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




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



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


System flush

Time


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



Commercially available ATR-FTIR instrument optimized for FC

stoichiometry temperature

Agenda




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


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



Experimental setup of the single-

operation protocol for the synthesis of

(5R,6S)-3

Process flow scheme: One-flow hydrogenation and epimerization


IR bands determination for online monitoring


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


Time course of flow synthesis of cis-ketone

Time course of flow synthesis of trans-ketone


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

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ACS National Meeting 2013 New Orleans

Technology

Transcript of ACS National Meeting 2013 New Orleans