Enhanced Development and Control of

Continuous Processes using

Real Time In Situ FTIR Analytics

Dom Hebrault, Ph.D.

Flow Chemistry Congress

April 24th 2012

For further conversation…

For further conversation…

Continuous Flow Chemistry - Analysis Challenges

ReactIR™ In Situ IR Spectroscopy

Case studies:

- A Visual, Efficient, Method to Optimize Reaction Conditions: Case study on a Doebner

Modification

- Safer Use and Monitoring of Hazardous Substances: A General, One-Step Synthesis

of Substituted Indazoles using a Flow Reactor and a FlowIR

- Troubleshooting and Improving Product Quality of a Grignard Batch Process in a 6-

Step Drug Synthesis

Today’s Agenda

Continuous Chemistry - Analysis Challenges

Chemical information

- Continuous reaction monitoring superior to traditional sampling for offline

analysis (TLC, LCMS, UV, etc.)

→ Stability of reactive intermediates

→ Rapid optimization procedures

Technical knowledge

- Dispersion and diffusion: Side effects of continuous flow – must be

characterized

Today: Limited availability of convenient,

specific, in-line monitoring techniques

In-Line IR Monitoring

Monitor Chemistry In Situ, Under Reaction Conditions

- Non-destructive

- Hazardous, air sensitive or unstable reaction species (ozonolysis, azides etc.)

- Extremes in temperature or pressure

- No interference from bubbles, solid, color,…

Attenuated Total Reflectance (ATR)

Spectroscopy

In-Line IR Monitoring

Real-Time Analysis, “Movie” of the reaction

- Track instantaneous concentration changes (trends, endpoint, conversion)

- Minimize time delay in receiving analytical results

In-Line IR Monitoring

Determine Reaction Kinetics, Mechanism and Pathway

- Monitor key species as a function of reaction parameters

- Track changes in structure and functional groups

ReactIRTM Flow Cell: An Analytical Accessory

for Continuous Flow Chemical Processing

Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404

In-Line FTIR Micro Flow Cell in the Laboratory

Internal volume: 10 & 50 ml

Up to 50 bar (725 psi)

-40 → 120 ºC

Wetted parts: HC276, Diamond, (Silicon) & Gold

Multiplexing

Spectral range 600-4000 cm-1

FlowIR: Flow chemistry and beyond…

Internal volume: 10 & 50 ml

Up to 50 bar (725 psi)

-40 → 120 ºC

Spectral range 600-4000 cm-1

FlowIRTM: A New Plug-and-Play

Instrument for Flow Chemistry and

Beyond

9-bounce ATR sensor

(SiComp, DiComp) and head

Small size, no purge, no

alignment, no liquid N2

Optimization of a Doebner Modification of

Knoevenagel Reaction in a Continuous

Mode

Introduction

Can reaction optimization and conditions

screening be conducted inline?

How does dispersion affect fraction

collection?

Rapid Analysis of Continuous Reaction Optimization

Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

On-the-fly reaction optimization with

inline FTIR analytics

Vapourtec R2+/R4

FlowIRTM

+ CO2

Results

Reference spectra of 4 main components

3 main/unique bands

7 reaction “plugs”, on-the-fly variation of

residence time and temperature (1:1.1

benzaldehyde/malonic acid ratio)

Few hours experiment only

Rapid Analysis of Continuous Reaction Optimization

Malonic

Acid

(1729cm-1)

Benzaldehyde

(828cm-1)

Cinnamic acid

(772cm-1)

Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

80°C, 10’

100°C, 10’

120°C, 20’

120°C, 10’ 100°C, 20’ 100°C, 30’

150°C, 10’

4.5 h

Results

Development of an in-situ real time assay

method

- ReactIR algorithm: iC Quant and iC IR

- Simple univariate model (trans-

cinnamic acid 772 cm-1 with 2 baseline

points)

“Proof of concept” univariate model

Limited number of datapoints

Model used to predict concentration

Rapid Analysis of Continuous Reaction Optimization

Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

Trans-cinnamic acid

(772 cm-1)

(0.1-0.5M)

Results

Development of an in-situ real time assay

method:

- Application to the previous screening

- 100°C, 20’ to 30’ represent an optimum

at (1:1.1 benzaldehyde / malonic acid

ratio)

Rapid Analysis of Continuous Reaction Optimization

Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

[M]

0.35

0.30

0.25

0.20

0.15

0.10

80°C, 10’

100°C, 10’

120°C, 20’

120°C, 10’ 100°C, 20’ 100°C, 30’

150°C, 10’

Variation of benzaldehyde / malonic acid:

- From 1:1.1 to 1:2 (100°C, 20’)

- No significant improvement

- Real time FTIR provides confirmation of

steady state and concentrations in the

plug

1:2

1: 1.1 1:1.5

1:1.2

1:2

Steady state

3.5 h

Conclusions

No issue with CO2 bubble

Faster, more efficient, optimization

Off-line analysis requires accurate

sampling when plugs are short, which can

be difficult

Rapid Analysis of Continuous Reaction Optimization

Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

How about FlowIR for batch reaction?

Use of a recirculation loop, or a syringe

pump

Preliminary results promising

Goal is to cover 95% of standard chemical

conditions

A General, One-Step Synthesis of

Substituted Indazoles using a Flow

Reactor and a FlowIR

Introduction

Time-efficient and safe production of

small amounts of pharma-relevant

fragments

Reduce inventory of hydrazine under

“forced” conditions in flow mode

Safer Use and Monitoring of Hazardous Substances

Rob C. Wheeler, Emma Baxter, Ian B. Campbell, and Simon J. F. Macdonald GlaxoSmithKline, Stevenage, U.K.; Organic Process Research and

Development, 2011, 15 (3), 565–569; Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

Real time monitoring of concentrations

• indazole

• azine

• hydrazone

Faster optimization of conditions

• reagent excess

• temperature

• residence time

Vapourtec R2+/R4

FlowIRTM

F

O2N CHO

NH2

NH2

F

O2N

NNH

2

O2N

N

N

F

O2N

N N

F

NO2

Hydrazone

Indazole (major)Azine (minor)

Hydrazine

+

+

Results

Screening (7 experiments in 2.5 h):

hydrazine excess, temperature, and

residence time

Safer Use and Monitoring of Hazardous Substances

Rob C. Wheeler, Emma Baxter, Ian B. Campbell, and Simon J. F. Macdonald GlaxoSmithKline, Stevenage, U.K.; Organic Process Research and

Development, 2011, 15 (3), 565–569; Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

No reaction at 25°C

Hydrazone only at 50°C: 1st step is faster

No full conversion of hydrazone even at

150°C

0.2 eq. excess hydrazine: 4% more

indazole 2.5 h

1:1.2, 150°C

15’

1:1, 150°C

15’ 1:1.2, 100°C

15’

1:1, 100°C

15’

1:1.2, 50°C

15’

1:1, 50°C

15’

1:1, 25°C

15’

Indazole

Intermediate

Azine

Introduction

Is 150°C still too low?

Temperature more efficient than

increase of residence time

Safer Use and Monitoring of Hazardous Substances

Rob C. Wheeler, Emma Baxter, Ian B. Campbell, and Simon J. F. Macdonald GlaxoSmithKline, Stevenage, U.K.; Organic Process Research and

Development, 2011, 15 (3), 565–569; Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

Integration of ReactIR software (iC IR)

with Flow CommanderTM software

Facilitates automated experiment

optimization

Allows accurate sampling of plugs for

fraction collection and analysis

1:1.2, 150°C

5’

1:1.2, 150°C

30’

1:1.2, 200°C

15’

1:1.2

200°C

5’

Ar

O

OEt Ar

OMgBr

Ar

O

Ar

OMgBr

Ar

OH

Ar

O OH

MeMgBr AcOH

MeMgBrAcOH

AcOH

Troubleshooting and Improving Product

Quality of a Grignard Batch Process in a

6-Step Drug Synthesis

Introduction

Impurity headache

• <10% aldol during development study

• 40% during 1000 L campaign

Real Time Product Quality Control for Flow Processes

“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012

Challenges and Objectives

• Flow process

• Real time process quality control(*)

• Proof of concept on 40 Kg scale

• Aldol ≤ 1%

• Conversion ≥ 97%

(*) Off-line analysis (HPLC) takes 20-40’

Aldol

Ketone

Alcohol

PhMe/THF

2-Me-THF

Preliminary results in flow

• Eq. MeMgBr: 2 → 1.5

• Eq. NEt3: 6 → 3.5

• T°: -10 → 0°C

• Fast reaction < 20 s

Aldol: 40% → ≈ 1%

Real Time Product Quality Control for Flow Processes

Alfa Laval ART® Plate Reactors

Ester carbonyl

at 1752cm-1

Ketone carbonyl

at 1721cm-1

2-Methyl-THF

at 1383cm-1

Toluene

at 730cm-1

Starting

material Product Grignard

reagent

Reference

spectra

Reaction

spectra

No ester

starting material

No product

ketone!!

Enolate

at 1252cm-1

“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012

Excellent system stability upon flow

rate changes

Real Time Product Quality Control for Flow Processes

Starting material, ester at 1752cm-1

2-Me-THF

7 mL/min

2-Me-THF

14 mL/min

2-Me-THF

1 mL/min Stop flow

Solvent, 2-Me-THF at 1383cm-1

10%

1% 3%

[Ester]1752cm-1

Conversion measurement ≥ 97% with

qualitative/quantitative peak height(*)

Conversion measurement ≥ 99%

requires quantitative model

(*) results within +10% versus IPC-HPLC

“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012

Real Time Product Quality Control for Flow Processes

Starting material, ester at 1752cm-1

Solvent, 2-Me-THF at 1383cm-1

Toluene, Grignard at 730 cm-1

Start Grignard

reagent and

ester pumps

Switch

off ester

pump

Increase Grignard

to 2 eq., switch

ester pump on

Increase ester flow

rate, decrease

Grignard to 0.8 eq.

Increase ester,

increase

Grignard to 1 eq.

increase Grignard

to 1.1 eq.

“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012

Scale-up validation - Lab

• 500 g ketone product

• 4-5 s residence time

• 25 mL/min

• 4-6 h

Real Time Product Quality Control for Flow Processes

Scale-up validation - KiloLab

• 30 kg ketone product

• Same residence time

• 72 mL/min

• 92 h

• Project timeline ≤ one week

“Leaving the Tap Open…”, Fabrice Odille, AstraZeneca, Continuous Flow Technology in Industry, RSC, York, UK, March 19-21 2012

Acknowledgements

Vapourtec Ltd. (U.K.)

- Chris Butters, Duncan Guthrie

Flow Chemistry Solutions (U.K.)

- Andrew Mansfield

AstraZeneca, Sodertalje (Sweden)

- Fabrice Odille, Mats Ridemark, Daniel Fahlen

Mettler Toledo Autochem

- Will Kowalchyk (USA), Jon Goode (U.K.)