anna codina, product portfolio manager, pharma market, bbio// … · 2018-03-07 · professor guy...
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InsightXpress 12 Sep 2017
Anna Codina, Product Portfolio Manager, Pharma Market, BBIO// Matteo Pennestri, PM InsightXpress, BBIO
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Professor Guy Lloyd-Jones, FRS
How Fast is Fast?
Mixing
Acquisition
Standard NMR tubes On-line –> InsightMR (with batch reactor)
Transfer times in the order of minutes
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Professor Guy Lloyd-Jones, FRS
When do we Need to go Faster?
1. Repeating the reaction varying conditions
Labour - intensive
Time consuming
0.000
0.005
0.010
0.015
0.020
0.025
0.030
0.035
0.040
0.045
0.050
0 5 10 15 20 25 30
Co
nc
(M
)
Time (s)
t½ ≈ 5 s mix
insert
lock
start….
2. Fast Reactions (seconds)
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Professor Guy Lloyd-Jones, FRS
Automated in-situ Monitoring
InsightXpress: move the reactor into the spectrometer!
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Professor Guy Lloyd-Jones, FRS
1. Flow Unit 2. High speed delivery
pumps 3. NMR system
The Solution for Fast Reaction Monitoring and Optimisation
Automated in-situ Monitoring
+ +
Xpress
Reactor
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Professor Guy Lloyd-Jones, FRS
Schematics
waste
130 msec deadtime
300 uL
600 uLshot
A B C
RESERVOIRS
DELIVERYMODULE
CONSOLE
W S
W
300 uL
trigger
C
A
BFlow cell
variable delay (D1 ). pluse, FIDvariable delay (D2)cycle
solvent flush ( n x 1ml)
ON TOP OFMAGNET
IN MAGNET
thermostattedby spectrometer
A B C
S
S
AWAY FROM MAGNET (e.g. in fume hood)
CONTROL SOFTWARE
i) VTOT
ii) velocity (ml / sec)
iii) fractions A, B, and C
SPECTROMETER
PRE-CONDITIONER(temp, magnetisation)
W
shotsignal
thermostattedby Reaction Express
IN MAGNET
Xpress
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Professor Guy Lloyd-Jones, FRS
Automated in-situ Monitoring
Stop-Flow with added Flexibility
• unlimited ‘shots’
• variable conc.
• variable reagents
• temp. control
• fast
• reproducible
Xpress
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Professor Guy Lloyd-Jones, FRS
1. Remove SampleXpress 2. Place Delivery Module 3. Insert Flow Tube
Easy Set Up
Xpress
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Professor Guy Lloyd-Jones, FRS
3A 3B 3C
Insertion of the Flow Tube Assembly
Xpress
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Professor Guy Lloyd-Jones, FRS
A example reaction that has been studied
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Professor Guy Lloyd-Jones, FRS
Manual Sample Preparation
protodeboronation
aq. dioxane, KOH
BOH
OH
FF
F
H
FF
F
F F
14 Kobs (rate) values
X 20 data points = 280 NMR tubes
~ 1-2 weeks work
In-situ stop flow monitoring
0
0.0005
0.001
0.0015
0.002
0.0025
0.003
0.0035
0 0.5 1 1.5 2
Rat
e
equiv OH
14 ‘shots’
14 Kobs (rate) values
3 h
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Professor Guy Lloyd-Jones, FRS
Some experimental detail…and results
max. signal without
pre-mag.19F with a 4 sec T1
t½ ≈ 1 second
Cox, P. A.; Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2016 DOI: 10.1021/jacs.6b03283.
Cox, P. A.; Reid, M.; Leach, A. G.; Campbell, A. D.; King, E. G.; Lloyd-Jones, G. C. submitted, 2016.
Xpress
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Professor Guy Lloyd-Jones, FRS
Processes Run since Apr16
• TMS-CF3 desilation (THF, 21 °C)
• Bee-venom enzyme kinetics (H2O; 37 °C
• protodeboronation (diox. / H2O; 0-70 °C)
• Ru-cat. hydrophosphination (C6D6, 30 °C)
• Rh-cat transfer hydrog. (iPrOH, 27 °C)
• Ar-IX2 speciation (CDCl3, CD3OD, 27 °C)
• Ar-B(OH)2 oxidation (D2O, 27 °C)
Xpress
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Professor Guy Lloyd-Jones, FRS
Features at a Glance
• Used when needed seats on SampleXpress base
• Simple install 10-15 min
• Low sample vol a+b+c ≤ 600 uL / shot
• Time efficiency unlimited shots
• Variable ratios explore
• Temp. control detailed kinetics
• Pre-magnetisation quantitative
• Precise timing triggered pulse trains
• Reproducible stable measured vol.
• fast reactions <150 ms dead-time
• In-situ clean solvent flush line
Xpress
A very fast and reproducible way to screen reaction conditions
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Professor Guy Lloyd-Jones, FRS
Software Features
AUTOMATION:
• Protonated solvents – run
unlocked
• Automatic solvent finding and
suppression (multiple peaks)
• Automatic spectra referencing
• Preparative experiments to
set-up the system (tuning,
shimming, RG, calibrated
shaped pulses for solvent
suppression)
• Different Multiple 1D
experiments to monitor fast
reactions
• On-the-fly tracking
• On-the-fly fitting
• Real time profiles
Xpress
Acetic Anhydride Hydrolysis in H2O 250 mM, 35 C
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Professor Guy Lloyd-Jones, FRS
Software Features
Flow rate 1 ml/sec 450 uL (A 50%; B 50%) A: Ethyl Acetate 100mM B: KOH 1M Temp = 27 °C
Td = 32 d1 = 0 s, d20 =3 s d21 = 0.0 s; 1.0 s; 2.0 s T1/2≈ 12 s
Xpress
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Professor Guy Lloyd-Jones, FRS
Xpress
Flow rate 1 ml/sec 450 uL (A 50%; B 50%) A: Ethyl Acetate 100mM B: KOH 1M Temp = 37 °C
Td = 32 d1 = 0 s, d20 =3 s d21 = 0.0 s; 1.0 s T1/2≈ 6 s
Software Features
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Professor Guy Lloyd-Jones, FRS
Xpress
Flow rate 1 ml/sec 450 uL (A 50%; B 50%) A: Ethyl Acetate 100mM B: KOH 1M Temp = 57 °C
Td = 16 d1 = 0 s, d20 =3 s d21 = 0.0 s; 0.5 s ; 1.0 s; 1.5 s; 2.0 s T1/2≈ 2 s
Software Features
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In-situ Fast RxM
Acknowledgments
Prof. Guy Lloyd Jones Ted King Ruth Dooley Ariana Jones Dusan Uhrin
Peter Neidig Martin Hofmann Mark Garvey Ulrich Braumann Ian Clegg
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© Copyright Bruker Corporation. All rights reserved.
Innovation with Integrity
Copyright © 2011 Bruker Corporation. All rights reserved. www.bruker.com
Innovation with Integrity
Copyright © 2017 Bruker Corporation. All rights reserved. www.bruker.com
www.bruker.com/InsightMR