Advances in Process Spectroscopy: Mid-Infrared in-situ Reaction Monitoring Case Studies ·...

Jeffrey W. Sherman, Ph.D.The Cortona Conference

September 22, 2010

Advances in Process Spectroscopy: Mid-Infrared in-situ Reaction Monitoring

Case Studies

IntermediateReactant

Product

IntermediateReactant

Product

2006 Mettler-Toledo AutoChem, Inc.1

ReactIR™ as a PAT tool for the organic chemists

Reaction analysis with ReactIR™ technology- Case study 1: Amide formation through mixed anhydride

- Case study 2: Reductive Amination

- Case study 3: N-acylation to amide (C-N formation)

- Case study 4: Sandmeyer reaction

- Case study 5: Rosenmund reduction (Hydrogenation)

Questions and answers

Overview


Challenges of process chemistry - Did the reaction go?

- Determine reaction kinetics

- Understand reaction selectivity and reactivity

- Identify intermediates, by-products and side products

- Identify reaction end-points (intermediate and/or final product)

- Impact on reaction with change of solvent, catalyst, temperature, etc.

- Identify key design/control parameters

- Determine early if the process scalable

ReactIR as a PAT Tool for the organic chemist


Capabilities and advantages of ReactIR™ technology

Continuous monitoring of:- Reaction components (reactant, intermediate, product, by-product, etc.)

- Reaction progression (initiation, dynamics/rate, end-points, concentration, etc.)

- Reaction kinetics, pathway, mechanism (fundamental understanding)8For critical process parameters (boundary conditions, safety, control, etc.)

8For process efficiency and robustness (yield, productivity, reproducibility)

8For consistent product quality (purity, specs, variability, etc.)

In situ real time analysis:- of components difficult to analyze otherwise

- of O2 or H2O sensitive or instable reaction mixtures

- of highly toxic, hazardous or explosive reaction mixtures

- at low/high temperatures and/or pressures

- without perturbation, intrusion, material loss

2010 Mettler-Toledo AutoChem, Inc.

Low Temperature Reactions-Anhydride and Amide

Monitoring ObjectiveDevelop in-depth knowledge of complex, low temperature reaction

- identify key intermediates- develop method to track reaction species

Improve performance of process for generic antibiotics- increase yield- reduce impurities; process cycle time

Extend improvements to all antibiotic product lines

+

+

O

R C Cl

O

R C Cl R ' C

O

O K

O O

O

O

CCCR R ' R ''H 2 N N R ''R '''

O O

OC CR R

O O

OC CR R '


Readily Track Acid Chloride Consumption and Critical Mixed Anhydride Formation

0.120

0.080

0.060

0.040

0.100

1790 1780 1770 1760 1750 1740

50.0

0.0

40.0

30.020.00.020

0.000

1730 1720

60.0

10.0

WavenumberMinutes

Abs

O

R C Cl

O

R C Cl

O O

OC CR R

O O

OC CR R


Correlate Reaction Variables to Process Understanding

0.0 40 6020

Minutes

Auto

scal

edAb

sorb

ance

O

R C Cl

O O

OC CR R

0.0 40 6020

Minutes

Auto

scal

edAb

sorb

ance

O

R C Cl

O

R C Cl

O O

OC CR R

O O

OC CR R

EndEnd--point detection is critical for optimal point detection is critical for optimal product yield and purityproduct yield and purityAdjustment to the current hold time will Adjustment to the current hold time will result in production cost savings by result in production cost savings by reducing batch cycle timereducing batch cycle time


By controlling hold time, temperature, and feed rate, decomposition of critical anhydride intermediate was minimized

Overall yield improvement; less decomposition - better purity product

Over $1M/yr improved profitability

Refinements to Process Variables Enhances Production Efficiency

75.0

77.0

79.0

81.0

83.0

85.0

87.0

89.0

91.0

93.0

95.0

75.0

77.0

79.0

81.0

83.0

85.0

87.0

89.0

91.0

93.0

95.0

Batch Number

%Yi

eld

125 250150 175 200 2250 25 50

shortened hold time

75 100


In-Situ FTIR Monitoring of Nitrobenzene Hydrogenation

Monitoring ObjectivesTrack nitrobenzene consumption and aniline formation

Determine effect of modifying catalyst (DMSO) on reaction mechanism

Define reaction end-point using aniline formation

Eliminate oxygen contamination and hazards associated with grab sampling

Reduce the dependency on time consuming and potentially hazardous “grab sample” analytical methods

NH2NH2

+ H2

NO2NO2

Nitrobenzene Aniline

CatalystDMSO


Readily Track Nitrobenzene Consumption and Aniline Formation

water

nitrobenzene

anilinemethanol

aniline

0.25

0.20

0.15

0.10

0.05

0.00

1600 1500 1400 1300

2.5

2.0

1.5

1.0

0.5

0.0

Abs

Wavenumber (cm-1)Hours


Infrared Profiles Indicate Direct Conversion to Aniline

Abs.

0.16

0.02

0.14

0.12

0.10

0.08

0.06

0.04

0.00

0.5 2.01.51.0

Hours

NH2NH2

NO2NO2

Absence of DMSO, which acts as a Absence of DMSO, which acts as a catalyst modifier, results in direct catalyst modifier, results in direct conversion to aniline.conversion to aniline.Reaction is complete in 2 hoursReaction is complete in 2 hours


Infrared Profiles Suggest a Intermediate or Side Products

Abs.

0.16

0.02

0.14

0.12

0.10

0.08

0.06

0.04

0.00

1.0 4.03.02.0 5.0

Hours

NH2

NO2

Abs.

0.16

0.02

0.14

0.12

0.10

0.08

0.06

0.04

0.00

1.0 4.03.02.0 5.0

Hours

NH2NH2

NO2NO2

Addition of DMSO modifies catalyst selectivity, Addition of DMSO modifies catalyst selectivity, which causes an intermediate to form.which causes an intermediate to form.The modifier extends the reaction time to greater The modifier extends the reaction time to greater than 5 hours.than 5 hours.


An Infrared Band for Aniline Reveals a Reaction Intermediate

Intermediate

WavenumbersHours

Abs.

1480149015001510

0.06

0.05

0.04

0.03

0.02

0.01

0.00

1.0

2.0

3.0

4.0

5.0

NH2

Intermediate

WavenumbersHours

Abs.

1480149015001510

0.06

0.05

0.04

0.03

0.02

0.01

0.00

1.0

2.0

3.0

4.0

5.0

NH2NH2


ConcIRT Extracts Reactive Intermediate Phenylhydroxylamine

aniline

nitrobenzene

PHA

1.0 4.03.02.0 5.0

Hours

NO2NO2 NHOHNHOH

+Catalyst

DMSO

NH2NH2NH2

H2

Rela

tive

Conc

entr

atio

n


Reactivity issues:

- Reaction is fast so control is important- Toxic, hazardous chlorinating agents (worker exposure issue)- Gas evolution (scale-up issue)- Corrosive, acidic environment (worker exposure issue)

R OH

O

R Cl

O

R Cl

O

R Cl

O

+ SO2 + HCl

+ POCl3 + HCl

+ H3PO3

PCl3

PCl5

SOCl2

N-acylation to amide via acid chloride


Process challenges - Accurate acid chloride end point determination- Process understanding to identify critical parameters - Understand reactivity- Monitoring with conventional offline techniques is challenging8 Air-sensitive intermediate with decomposition issues8 HPLC monitoring requires tedious derivative formation

R1 OH

O

R1 Cl

O

R1 NH

O

R2+ SOCl2R2-NH2THF/DMF

60 °C



Experimental procedure:- Stepwise additions in THF at RT of 8 RCOOH8 DMF 8 SOCl2

- T increased and held at 60°C- Et3N addition (kills excess SOCl2)- Amine addition

R1 OH

O

R1 Cl

O

R1 NH

O

R2+ SOCl2R2-NH2THF/DMF

60 °C



R-COCl1782/1735 cm-1

R-COOH1726 cm-1

Amide1674 cm-1 SOCl2

1239 cm-1



Acid

Acid chloride

Amide

SOCl2

• N.B. Colthup, L.H. Daly and S.E. Wiberley, “Introduction to Infrared and Raman Spectroscopy”, 3rd Edition, Academic Press, San Diego, 1990, ISBN 0-12-182554-X• George Socrates, “Infrared and Raman Characteristics Group Frequencies” Third Edition, John Wiley & Sons, 2002, ISBN 0-470-09307-2



RCOOH addition

SOCl2 addition

Reaction initiation

Reaction endpoint

Amine addition

Acid

Acid chloride

Amide

SOCl2

Acid chloride is formed within 65 minutes after initiationFinal amide is formed very rapidly (~2 minutes) upon amine addition



Summary

ReactIR™ in situ data provided the following information:- SOCl2 accumulates in solution at room temperature- Heating initiates the reaction- Acid chloride forms in ~65 minutes- Acid chloride is stable at 60°C- Amide formation is very rapid (~2 minutes)

Offline analysis may not be reliable:- Hydrolysis of intermediate acid chloride during sampling- Derivitization required…potential errors



Sandmeyer Reaction

NH2

X Y X Y

N+

NBr

YX

Br

HBr, NaNO2 CuBr, heat+ N2

'Diazonium salt'Aniline Aryl Bromide

Process challenges:- Determine if the diazonium salt remains in solution until converted to the aryl

bromide- Determine whether the diazonium salt is a well-behaved intermediate- Potentially explosive if the diazonium salt precipitates


Aniline reacts to cleanly form diazonium intermediate Intermediate remains stable during hold

05

1015202530354045505560

2.0 2.3 2.5 2.8 3.0

Time (hrs)

Hea

t flo

w (w

atts

)

0

10

20

30

40

50

60

Abs

orba

nce

(nor

mal

ized

)

Heat flow Diazo Symetrical Ar-N2 1586cm-1 Aniline sym NH3+ 1500cm-1

NaNO2 add'n

Sandmeyer Reaction

NH2

X Y X Y

N+

NBr

HBr, NaNO2

'Diazonium salt'Aniline


Diazonium intermediate reacts to aryl bromide productReactIR™ profiles indicate a possible intermediate exists

Sandmeyer ReactionX Y

N+

NBr

YX

Br

CuBr, heat+ N2

'Diazonium salt' Aryl Bromide

-505

10152025303540455055

3.5 4.0 4.5 5.0 5.5 6.0

Time (hrs)

Hea

t flo

w (w

atts

x 3

)A

bsor

banc

e (n

orm

aliz

ed)

0

10

20

30

40

50

60

70

80

Gas evolution (m

L/min)

Heat flow Diazo Symmetrical Ar-N2 1586cm-1 Product ArBr1097cm-1 Gas evolution

CuBr add'n ramp to 70 °C


ReactIR™ data defines an aryl radical intermediate is formedIntermediate gives insight into reaction mechanism

Sandmeyer ReactionX Y

N+

NBr

YX

Br

CuBr, heat+ N2

'Diazonium salt' Aryl Bromide

-505

10152025303540455055

3.5 4 4.5 5 5.5 6

Time (hrs)

Abs

orba

nce

(nor

mal

ized

)

Diazo Symmetrical Ar-N2 1586cm-1 Intermediate 1258cm-1 Product ArBr1097cm-1

CuBr add'n ramp to 70 °C


ReactIR™ data confirms an aryl radical intermediate is formed

Sandmeyer Reaction

X Y

N+

NBr

YX

Br

C

X Y

CuBr, heat

Cu(I)

Cu(II)

-N2

Cu(II)

Cu(I)

Cu +2

2Br-

++

+ N2

Advanced Organic ChemistryJerry March4th Edition


Summary

ReactIR™ showed that the diazonium salt remains in solution and is a well-behaved intermediate

- Allowed for safe scale-up of this chemistry

ReactIR™ detemined the endpoint of the diazonium intermediate step

ReactIR™ gave insight into the proposed mechanism of the Sandmeyer reaction

- Identified aryl radical intermediate

Sandmeyer Reaction


H2, Pd/C

DIEA, thioanisole, toluene

NC

O O

CH2

CO Cl

Ncbz

CO H

N

cbz

O N

H

OImpurity

For a growth hormone

secretagogue

Process challenges:- Slow and incomplete conversion (≥ overnight), even with additional catalyst

- Wide variation of yield: 50~96%, with formation of a dimeric impurity

Merck: J. Wang, K. Rossen, J. Kukura, F. Gortsema, J. Sager, P.J. Pye, C.J. Orella, and Y.-K. Sun, Merck & Co., Inc., Rahway, NJ, “Kinetic and Pathway Analysis of Rosenmund Reduction of N-cbz-Isonipecotic Acid Chloride,” 4th International Conference on Organic Process Research & Development, Hong Kong, March 18-21, 2001

Rosenmund reduction


0

2

4

6

8

10

12

14

16

18

0 2 4 6 8 10 12 14 16 18

[Acid]/[Acid-Cl @t=0] ( % )

Y = X

100

-yie

ld

Apparent incomplete conversionobserved across a wide range of

conditions

RCOCl+

RCOOH

RCOOCOR

t-amine

RCOClH2O

Anhydride formation due to H2O intrusion

Not detected by HPLC assayAcid not counted in yield calculation

Rosenmund reduction


R-COOH + R-COCl R-CO-O-CO-R + t-Amine.HClt-Amine

n 100 n

R-CHO

H2, Pd/C, PhSMe, t-amine, 20C Hydrogenation

(100-n)

NH2R’

R-CO-NHR’

HPLC assayNH2R’

n

n

00

HPLC assay ‘sees’ no acidic anhydride

Rosenmund reduction


0.5

0.4

0.3

0.2

0.1

0.0

200150100500

Time (min)

anhydride

acid chloride

aldehyde

Anhydride 1815 cm-1

Acid Chloride 1795 cm-1

Anhydride 1745 cm-1

Aldehyde 1725 cm-1

Reaction conditions:20 oC, 40 psig H2, 350 ml (in a 1L vessel), 1000 rpm, DIEA:Substrate=1.25,4.1 g-cat, 7.2 mg thioanisole/g-cat (>Lc)

Anhydride formation confirmed by ReactIR™

Inject H2O

H2 on

Rosenmund reduction

ConcIRT


Two kinetic regimes: 1) Acid-Cl Aldehyde

2) Anhydride + Aldehyde Dimer

more Anhydride more Dimer less Aldehyde

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20

Time ( hr )

Con

vers

ion

of A

cid-

Cl (

% )

Anhydride:AcidCl = 16:100Anhydride:AcidCl = 1.5:100 [1 - exp(-0.06t)]*100

0

20

40

60

80

100

0 20 40 60 80 100

Conversion of Acid-Cl ( % )

Yie

ld to

Pro

duct

s ( %

)

Anhydride:AcidCl = 16:100Anhydride:AcidCl = 16:100Anhydride:AcidCl = 1.5:100Anhydride:AcidCl = 1.5:100

Aldehyde

Dimer

Effect of anhydride on dimer formationwithout PhSMe (catalyst modifier)

Rosenmund reduction


Rosenmund reductionSummary

Offline analysis by HPLC failed to detect:- RCOOCOR, a key by-product - The inertness of RCOOCOR, cause of incomplete conversion

ReactIR™ revealed RCOOCOR formation and its inertness to reduction:- The key to incomplete conversion- The cause of formation of dimer impurity- The key to poor selectivity, low and inconsistent yield

ReactIR™ monitoring of the reaction in real time without sampling helped to gain fundamental understanding of the process problem, and to develop a robust high yielding process


Case study 4: N-Substitution via reductive amination

+ 2H-H2OC

R1

R2

O NR'2

R'1H+ N

R'2

R'1HC

R1

R2

NR'2

R'1C

CHOHR1

R2

R2

R1

HO

NR'2

R'1C

R1

R1

+2H+2H -H2O

+OH- -OH-

Dimer(s)

Unstable Difficult to analyze offlineSpecial care for storage

Over reductionNeed to know EOR timely

Need optimization


ReactIR™ as a PAT tool for the organic chemist

Successful and fast development and scale-up:- Monitor and control in real time from bench scale to pilot scale

- Gain insight into root causes of process problems

- Change or optimize existing process for robust performance

- Design better processes for the future

- Gain chemical specific and information rich data which provides8Information on selectivity and reactivity

8Identification of intermediates, by-products and side products

8Pin-point end of reaction for intermediates or final product

- Record, observe, analyze detailed changes from batch to batch8Catch differences throughout reaction between batches

8Obtain critical information difficult to have otherwise


We would like to thank the following contributors:

Bob Cooley - GlaxoSmithKline - Real-time Analytics User Forum -February 2005, NYC - USA

Teva – BioCraft, St. Louis, MO

Claude Didierjean, Ph.D. - METTLER TOLEDO

Will Kowalchyk, Ph.D. - METTLER TOLEDO

Jennifer Andrews, Ph.D. – METTLER TOLEDO

Acknowledgements

Advances in Process Spectroscopy: Mid-Infrared in-situ Reaction Monitoring Case Studies ·...

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