anna codina, product portfolio manager, pharma market, bbio// … · 2018-03-07 · professor guy...

InsightXpress 12 Sep 2017

Anna Codina, Product Portfolio Manager, Pharma Market, BBIO// Matteo Pennestri, PM InsightXpress, BBIO

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


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)


Automated in-situ Monitoring

InsightXpress: move the reactor into the spectrometer!


1. Flow Unit 2. High speed delivery

pumps 3. NMR system

The Solution for Fast Reaction Monitoring and Optimisation


+ +

Xpress

Reactor


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



Stop-Flow with added Flexibility

• unlimited ‘shots’

• variable conc.

• variable reagents

• temp. control

• fast

• reproducible

Xpress


1. Remove SampleXpress 2. Place Delivery Module 3. Insert Flow Tube

Easy Set Up

Xpress


3A 3B 3C

Insertion of the Flow Tube Assembly

Xpress


A example reaction that has been studied


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


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


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


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


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


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


Xpress


Td = 32 d1 = 0 s, d20 =3 s d21 = 0.0 s; 1.0 s T1/2≈ 6 s

Software Features


Xpress


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

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

© 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

[email protected]

www.bruker.com/InsightMR

anna codina, product portfolio manager, pharma market, bbio// … · 2018-03-07 · professor guy...

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