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(S)-Metolachlor
From Dream to Production Process
Hans-Ulrich Blaser, SOLVIAS AG, Basel Switzerland
Uni Rostock, Gastvorlesung Asymmetrische Katalyse, 7.-8. Dez. 2007
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Outline
� Background
The Molecule, the situation, possible approaches
� In Search of the Ideal Catalyst
�Moving in a Labyrinth (in the Fog)�
� The Technical Process
Ligand Scale-up, Imine Synthesis, Choice of Reactor,
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MetolachlorThe Molecule
(R,S)
N
CH3
OCH3
CH3 CH3
O
Cl
� Herbicide for maize
� > 20�000 t/y
� Only (S)-enantiomers active
Ca. 35% less loadingfor enriched form
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The Four Stereoisomers of Metolachlor
H. Moser, G. Rihs, H.P. Sauter 1982
N
CH3O
CH2Cl
O
N
CH3O
CH2Cl
O
R,1'S S,1'S
2 active stereoisomers
N
CH3O
CH2Cl
O
N
CH3O
CH2Cl
O
R,1'R S,1'R
2 inactive stereoisomers
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Herbicidal Activity of Metolachlor Stereoisomers
H. Moser, G. Rihs, H.P. Sauter 1982
0%
20%
40%
60%
80%
100%
0 200 400 600 800 1000
application rate (g/ha)
R,1'S S,1'S rac-metolachlor S,1'R R,1'R
CH3
N
Cl
O
CH3
H3COCH3H
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The History of rac-Metolachlor and (S)-Metolachlor
1970 Discovery of biological activity
1978 Full-scale plant >20�000 t/y
1982 Bioactivity of (S) enantiomers detected
1983 First attempts to make (S)-metolachlor
1985 Rh - cycphos (UBC Vancouver)
1987 Ir - diphosphine (F. Spindler; J.A. Osborn)
1993 Ir - ferrocenyl diphosphine catalysts
1993/4 Patents of rac. metolachlor expired
1995/6 Pilot results: e.e. 79%, ton 1�000�000, tof >200�000/h
16. Nov. 1996 First production batch
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Metolachlor: The Problem
O
NH2
NOCH3H
ClCOCH2Cl
N
CH3O
CH2ClO
N
CH3O
CH2ClO
N
CH3O
CH2ClO
N
CH3O
CH2ClO
H2 - Pt/C
NAA
aR,1'S aS,1'S
aR,1'R aS,1'R
active stereoisomers
inactive stereoisomers
OCH3
Production process for racemate
?NH2
O
ClCOCH2Cl
+
+
OCH3
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(S)-MetolachlorThe Challenge
Productionprocess
Enantioselectivity
Catalystproductivity (ton)
>1'000'000(70 recycles)
Space-time yield very high
-
Catalyst activity(tof)
>4000/hat 50°C, 5 bar
Minimumrequirements
ee >80%
>50'000(s/c ratio)
high
>10'000/h
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100
80
60
40
20
0
Moving in the "ee � ton" Space
10 100 1000 10�000 100�000 1�000�000
ee >80%
ton > 50�0000
20
40
60
80
100
10 100 1'000 10'000 100'000 1'000'000
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100
80
60
40
20
0
Moving in the "ee � ton" SpaceA Labyrinth!
10 100 1000 10�000 100�000 1�000�000
0
20
40
60
80
100
10 100 1'000 10'000 100'000 1'000'000
ton > 50�000
ee >80%
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Development Phases for EPC Synthesis
Phase 1: Design and assessment of synthetic routes
Phase 2: Demonstrating chemical feasibility
Phase 4: Optimizing the over-all process
Phase 3: Optimizing the key (catalytic) reaction(s)
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N
OCH3
COCH2Cl N
CH3O
COCH2Cl+ H2or
?
chiral cat
Hydrogenation / substitution
Hydrogenation of enamide (isomers) Hydrogenation of imine (isomers)
Routes to (S)-Metolachlor
OH
OMe
NH2
+chiral cat
?
N
CH3Ochiral cat
+ H2
?
OTs
OMe
O
OMe
NH R
+ 2. T sX
R = H or COCH2Cl
?1. H2, chiral cat
?
Direct alkylation
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(S)-MetolachlorRoute Assessment
route catalytic step
enamide close analogy ee >90%
substitution weak analogy ee >80%
imine weak analogy ee <30%
direct alkylation
no precedent
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(S)-Metolachlor:Route Assessment
route catalytic step other steps
enamide close analogy ee >90%
enamide synthesis difficult
substitution weak analogy ee >80%
substitution difficult
imine weak analogy ee <30%
as in current process
direct alkylation
no precedent as in current process
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(S)-Metolachlor:Route Assessment
route catalytic step other steps cost (ecology) priority
enamide close analogy ee >90%
enamide synthesis difficult
high (medium)
1
substitution weak analogy ee >80%
substitution difficult
high (bad)
2
imine weak analogy ee <30%
as in current process
medium (good)
3
direct alkylation
no precedent as in current process
low (very good)
4
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Development Phases for EPC Synthesis
Phase 1: Design and assessment of synthetic routes
Phase 2: Demonstrating chemical feasibility
Phase 4: Optimizing the over-all process
Phase 3: Optimizing the key (catalytic) reaction(s)
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The Enamide Route
H.U. Blaser, F. Spindler 1983
The Analogy: L-DopaRh-dipamp
(Monsanto)
The Result: (All) available Rh/P^P(up to 20 bar / 50°C)
ee 96%ton 10�000
NO activity at all!!
N COCH2Cl
MeO
N COCH2Cl
MeO
N COCH2Cl
OMe
NCOCH2Cl
MeO
oror
COOH
N
MeOMeO
H
O
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From Dream to ProcessImportant Milestones (1983)
100
80
60
40
20
010 100 1000 10�000 100�000 1�000�000
ee >80%
ton > 50�000enamide
40
60
80
100
100 1'000 10'000 100'000 1'000'000
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Substitution RouteHeterogeneous Hydrogenation
H.U. Blaser, H.P. Jalett 1983
The Analogy: Pt/Al2O3-Cinchonidine
(Orito, 1979) ee >85%
O
O
OCH3
activity okee 12%!!
The Result: Pt/Al2O3-Cinchonidine
O
OCH3
ee 0%!!N
OCH3
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From Dream to ProcessImportant Milestones (1983)
100
80
60
40
20
010 100 1000 10�000 100�000 1�000�000
ee >80%
ton > 50�000Pt/cinch
0
20
40
60
80
100
10 100 1'000 10'000 100'000 1'000'000
enamid
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Imine Hydrogenation
N
CH3O
NH
CH3O
???????
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Enantioselective C=N ReductionState of the Art Around 1982
0
20
40
60
80
100
1940 1950 1960 1970 1980
ee (%)
N
HydrogenationLevi et al.CC (1975) 6
HydrosilylationKagan et al.JOMC 90 (1975) 353
Rh / diop
No report on N-aryl imine hydrogenation
mostly heterogeneous catalysts
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Industry�s Approaches for Solving Difficult Problems
� UBC Vancouver (Cullen, Fryzuk, James, Kutney et al.)Search for a catalyst� ULP Strasbourg (J.A. Osborn)Investigate Ir-diphosphine catalysts (active species, deactivation behavior)
Do-it-yourself Outsource to a specialized department Outsource to a specialized company (Solvias!) Collaboration with universities
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UBC: Rh-CycphosA First Success
Cullen, Fryzuk, James, Kutney, et al. UBC Vancouver 1984-89
D M A-im ine
NO
NOH
H
H2
R h-PP
s/c Temperature t Conv. tof ee[°C] [hrs.] [%] [h-1] [%]
100 20 44 99 2.3 53
100 -10 20 100 5 69
1000 -10 168 67 4 69
100 -25 70 100 1.4 73
PPh2
Ph2P
(R)-cycphos
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From Dream to ProcessImportant Milestones (1985)
Rh/cycphos
100
80
60
40
20
010 100 1000 10�000 100�000 1�000�000
ee >80%
ton > 50�000enamid Pt/cinch
0
20
40
60
80
100
10 100 1'000 10'000 100'000 1'000'000
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New Idea: Ir - P^P Complexes
F. Spindler 1986
Ph2P PPh2 N
PPh2
CH2PPh2
COO-t-Bu
P POCH3CH3O
Ph Ph
CH3
OHH
PPh2
PPh2
Fe
PP
O
OH
H
R
R
R'
R'
R
R
bdpp (skewphos)dipamp bppmbppfohsubstituted diop
2
2
Ligand tof (4h) tof (24h) eediop 165 32 61subst-diop 89-146 28-32 56-61bppm ( tBuOMe) 6 79bppm (MeOH) 30 6dipamp 19 7bppfoh 21 28bdpp 114 26 78pN(Me)2-bdpp 31 rac
10-20 °C, 30-80 bar, conversion: 17-96%
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Why Iridium?
[Ir(cod)(py)(Pcy3)]PF6: Extremely activecatalysts for olefin hydrogenation
Olefin maximum tof (1/h)
6400
8300
4000
Drawback: Very fast deactivation via dimerization
R. Crabtree et al. J. Organomet. Chem. 141 (1977) 205
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1997: Chiral Iridium � PN Catalysts: Effective for C=C Hydrogenation
Review: A. Pfaltz, W.J. Drury, Proc. Nat. Acad. Sci. USA 101 (2004) 5723
R2
R1
R'R3
P N
O
R3R2
R1N
OO
R1 R1
R3
R2
PPh2
R2
R1
R'R3
Ir+ / PN / X-
A. Pfaltz
ee up to >99%ton >5000
tof 1250 h-1
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Iridium: Best Results afterOptimization
N
CH3O
NH
CH3O
Ir - P^P, iodidePPh2
PPh2
O
O
CH2PPh2
CH2PPh2
bdpp diop
bdpp ee 84% ton 100 (at 0°C)
diop ee 52% ton 10'000 (at 30°C)
F. Spindler, B. Pugin 1986
PROBLEM
CATALYSTDEACTIVATION
(Dimerization??)
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From Dream to ProcessImportant Milestones
Rh/cycphos
100
80
60
40
20
010 100 1000 10�000 100�000 1�000�000
ee >80%
ton > 50�000enamid Pt/cinch
Ir/diop
Ir/bdpp
0
20
40
60
80
100
10 100 1'000 10'000 100'000 1'000'000
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Fighting Catalyst Deactivation
Understanding
Nature of active species: Collaboration with JAO
Stabilizing Additives
Avoid dimerization by complexation
Immobilization
Avoid dimerization by �site-isolation�
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Fighting DeactivationImmobilization of Ir - bppm
B. Pugin 1988
0
20
40
60
80
100
120
0 3 6 9 12 15 18raction time [h]
imin
e [%
]
soluble catalyst; ee = 38%
NP
P
O
OIr
HN
P
P
O
OIr
H
inactive dimer???
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Fighting DeactivationImmobilization of Ir - bppm
0
50
100
150
200
250
300
350
0 0.05 0.1 0.15 0.2Loading (mmol Ir/g)
tof
0
10
20
30
40
50
60
ee
B. Pugin 1988
NP
P
O
OIr
HN
P
P
O
OIr
H
inactive dimer
N
P P
O N
SiO
O O
Ir
N
P P
O N
SiO
O O
Ir
dilution
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Fighting DeactivationHomogeneous Ir � bppm Catalyst
B. Pugin 1988
0
20
40
60
80
100
120
0 3 6 9 12 15 18raction time [h]
imin
e [%
]
soluble catalyst; ee = 38%
Immob. catalyst; ee >50%
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From Dream to ProcessImportant Milestones
Rh/cycphos
100
80
60
40
20
010 100 1000 10�000 100�000 1�000�000
ee >80%
ton > 50�000enamid Pt/cinch
Ir/diop
Ir/bdpp
0
20
40
60
80
100
10 100 1'000 10'000 100'000 1'000'000
Ir/bppmimmob
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Intermezzo 1988-1992
1988: Project stopped by Agro Division
A. Togni: Ligands for Au-Aldol reaction
Enlargement of ligand library
Systematic immobilization studies
Technical ligands syntheses
Various process developments
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A. TogniLigands Studies: Josiphos
A. Togni, F. Spindler, B. Pugin
N(CH3)2
Fe
N(CH3)2
PR 2Fe
PR'2
PR 2Fea) BuLi
b) ClPR2
HPR'2
AcOH
OAc
PPh2
X
SAc
PPh2
PPh2
NRR'
PPh2
PPh2
PCy2
PPh2
H
Fe
X = H, PPh 2
Fe
Fe
Fefirst Josiphos
ligands for Au-Aldol
Modular, tunable ligands
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The Final BreakthroughIr � Xyliphos / AcOH / Iodide
Best results (laboratory)
R´ = p-tBu-phenylee 87% low tof at -15°C
R´ = 3,5-xylylee 76-80% ton 1�000�000; tof ca. 30'000 h-1
F. Spindler, H.P. Jalett, H.P. Buser 1992
BUT:only on presenceof acid AND iodide!!
PR'2
PPh2Fe
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Ir - Xyliphos: Effect of Solvent
Solvent t (100% )(h)
initialrate
ee
thf 7 0.3 74CH 2Cl2 4 0.3 74(CH 3)3CO CH 3 12 0.2 75acetone 6 0.4 73to luene 12 0.4 73i-PrO H 0.75 1.1 79t-BuO H 1 1.0 77CH 3CO O Et 8 0.7 72none 10 0.3 73CH 3CO O H 0.5 1.5 79R eaction conditions: MEA-Im ine; s/c : 800; 150 mg TBAI; solvent: 2 m l; 25 bar H 2; 30°C .
H.P. Jalett, F. SpindlerHH69
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Why Acetic Acid
solvent ee EtOH 82%
toluene 87% acetic acid 92-94%
R
H
COOEt
OH
R COOEt
OPt/Al2O3 - cinchona
+ H2
R = CH3 and PhCH2CH2 R-hydroxyester
H.P. Jalett, H.U. Blaser, Wiehl 1991
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Ir - XyliphosEffect of AcOH and I-
General acid effect:- CF3COOH- H2SO4
CH3
PH
P(C6H5)2 Fe 2
Xyliphos
H.P. Jalett, F. Spindler 1993
------
---AcOH
Iodide---
IodideAcOH
0
200
400
600
800
1000
1200
1400
1600
1800
0
20
40
60
80TOF ee
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100
80
60
40
20
0
enamid
From Dream to ProcessImportant Milestones
Ir/xyliphosAcid / iodide
Ir/PPF-P
Ir/bppmimmob
Ir/bdpp
Ir/diopRh/cycphos
10 100 1000 10�000 100�000 1�000�000
ee (%)
tonPt/cinch
ee 80%ton >50�000tof >10�000/h
0
20
40
60
80
100
10 100 1'000 10'000 100'000 1'000'000
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Reductive Alkylation of MEAIr-xyliphos, AcOH: Solvent Effect
NH2
NO
H
H
OO
H2
Ir-PP+
MEA MOA S-NAA
Solvent Time Rate Conv. ee[h] [mmol/min] [%] [%]
none 22 0.5 87 76 2 phases
Cyclohex (10 ml) 21 0.9 92 77 2 phases
EtOH (10 ml) 18 0.3 24 15 1 phaseReaction conditions: 0.1 mol MEA; 0.12 mol MOA (dry); AcOH: 2.5 ml; 20 mg TBAI; 80 bar H2;
50°C.
s/c 10'000
H.U. Blaser, H.P. Jalett
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Functionalization of Xyliphos
NMe2
Fe
NMe2
PPh2
Si
Cl
Fe
Pxyl2PPh2
Si
Cl
Fe
Immobilization
1) BuLiBuLi /TMEDA
2) mixture of
Si ClCl
andCl-PPh2
Pxyl2PPh2
Si
N
Fe
H-Pxyl2
(53%)
(60-70%)
(90%)
Gabriel
xyl=
B. Pugin, H. Landert 1995
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homogeneous heterogeneous
Metolachlor: Recycling??
free extractable immobilized silicagel
immobilized polystyrene
P(xyl)2
PPh2Fe
P(xyl)2
PPh2
Si
COO-
-OOC
Fe
Silicagel
P(xyl)2
PPh2
Si NH
ONH
SiO OO
Fe
P(xyl)2
PPh2
NH O
NHNH
O
NH
Fe
Polystyrene
S/C 50'000 120'000 120'000 50'000 120'000 50'000 time 1h 2.1h 3h 8h 10h 30h ee 79% 80% 79% 78% 78% 74% separation distillation extraction
> 90% filtration
95% filtration
95%
B. Pugin, H. Landert, F. Spindler, H.U. Blaser, Adv. Synth. Catal. 344 (2002) 974
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Hydrogenation of ImineBest Ir / Xyliphos Systems
F. Spindler, B. Pugin, H.U. Blaser, H.P. Jalett
ImmobilizedHomogeneous Reductivealkylation
No acid
0
2'000
4'000
6'000
8'000
10'000
12'000
14'000
tof
0
20
40
60
80
100
ee (%
)
s/c 100'000s/c 10'000
s/c 2'000'000
AcOH
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Development Phases Metolachlor Imine Route
Phase 1: Assessing synthetic routes
Phase 2: Demonstrating chemical feasibility
Phase 4: Optimizing the over-all process
Phase 3: Optimizing the key (catalytic) reaction(s)
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Process Optimization
Ligand fine tuning
Optimization of reaction conditions
Strategy for the development of the over-all process
The Production of the MEA Imine in the Required Quality
Technical Ligand Synthesis
Choice of Reactor Technology
Scale up
Work-up
Separation of the Catalyst from the Product
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Fine Tuning(S)-Metolachlor Process
NH
CH3O
N
CH3OMEA imine (S) -NAA
Ir - PP
Catalyst: [Ir(COD)Cl]2, NaI, H2SO4, (R)-(S)-R2PF-PR�2; p(H2), 80 bar, 50°C
ee %tontof [h-1]
P
P
HCH3Fe
792�000�000>400�000
P
P
HCH3
F3C
F3C
Fe
82800400
P
P
HCH3Fe
875�000
80
P
P
HCH3
N
N
Fe
83100�00028�000
F. Spindler
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Ligand Finetuning: N Substituents at Xylyl Group
F. Spindler, H.P. Buser 1994
CH3
CH3
e.e.: 76%rate: 26 mmol/min
CH3
CH3
N
e.e.: 83%rate: 1 mmol/min
CH3
CH3
N
e.e.: 69%rate: 10 mmol/min
N
CH3
CH3
e.e.: 76%rate: 2 mmol/min
CH 3
CH3
N
e.e.: 82%rate: 0.5 mmol/min
CH3
CH3
N
e.e.: 80%rate: 25 mmol/min
CH3
PR2
H
P(C6H5)2Fe
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Reaction ConditionsEffect of H2 Pressure
0
2
4
6
8
10
12
14
0 20 40 60 80 100 120 140
Pressure (bars)
r max
(mm
ol H
2/m
in)
ee: 75 - 76%
F. Spindler, H.P. Jalett 1994
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Development Phases for EPC Synthesis
Phase 1: Design and assessment of synthetic routes
Phase 2: Demonstrating chemical feasibility
Phase 4: Optimizing the over-all process
Phase 3: Optimizing the key (catalytic) reaction(s)
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Process Development
Ligand fine tuning
Optimization of reaction conditions
Strategy for the development of the over-all process
The Production of the MEA Imine in the Required Quality
Technical Ligand Synthesis
Choice of Reactor Technology
Scale up
Work-up
Separation of the Catalyst from the Product
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Imine Production
NH2 N
CH3O
O
OMe + H2O+
H+
Simple chemistry
BUT
Scale up difficult due to thermal instability of the imine Fast removal of water neccessary
Significant catalyst deactivation High purity required
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Effect of MEA Concentration
Ir/xyliphos, Acetic Acid, TBAI
F. Spindler, H.P. Jalett
0
1
2
3
4
5
6
7
0 1 2 3 4 5MEA (%)
inita
l rat
e (m
mol
H2/
min
)
t(100%): 18 h
t(100%): 0.5 hNH2N
O
MEA imine
MEA
ee not affected!
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Imine Production: Water Separators
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Process Development
Ligand fine tuning
Optimization of reaction conditions
Strategy for the development of the over-all process
The Production of the MEA Imine in the Required Quality
Technical Ligand Synthesis
Choice of Reactor Technology
Scale up
Work-up
Separation of the Catalyst from the Product
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Technical Ligand Synthesis
OO
Fe
OH
Fe
Fe PPh2
NMe2
Fe PPh2
PH
FeO
Fe
OH
Fe
NMe2
Fe
+
2
enzymatickinetic
resolution
Ugi amine
30 Kg scale unproblematic
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Process Development
Ligand fine tuning
Optimization of reaction conditions
Strategy for the development of the over-all process
The Production of the MEA Imine in the Required Quality
Technical Ligand Synthesis
Choice of Reactor Technology
Scale up
Work-up
Separation of the Catalyst from the Product
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Choice of Reactor Technology
Issues
Fast exothermic reaction -> heat removal important
High pressure (80 bar) -> high investment
Sensitive catalyst -> handling and loading
Alternatives
Loop reactor
Stirred tank reactor
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Coice of Reactor
pump
stirred tank loop reactor
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Coice of Reactor
pump
cooling
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Process Development
Ligand fine tuning
Optimization of reaction conditions
Strategy for the development of the over-all process
The Production of the MEA Imine in the Required Quality
Technical Ligand Synthesis
Choice of Reactor Technology
Scale up
Work-up
Separation of the Catalyst from the Product
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16. November 1996Happy End: First Production Batch
NO
NOH
H
amount mol
MEA-imine 10'000 kg 48'700[Ir(COD)Cl]2 34 g 0.05Ligand 68 g 0.11NaI 92.5 g 0.6H2SO4 250 g 0.5
N. Pericles, R. Hanreich
CH3
Pxyl2
H
PPh2Fe
reaction time 2h
conversion 99.6%
ee 79%
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100
80
60
40
20
0
enamid
From Dream to ProcessImportant Milestones
Ir/xyliphosAcid / iodide
Ir/PPF-P
Ir/bppmimmob
Ir/bdpp
Ir/diopRh/cycphos
10 100 1000 10�000 100�000 1�000�000
ee (%)
tonPt/cinch
ee 80%ton >50�000tof >10�000/h
0
20
40
60
80
100
10 100 1'000 10'000 100'000 1'000'000
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Some Lessons
Enantioselectivity is not always the major problem ton and tof can be just as critical!!
Screening capabilities are crucial Parallel screening equipment
NO SUCCESS WITHOUT TOP EXPERTISE
Success often depends on availability of ligands Modular ligands are an optimal solution Solvias Ligand Kit
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The Key Players
B. PuginF. Spindler H.P. Jalett
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Think catalytic!