Download - Recent Advances Webinar Part 7
Flow Analysis Methodologies
Recent Advances Part 7
Dom Hebrault, Ph.D.
Principal Technology and
Application Consultant
May 16th 2012
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
Provides a picture of flow dispersion,
helps enhance separation and off-line
analysis
Rapid Analysis of Continuous Reaction Optimization
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
Compared to former in-house solutions
Can be heated, cooled, pressurized
Wide spectral range and high sensitivity
Turn-key, affordable, space efficient
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.)