ACS National Meeting 2013 New Orleans
-
Upload
dominev -
Category
Technology
-
view
156 -
download
1
Transcript of ACS National Meeting 2013 New Orleans
Recent Advances in Continuous Flow
Chemistry Using Real-Time In Situ FTIR
Dominique Hebrault
Principal Scientist
New Orleans: April 7, 2013
Agenda
What’s Different with Flow Chemistry?
Safer Strecker Reaction
Stereoselective Preparation of Lactones
On Adopting Continuous Processing
Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
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
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
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
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
Agenda
What’s Different with Flow Chemistry?
Safer Strecker Reaction
Stereoselective Preparation of Lactones
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
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
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
Agenda
What’s Different with Flow Chemistry?
Safer Strecker Reaction
Stereoselective Preparation of Lactones
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
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
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
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
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
Email us at [email protected]
OR
OR
Call us + 1.410.910.8500