flohet 2013 university of florida gainesville fl

Recent Advances in Organic Synthesis using

Real-Time In Situ FTIR Spectroscopy

Dominique Hebrault, Ph.D.

Gainesville, March 4th 2013 FloHet - 2013

Acceleration of Petasis reactions

Continuous Asymmetric Hydrogenation

Flow Chemistry on Polymer Supported Reagent

Preliminary Kinetic Study of Amide Formation

Agenda

Acceleration of Petasis Reactions of

Salicylaldehyde Derivatives with

Molecular Sieves

Introduction

Petasis reaction developed to synthesize

BIIB042, a γ-secretase modulator (Alzheimer)

Milder conditions required to preserve

stereocenter

Acceleration of Petasis Reactions

H2O removal → rate and yield increase

under mild conditions?

Xianglin Shi, Dominique Hebrault, Michael Humora, William F. Kiesman, Hairuo Peng, Tina Talreja, Zezhou Wang, Zhili Xin Beilstein J. Org.

Chem., 2012, 77 (2), 1154–1160

Petasis reaction: General equation

Drug candidate for Alzheimer

Conversion of key intermediate 2 into BIIB042

Process enhancements:

- Solvent screening → No racemization at RT

but low conversion and stall

- Screening of drying agents: MS, MgCl2

accelerate and drive to completion (>2d)

Best results from drying agent and solv. screening



Chem., 2012, 77 (2), 1154–1160

MgCl2 MS

Conversion 62% 64%

Sol. DCM, RT, 4h

- Preliminary optimization: 1.2-1.5 equiv.

amine, boronic acid → reaction time ≤ 24h

- No loss of stereoselectivity

- 97% conversion, 85-90% isolated yield, 99%

purity after work-up

Petasis route to key intermediate 2

Conditions:

Mechanistic considerations:

- MS favor formation of 5

- Reduce chances of hydrolysis of 6

ReactIR data: salicylaldehyde, piperidine, MS



Chem., 2012, 77 (2), 1154–1160

Possible mechanism

1665 cm-1

(C=Nstretch)

1010cm-1

(CAr-O-)

1667 cm-1

(C=Ostretch)

Real time monitoring and spectroscopic

evidence (mid-IR) show:

- The fast disappearance of salicylaldehyde

- Formation of iminium 5 upon addition of MS

1250, 1460 cm-1

(NR3bend, O-Hbend),

ReactIR data: Reaction of arylboronic acid with iminium 5, MS



Chem., 2012, 77 (2), 1154–1160

1665 cm-1

(C=Nstretch)

5h

Real time monitoring and spectroscopic evidence

(mid-IR) show:

- Low concentration formation of iminium 6 (5h)

- Formation of product 7 over 22h

1665 cm-1

C=Nstretch

O

N

B OH

F

OH+

-

1225 cm-1

F-ArB(OH)2

1510 cm-1

Arstretch

O

N

B OH

F

OH+

-

5

6

6

ReactIR data: 3-D / waterfalll plot (wavelenght/time/intensity)



Chem., 2012, 77 (2), 1154–1160

Conclusions:

The use of ATR-FTIR with ReactIR allowed to:

- Optimize reaction conditions faster

- Through a better understanding of reaction

processes, their rate and degree of completion

in real time

- MS accelerate Petasis reactions at RT

- Preserve integrity of stereocenter

- Strategy applicable to the preparation of

BIIB042





Agenda

On Adopting Continuous Processing…

Source: Chemistry Today, 2009, Copyright Teknoscienze Publications

Continuous-flow catalytic asymmetric

hydrogenations: Reaction optimization

using FTIR inline analysis

Introduction

Microreactors setup coupled with ATR-FTIR

microflowcell (ReactIR)

Asymmetric hydrogenation of benzoxazines,

quinolines, quinoxalines, 3H-indoles with

Hantzsch dihydropyridine


ReactIR microflowcell benefits:

- More rapid screening of reaction para-

meters

- Faster reach of optimum reaction conditions

Magnus Rueping, Teerawut Bootwicha and Erli Sugiono; Institute of Organic Chemistry, Aachen Univ., D, Beilstein J. Org. Chem. 2012, 8, 300–307

Commercial glass microreactor / In single glass reactor with inlets

Schematic of experimental setup and chemistry

Asym. ligand

Solvent: CHCl3


Method and results:

- Collection of reference spectra for solvent,

starting material, and reagents

- Optimum conditions after fast screening

thanks to real time analytics: T 60°C, t 20

min, flow rate 0.1 mL.min-1

Further reported investigations

- Scope

- Conditions optimization: Flow conditions,

catalyst loading, reagent Trend curve of product formation at different temperatures


IR spectra for substrate

consumption and product

formation at different

temperature


Conclusions:

- Microreactors setup coupled with ATR-FTIR

microflowcell (ReactIR)

- Inline real time analysis of the microreactor

reaction stream right at the outlet

- Faster, more precise feedback or reaction

mixture composition and component

concentration

- More rapid screening of reaction

parameters

- Faster reach of optimum reaction

conditions

- Ongoing development: automated

integration and feedback optimization of

reaction parameters






Agenda

A Solid-Supported Organocatalyst for

Stereoselective Continuous – Flow

Mannich Reactions

Introduction - How to?

– Perform reaction sequences in a selective

manner without isolation/purification?

– Avoid catalyst poisoning/instability?


Cambeiro, X. C.; Martín-Rapún, R.; Miranda, P. O.; Sayalero, S.; Alza, E.; Llanes, P.; Pericàs, M. A. Beilstein J. Org. Chem. 2011, 7, 1486–1493; Jon

Goode, D. Hebrault*, “Process Analytical Technology (PAT) for enhanced development and control of continuous processes” Chimica Oggi /

Chemistry Today - vol. 30 n. 6 November/December 2012

+

Answers:

– Immobilize active catalytic species

– Use the power of inline real time analytics

General equation Mannich reaction

Flow chemistry instrument connected to a FlowIR™

Process enhancements:

- Unique bands for imine reagent, Mannich

product using FlowIR™ → real time

monitoring

- Residence time → Yield, impurity profile,

catalyst poisoning / stability

Spectral changes: Imine, Mannich product

Product

(828 cm-1)

Imine (846 cm-1)

Concentration profiles of the imine, Mannich product versus

flow rate

- Flow rate decrease → residence time

increase → favors conversion and yield

- Further residence time increased likely

beneficial

- Time to steady state reach

- Determine column life time

http://www.beilstein.tv/tvpost/continuous-flow-%CE%B1-aminoxylation-monitored-by-in-situ-ir-spectroscopy/

























Agenda

Kinetics is all about comparing rates…

Amide Bond Formation via Mixed

Anhydride Activation: New Kinetic

Approach to Chemical Development

Introduction

Improvements over discovery route →

Mixed anhydride protocol / tosyl chloride

Real time reaction monitoring for fundamental

understanding → Robust dipeptide process

Implemented on a 18 kg scale


Nizar Haddad, Bo Qu, Dominique Hebrault, to be published, 2013

P1N

OH

O

NH

OHO

OP2

P1N

N

O

OH

OOP

2

Synthetic route to dipeptide HCV protease inhibitor

- Driving force analysis – DFA (conc., T°)

- Process & mechanistic understanding for

- Better operation efficiency

- More robust process (consistency,

reproducibility)

- Endpoint and yield predictions

Reaction setup: EasyMax™, inline ATR-FTIR ReactIR™

Implementation of inline analysis for

reaction monitoring

- Validation of real time ATR-FTIR/ReactIR™

using univariate and multivariate analysis

- Confirmation with an orthogonal method:

EasyMax™ heat flow monitoring



P1N

O

O

S

O

O

P1N

N

O

OH

OOP

2

Reaction setup: EasyMax™, inline ATR-FTIR ReactIR™

Heat flow

conversion

Consistency of independent monitoring techniques:

EasyMax™ heat flow, inline ATR-FTIR ReactIR™

Abs

Time

Preliminary kinetic analysis - RPKA

- Input data from various analysis into

iCxKinetics

- Check for data consistency: Reaction

parameters, graphical display of kinetic data

- Model developed out of 3 different excess

experiments

- Model offers good fit (R2 0.99) and

consistency across conversion range

(stable mechanism)

- Non partial order as not an elementary step


Donna G. Blackmond, Angew. Chemie Int. Ed. 2005, 44, 4302

Conversion profiles of different excess experiments

RPKA data manipulation to determine kinetic equation

[e] = 0.001 (1.1 eq Boc-L-t-Leu)

[e] = 0.005 (1.5 eq)

[e] = 0.01 (2 eq)

[HO-Pro.HCl]

Time

Testing and using the model

- Check prediction of reaction evolution and

endpoint against experimental data

- Reaction rate sensitivity to reactants

concentration

- Simulated experiments can be used to find

optimum and design space (QbD)

- Guide experimental approach, reduce

number of experiments


400 simulated experiments out of ≥ 2 experiments

Starting material concentration decrease:

predicted versus experiment

Time to 90%

conversion Current process conditions:

[BOC-L-t-leucine] [HO-Pro.HCl]


HO-Pro.HCl 9.9mM,

Boc-L-t-Leu 15.4mM

(1.5 eq), 10˚C, ACN

Time hh:mm:ss

[HO-Pro.HCl]

Influence of temperature

- Temperature model -10ºC → +30ºC

- Adequate to excellent fit (R2 ≤ 0.998)

- Activation energy: 27.5 kJ/mol (most

chemical reactions: 10-50 kJ/mol)

- Rate of reaction approx. doubles for each

10 K when Ea = 50 kJ/mol; 1.5 for each 10

K increase when Ea = 27 kJ/mol

- Reaction rate sensitivity to temperature

change


Conversion profiles as a function of reaction temperature

Arrhenius plot


0ºC 10ºC

20ºC

30ºC

-10ºC

[HO-Pro.HCl]

Time

Ln

(k)

1/T

Acknowledgements

The SCRIPPS Research Institute, CA Campus, Department of Chemistry

(USA)

- Donna Blackmond, Ph.D.

Biogen idec, Cambridge, MA (USA)

- William Kiesman et al.

Institute of Organic Chemistry, Aachen University, Germany

- Pr. Magnus Rueping et al.

Institute of Chemical Research of Catalonia, Tarragona, Spain

- Miquel A. Pericàs et al.

Mettler Toledo Autochem

- Nilesh Shah (USA)

- Jon Goode (U.K.)

Email us at [email protected]

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flohet 2013 university of florida gainesville fl

Education

biib042 petasis reaction

zhili xin beilstein

tina talreja

zezhou wang

michael humora

hairuo peng

flow conditions

nstretch formation