advances in process spectroscopy: mid-infrared in-situ reaction monitoring case studies ·...
TRANSCRIPT
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
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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
2006 Mettler-Toledo AutoChem, Inc.3
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
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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 '
2010 Mettler-Toledo AutoChem, Inc.
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
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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
2010 Mettler-Toledo AutoChem, Inc.
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
2010 Mettler-Toledo AutoChem, Inc.
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
2010 Mettler-Toledo AutoChem, Inc.
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
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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
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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.
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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
2010 Mettler-Toledo AutoChem, Inc.
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
2006 Mettler-Toledo AutoChem, Inc.14
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
2006 Mettler-Toledo AutoChem, Inc.15
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
N-acylation to amide via acid chloride
2006 Mettler-Toledo AutoChem, Inc.16
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
N-acylation to amide via acid chloride
2006 Mettler-Toledo AutoChem, Inc.17
R-COCl1782/1735 cm-1
R-COOH1726 cm-1
Amide1674 cm-1 SOCl2
1239 cm-1
N-acylation to amide via acid chloride
2006 Mettler-Toledo AutoChem, Inc.18
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
N-acylation to amide via acid chloride
2006 Mettler-Toledo AutoChem, Inc.19
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
N-acylation to amide via acid chloride
2006 Mettler-Toledo AutoChem, Inc.20
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
N-acylation to amide via acid chloride
2006 Mettler-Toledo AutoChem, Inc.21
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
2006 Mettler-Toledo AutoChem, Inc.22
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
2006 Mettler-Toledo AutoChem, Inc.23
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
2006 Mettler-Toledo AutoChem, Inc.24
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
2006 Mettler-Toledo AutoChem, Inc.25
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
2006 Mettler-Toledo AutoChem, Inc.26
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
2006 Mettler-Toledo AutoChem, Inc.27
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
2006 Mettler-Toledo AutoChem, Inc.28
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
2006 Mettler-Toledo AutoChem, Inc.29
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
2006 Mettler-Toledo AutoChem, Inc.30
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
2006 Mettler-Toledo AutoChem, Inc.31
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
2006 Mettler-Toledo AutoChem, Inc.32
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
2006 Mettler-Toledo AutoChem, Inc.33
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
2010 Mettler-Toledo AutoChem, Inc.34
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
2010 Mettler-Toledo AutoChem, Inc.35
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