, August 2010)

0.12

0.14

0.16

0.18

0.2

Hyd

rog

en f

low

Hydrogen added

to maintain operating

pressure, no excess H2

Conversion Limited by Solubility - flowCAT Hydrogenation of nitrotoluene to aniline

0

0.02

0.04

0.06

0.08

0.1

0 20 40 60 80 100

Hyd

rog

en f

low

Pressure (bar)

Gas consumption (mmol/min)Gas Solubility

Gas feed on pressureLiquid flow 0.5ml/minute

Catalyst loading 0.1gBed volume 4ml (30% void)

FLOWCATContinuous Flow

Reactor

Sample

flowCAT in commercial R+D

■ Controlled by commercial, well established software/electronics, fully developed

■ Ideal for process development and large enough for prep-scale production

■ Possible to integrate with DOE package and optimise totally automatically.

better chemistry - faster

Reactor

WinISOHELs Reactor Control

Software

Controls Data

STAVEXDoE Software

Package

Set points Results

GCRaw Data

PAT integration - Real-time monitoring and feed back control

P

GAS VENT (pressure control)

Productfrom flowCAT

In-line sensor (eg FTIR flow cell),almost real-time data

Gas-liquid separation

better chemistry - faster

Virtually no producthold up (a few ml)

winISO real-time software monitoring

and feed back control

Gas-liquid separation

Integrating Process/Analytical Data

process data schedule

better chemistry - faster

chromatogram data analyser

Process Development Examples using DOE

■ Samples can be taken at each change of operating condition

■Wide range of conditions can be tested, sequentially, without operator involvement (no need to clean reactor after each change)

■ Integrated with Stavex software

Pressure

better chemistry - faster

Temp

Pressure

Flow rate

STAVEX software

EXAMPLE 2: Conversion of chloronitrobenzene to chloroaniline

Cl

NO2 NH2

Cl

NH2

H2

Pd/C

H2

Pd/C

better chemistry - faster

Cl Cl

NO2

H2 Pd/C H2Pd/C

GC Traces: chloronitrobenzene to chloroaniline

Fractions: 55.8% chloronitrobenzene

15.2% chloroaniline 6.1% aniline

Conditions:P=5bar T=22oC

Residence time=0.5min

min2.5 5 7.5 10 12.5 15 17.5 20 22.5

'mV'

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

AIA1,'VWD' of U:\FLOWCAT\ALEXIS\DATA\EXPERI~1\4-GCSA~1\CLORON~1\EXPERI~1\151220~1\S1\TESTRU~1.D\1.CDF (AIA imported)

7.0

20

8.8

86

13.

310

14.

635

Aniline

Chloroaniline

Chloronitrobenzene

better chemistry - faster

Fractions: 24% chloronitrobenzene

43.4% chloroaniline

24.2% aniline

Conditions:P=10bar T=61oCResidence time=1.96min

min5 7.5 10 12.5 15 17.5 20 22.5

'mV'

0.02

0.04

0.06

0.08

0.1

AIA1,'VWD' of U:\FLOWCAT\ALEXIS\DATA\EXPERI~1\4-GCSA~1\CLORON~1\EXPERI~1\181220~1\S14\TESTRU~1.D\1.CDF (AIA imported)

7.0

14

8.8

89

13.

302 1

3.51

9

14.

481

AnilineChloroaniline

Chloronitrobenzene

chloronitrobenzene to chloroaniline (Pressure-residence time)

Low and high pressures yield the better conversions at medium residence times

better chemistry - faster

at medium residence times

chloronitrobenzene to chloroaniline (Temp – residence time)

• Conversion favoured bylow temperatures and high

• Chloroaniline reacts to yield aniline at high temperatures

better chemistry - faster

low temperatures and highresidence times

• Wrong range of conditions selected – go back!

chloronitrobenzene to chloroaniline (Pressure – residence time)

• mid-range residence time favours chloroaniline

better chemistry - faster

• High or low residence time favours aniline

chloronitrobenzene to chloroaniline (Temp – Residence time)

• Mid-range residence time and low temperature favours high yield chloraniline

better chemistry - faster

• Aniline favoured by high or low residence time

Sterioselectivity through flowCAT Process Control

better chemistry - faster

(Example courtesy J. Hawkins, Pfizer Inc, August 2010)

• 100 g hydrogenated with 1 g of catalyst which was still active

Diastereoselectivity and Conversion vs. Pressure

80

100

120

140

Cis

/ T

rans

Rat

io

50

60

70

80

90

100

Conversion (%

)

0

20

40

60

0 10 20 30 40 50 60 70 80 90 100

Pressure (bar)

Cis

/ T

rans

Rat

io

0

10

20

30

40

Conversion (%

)Increased diastereoselectivity at the higher pressures easily accessible in flow

flowCAT - CONCLUSIONS

• Bench-scale flow system, industrially proven development

• Wide range of operating conditions

• Controls all important variables and reports progress in real time.time.

• Full integration of third party sensors for PAT

•Low flow version feasible, cartridge designs being tested

•Already in use for prep-scale work

.

better chemistry - faster