acs national meeting 2013 new orleans
TRANSCRIPT
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Recent Advances in Continuous Flow
Chemistry Using Real-Time In Situ FTIR
Dominique Hebrault
Principal Scientist
New Orleans: April 7, 2013
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Agenda
What’s Different with Flow Chemistry?
Safer Strecker Reaction
Stereoselective Preparation of Lactones
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On Adopting Continuous Processing
Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
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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 affordable, convenient,
specific, inline monitoring techniques
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On-line Monitoring
FTIR* Raman HPLC NMR UV MS
Destructive Lack of
specificity
Expensive
D-solvent
Clogging Solid
samples
More
universal
Evaluation of on-line techniques for the monitoring of flowing streams in real time
F.T. Mattrey , S. Dolman, J. Nyrop, P.J. Skrdla, Merck Research, American Pharmaceutical Review January 2012
(*) quantification can be achieved by calibration using standards
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Inline IR Monitoring
Monitor chemistry in situ, under all reaction conditions
“Movie” of the reaction
Determine reaction kinetics, mechanism and pathway
Attenuated Total
Reflectance (ATR)
Spectroscopy
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ATR-FTIR for flow chemistry
Internal volume: 10ml and
50ml
Up to 50bar (725psi)
-40ºC → 120ºC
Spectral range 600-4000cm-1
FlowIR™: A New Plug-and-Play Instrument
for Flow Chemistry
9-bounce ATR sensor
(SiComp, DiComp) and
head
Small size, no purge, no
alignment, no liquid N2
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Agenda
What’s Different with Flow Chemistry?
Safer Strecker Reaction
Stereoselective Preparation of Lactones
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Online FTIR Monitoring and Simultaneous
Optimization of a Strecker Reaction
Performed in a Laboratory Scale Flow-
Through Reactor
Introduction
The value of flow chemistry ATR-FTIR for
the cyanation step
“On-the-fly” process optimization to
maximize yield
Safer technique to manage HCN toxicity
Optimization of a Strecker Reaction
F.T. Mattrey , S. Dolman, J. Nyrop, P.J. Skrdla, Merck Research, American Pharmaceutical Review January 2012
Chemistry
Technology
Low volume custom-build flow cell for fiber
optic FTIR
Commercial FTIR system with integrated
flow cell
Home-build inline mixer for homogeneity of
liquid-liquid reaction mixture
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Method and results:
Feed amine, aldehyde in DCM/MeOH
(stream 1), KCN/H2O (2), and AcOH/DCM
(3). Final quench conducted separately
FTIR monitoring of resulting nitrile
Identification of specific wavelength
Trending of reaction components
Optimization of stoichiometry (individual
flow rate)
Trend curves of components – Preliminary FTIR validation
Optimization of a Strecker Reaction
System flush
Time
F.T. Mattrey , S. Dolman, J. Nyrop, P.J. Skrdla, Merck Research, American Pharmaceutical Review January 2012
Schematic of experimental setup
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Variation of flow rates to optimize
stoichiometry, [amine] is constant
Temperature increase 25 – 50 - 75°C: no
improvement
Max. productivity 2mL coil: 60g/h
Conclusions
FTIR key for high-throughput optimization
of flow rate and residence time
Safer use of Strecker chemistry
Use of inline dynamic mixer for liquid-
liquid homogeneity
Trend curves – Flow rates/stoichiometry optimization
Optimization of a Strecker Reaction
F.T. Mattrey , S. Dolman, J. Nyrop, P.J. Skrdla, Merck Research, American Pharmaceutical Review January 2012
Commercially available ATR-FTIR instrument optimized for FC
stoichiometry temperature
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Agenda
What’s Different with Flow Chemistry?
Safer Strecker Reaction
Stereoselective Preparation of Lactones
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Single Operation Stereoselective
Synthesis of Aerangis Lactones:
Combining Continuous Flow
Hydrogenation and Biocatalysts in a
Chemoenzymatic Sequence
Introduction
Catalytic hydrogenation and subsequent
biocatalyzed Baeyer–Villiger oxidation
(a) Hydrogenation step: Rh/C, Cs2CO3,
heptane, 30°C
(b) Epimerization: Amberlyst 15, heptane,
25°C,
(c,d) BVOx: Glucose-6-phosphate,
cyclododecanone/cyclopentanone
monooxygenase crude cell extract, Triton X-
100, NADP+, TrisHCl, water
Stereoselective Preparation of Lactones
Fink, M. J.; Schön, M.; Rudroff, F.; Schnürch, M.; Mihovilovic, M. D., Vienna Univ. of Technol.; ChemCatChem 2013, 5, 724–727.
Chemistry
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Process flow scheme:
Combined flow hydrogenation
and Baeyer-Villiger type
biotransformation
Stereoselective Preparation of Lactones
Fink, M. J.; Schön, M.; Rudroff, F.; Schnürch, M.; Mihovilovic, M. D., Vienna Univ. of Technol.; ChemCatChem 2013, 5, 724–727.
Experimental setup of the single-
operation protocol for the synthesis of
(5R,6S)-3
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Process flow scheme: One-flow hydrogenation and epimerization
Stereoselective Preparation of Lactones
IR bands determination for online monitoring
Fink, M. J.; Schön, M.; Rudroff, F.; Schnürch, M.; Mihovilovic, M. D., Vienna Univ. of Technol.; ChemCatChem 2013, 5, 724–727.
Method – Hydrogenation:
ThalesNano H-Cube Autosampler with
ReactIR 15 DS Micro Flow Cell
Safer operation due to lower H2 pressure, in
situ generation from water
Simpler due to single operation procedure
Method – IR monitoring:
Peak area to baseline points
Solvent subtraction
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Results – Hydrogenation:
Failed attempts to directly obtain trans-
ketone
Alternative epimerization on a strongly acidic
ion-exchange polymer
Stereoselective Preparation of Lactones
Time course of flow synthesis of cis-ketone
Time course of flow synthesis of trans-ketone
Fink, M. J.; Schön, M.; Rudroff, F.; Schnürch, M.; Mihovilovic, M. D., Vienna Univ. of Technol.; ChemCatChem 2013, 5, 724–727.
Conclusions – IR monitoring provided
Information about catalyst stability
Steady state reach, phase transition
Hydrogenation and epimerization
performance
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Acknowledgements
Merck Research Laboratories, Rahway, NJ
- Frederick T. Mattrey, Sarah Dolman, Jason Nyrop, Peter J. Skrdla
Vienna University of Technology
- Michael J. Fink, Michael Schoen, Florian Rudroff, Michael Schnuerch, and Marko D.
Mihovilovic*
METTLER TOLEDO
- Jon G. Goode, Brian Wittkamp, Will Kowalchyk, Paul Scholl
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