Transcript ChiraSource 2003

Process Requirements for the Development of
Asymmetric Hydrogenation Reactions:
From the Bench to Kilogram Scale
OH
Ph
O
H
NO2
O
MeO
t-BuO2C
O
CO2Na
O
HO2C
NH2
OH
NH2
CO2H
F
Ian C. Lennon
Dowpharma, Cambridge, UK
Outline of Talk
Process Requirements for the Development of
Asymmetric Hydrogenation Reactions:
From the Bench to Kilogram Scale
– Known Asymmetric Hydrogenation Processes
– Process Requirements
– Screening Methodology for 2-Methylenesuccinamic Acid
– Optimisation Studies for 2-Methylenesuccinamic Acid
– Case Studies (Candoxatril, Pregabalin, 4-F-Acetophenone)
– Imine Hydrogenation (Thiadiazine)
– Conclusions
Dowpharma Formation
Marion Merrell Dow
Corporate NBD
2002
Dowpharma
BCMS
2001
CMS
1995
2001
Early Applications of Asymmetric Hydrogenation
Pr
RhCl-L3
CO2H
CO2H
L=:P
CH3
Ph
15% ee
W.S. Knowles and M. J. Sabacky Chem. Commun. 1968, 1445
L. Horner et al. Angew. Chem., Int. Ed. Engl. 1968, 7, 942
Monsanto L-DOPA process
COOH
NHAc
AcO
COOH
[(R,R)-Me-DIPAMP-Rh(COD)]
H2
OMe
MeO
P
NHAc
AcO
P
OMe
95% ee
1000 Kg per year
DIPAMP =
OMe
W.S. Knowles Angew. Chem., Int. Ed. 2002, 41, 1998
COOH
Some of the First Applied Phosphine Ligands
Ligand
% ee
Ligand
% ee
NHAc
Ligand
% ee
MeO
Pr
P CH3
28%
P
Ph
95%
P
P CH3
OMe
95%
H
DIOP - 1971
CHIRAPHOS - 1977
Ph2P
87%
PPh2
N
BOC
Rhone-Poulenc - 1974
H
PPh2
PPh2
PPh2
88%
CAMP - 1970
O
PPh2
OMe
DIPAMP - 1974
O
Ph2P
83%
Ph
Ph
NHPPh2
NHPPh2
PNNP - 1974
PPh2
91%
BPPM -1976
NMe2
94%
Fe
PPh2
93%
PPh2
BPPFA - 1980
W.S. Knowles Acc. Chem. Res. 1983, 16, 106
Noyori’s Binap Complexes
O
O
[RuCl2 ((R)-Binap)]2NEt3
TBDMSO
OH O
OMe
H
OAc
OMe
NHCOC6H5
NHCOC6H5
PPh2
PPh2
Binap =
100% Conv.
98% ee, syn:anti =94:6
NH
O
120 tonnes per year
Carbapenem intermediate
Asymmetric Catalysis in Organic Synthesis, R. Noyori
John Wiley & Sons, 1994
O
[(R)-Ru-(Binap)Cl2]2.NEt3
O
OH O
S/C 3,000
OMe
OMe
0.1 mol% HCl, MeOH
40 psi H2, 40oC
S. A. King et al J. Org. Chem. 1992, 57, 6689
>98% ee
Largest Scale Industrial Asymmetric Hydrogenation
CH3O
Ir / Xyliphos
N
50oC, 1200 psi H2
CH3O
CH3O
NH
O
N
Cl
80% ee
ton 2,000,000;
tof 400,000 h-1
Metolachor
PXyl2
Xyliphos =
Fe
>10,000 tonnes per year
PPh2
1982 - Laboratory work
1996 - First Production batch
Hans-Ulrich Blaser Adv. Synth. Catal. 2002, 344, 17
Rh-DuPhos Asymmetric Hydrogenation
Me
Me
DuPhos licensed from DuPont since 1995:
license now assigned to Dow
BF4-
P
Rh
P
P
Me
Me
+
O
Rh
P
H2
Mechanism:
P
+
Rh
P
substrate
H2
solvent
P
+
H O
+ Rh
P H
P
solvent
Rh
P
solvent
solvent
O
precatalyst
H


H
The substrate binds to the metal
The substrate carbonyl group controls the orientation of
hydrogenation
Scope of the DuPhos / BPE Hydrogenation
O
R
CO2R
NH2
CO2R
2
R1
O
R
1
OH
NH2
Ph
O
R
NHAc
Ar
NH2
NHAc
CO2R
O
OH
R
R
NHBoc
MeO2C
R1
P
OH
R
R1
CO2H
P
RO2C
R
Me
DuPhos/BPE 1991
CO2
R
R2
CONH2
HO2C
NH2
OH
1
MeO
CO2R
R
O
R
CO2R
1
CN
R
t-BuO2C
H
CO2H
CO2H
OH
OH
M. J. Burk Acc. Chem. Res. 2000, 33, 363
Unnatural Amino Acids
Asymmetric Hydrogenation & Biocatalysis combined
R
O
N
H
Me
CO2H
1. Rh-(R,R)-DuPhos, H2
2. D-aminoacylase
1. Rh-(S,S)-DuPhos, H2
2. L-aminoacylase
R
R
H
L
H3N+
H
CO2- O2C
D
NH3
+
Combination of technologies provides an efficient process
100’s kg of several amino acids made this way
Asymmetric Catalysis on Industrial Scale
Eds Blaser and Schmidt. Page 269.
Amino Acids Prepared Using Chemo/Biocatalysis
CO2H
N
N(H)Fmoc
S
N(H)Fmoc
S
CO2H
CO2H
CO2H
CO2H
O
N(H)Fmoc
S
N(H)Fmoc
N(H)Fmoc
Br
OMe
Br
CO2H
N(H)Fmoc
Br
CO2H
CO2H
CO2H
N(H)Fmoc
N(H)Fmoc
N(H)Fmoc
Br
CO2H
N(H)Fmoc
Br
CO2H
Ph
N(H)Fmoc
Br
CO2H
CO2H
CO2H
N(H)Fmoc
N(H)Fmoc
N(H)Fmoc
N(H)Fmoc
N(H)Fmoc
CO2H
CO2H
H2N
CO2H
CO2H
N(H)Fmoc
Br
H2N
CO2H
H2N
N(H)Fmoc
CO2H
Fmoc(H)N
O
S
CO2H
CO2H
H2N
CO2H
N(H)Fmoc
CO2H
b-Branched a-Amino Acids
H
Ar
Me
H
Ar
Me
1. HCl
AcHN
(R,R)-Rh-Et-DuPhos
H
CO2Me
(2R, 3S)
Ar
H2N
2. D-AAO
NH3:BH3
H
CO2H
(2S, 3S)
Me
H2, MeOH, 100 psi
AcHN
CO2Me
Ar
H
Me
(S,S)-Rh-Et-DuPhos
AcHN
H
CO2Me
(2S, 3R)
93-98 % ee

1. HCl
Ar
H
Me
2. L-AAO
CO2H
H2N
H
NH3:BH3
(2R, 3R)
>98 % de
68 - 92% yield
Combination of asymmetric hydrogenation and amino acid oxidase
provides access to all four diastereoisomers of b-branched a-amino
acids
In Collaboration with Nick Turner
J. Am. Chem. Soc. 2004, 126, 4098
Process Requirements
 Choice of Catalyst Complex
 Synthesis and Purity of Substrate
 Solvent
 Temperature
 Pressure
 Concentration
 Enantiomeric Excess
 Substrate to Catalyst Ratio (Activity of the catalyst)
 Removal of spent catalyst from the product
 Availability of the Chosen Catalyst (Security of Supply)
Screening for Asymmetric Hydrogenation
R
R
R
P
P
R
R
P
R
DuPhos
R
P
R
Ph
P
P
Ph
BPE
Ph
R
PCy2
Fe
P
PPh2
Ph2P
PPh2
R
Ph
Ph-BPE
Fe
(R)-(S)-JOSIPHOS
(S,S)-CHIRAPHOS
PAr2
PAr2
R
P
5-Fc
R
Ar = Ph (R)-BINAP
Ar = 4MeC6H4 (R)-TolBINAP
R
Et
P
Ph
P
Et
R
Fe
P
R
(R)-EtPhenylLANE

FerroTANE
PPh2
H
O
PPh2
O
PPh2
R
H
PPh2
MeO
O
O
Ph2PO
O
P
OPh
OPPh2
CARBOPHOS
W.S. Knowles, 1983
Cl
N
MeO
MeO
PPh2
PPh2
PPh2
Cl
(R)-Cl-MeO-BIPHEP
(R)-QUINAP
(S,S)-DIOP
(2R,3R)-NORPHOS
Ph
"Since achieving 95 % e.e. only involves
energy differences of about 2 kcal, which is
no more than the barrier encountered in a
simple rotation of ethane, it is unlikely that
before the fact one can predict the type of
ligand structures will be effective"
P
Ph2P
N
BOC
O
Ph2P
N
Ph
OMe
(R,R)-DIPAMP
PPh2
BPPM
PR2
PPh2
PPh2
PXyl2
PXyl2
PR2
(R)-Phosphinooxazoline (R)-PhanePhos (R)-HexaPHEMP (R)-Xyl-TetraPHEMP
Ligand collection for asymmetric hydrogenation screening
COD Versus NBD Precatalysts
BF4
Heller’s Findings
R
R
P
Rh
ml
R
P
R
30
99.4 % e.e
99.4 % e.e
NBD-Precatalyst
BF4
R
R
P
CO2Me
Ph
0
0
NHAc
Time
“….the use of NBD precatalyst in the
asymmetric hydrogenation has significant
advantages over the application of the
usually sold and applied COD complexes”
15
Rh
R
P
R
COD-Precatalyst
“…..the frequently used COD complexes do not
imply optimal activity in the catalysis, at least
for five-membered chelates, and cannot
therefore be regarded very economically”
Borner & Heller, Tetrahedron Lett., 2001, 42, 223
challenges economy of use of COD precatalyst - but at S/C 100:1.
Methyl acetamidocinnamate
CO2Me
CO2Me
Ph
NHAc
3 bar H2, MeOH, RT
% Hydrogen uptake
[Et-DuPhos Rh (diene)]BF4
Ph
NHAc
>99 % e.e
Competition reactions:
(R,R)- COD + (S,S)- NBD
Time (min)
• At S/C = 2,000
e.e. = 23%
• At S/C = 5,000
e.e. = 7%
Candoxatril Precursor
MeO
[Me-DuPhos Rh (diene)]BF4
S/C = 4,200
MeO
O
t-BuO2C
CO2Na
5 bar H2, MeOH, RT
(1)
% Hydrogen uptake
(2)
O
t-BuO2C *
CO2Na
Reactor stirring efficiency:
(1)
Time (min)
Hydrogen availability more important than COD vs NBD
ChiroTech publication: Tetrahedron Letters, 2001, 42, 7481
(2)
Applications of Rh-Me-DuPhos Catalyst
MeO
O
O
H
O
H
N
O
CO2H
Candoxatril
+
Me
Me
-
BF4
CH3
OH
CF3
H
N
P
Rh
Me
P
Ph
O
S
O O
N
O
Me
Tipranavir
[(R,R)-Me-DuPhos Rh (COD)]BF4
NH2
CO2H
Pregabalin
Reviews: Synthesis 2003,1639
Curr. Opin. Drug Discovery Dev. 2003, 6, 855
[(Me-DuPhos)Rh(COD)]BF4 Manufacture
• Multiple Kilogram
quantities produced
• Using a scaleable process
Security of Supply
 Dowpharma manufactures a number of catalyst systems on a
multi-kilogram, kilogram and multi-100 g scale
 Dowpharma offer manufacturing operational excellence, based on
a history rooted in the manufacture of pharmaceuticals
 We have developed secure and robust supply chains for important
intermediates
 All catalysts are manufactured to a precise specification and are
subject to a use test prior to dispatch
 Dowpharma has the ability to manufacture catalysts at a variety of
sites in Europe and North America. In addition, we have the
capability to increase capacity as required
 We offer tailored commercial terms for licensing and supply
agreements
 Dowpharma has a well defined intellectual property position on all
catalyst systems
See: Chimica oggi, December 2003, 63-67
Substrate Synthesis: Manufacture of a-Amino Acids
1.
F
CHO
HO2C
[(S,S)-Me-DuPhos-Rh]+
NHAc
Ac2O, NaOAc
F
CO2H
S/C = 1400
NHAc
o
40 C, 100 psi H2
2. NaOH
MeOH
69% Th
F
CO2H
NHAc
86% ee
Key Issues
1. L-Acylase
F
CO2H
NHBoc
2. Boc2O, MeOH
69% Th over three steps
>99% ee, >98% purity
 Use of Erlenmeyer reaction is preferable to Horner-Emmons chemistry, which can
give low level of phosphorus impurities that poison catalysis
 Erlenmeyer route is scaleable and cost effective
 Conditions for the DuPhos Hydrogenation are mild and scaleable
 Many 100’s kg of product have been made using this route
Asymmetric Catalysis on Industrial Scale
Eds Blaser and Schmidt. Page 269.
Substrate Synthesis: Manufacture of a-Amino Acids
1.
N
HO2C
CHO
NHAc
Ac2O, NaOAc
CO2H
N
NHAc
2. NaOH
BF4
H
N
1. Esterify
2. HBF4
-
+
CO2Me
[(S,S)-Et-DuPhos-Rh]+
N
NHAc
30oC, 90 psi H2
MeOH
CO2Me
NHAc
98% ee
Key Issues
 Competitive binding to the pyridyl group made the catalysis inefficient
 The optimum substrate was the methyl ester-HBF4 salt
 >200 Kg produced
Activity of Catalysts: Ph-BPE
+ BF 4
Ph
Ph
P
Rh
Ph
P
MeO2C
CO2Me
AcHN
S/C 100 000
100% conv.
99% e.e.
CO2Me
AcHN
S/C 5000
100% conv.
97% e.e.
Ph
S/C 5000
100% conv.
99% e.e.
Ph
Ph
AcHN
MeO
CO2Me
S/C 5000
100% conv.
99% e.e.
O
t-BuO2C
CO2Na
S/C 1000
100% conv.
98% e.e.
• Enhanced selectivity and activity over alkyl BPE ligands
Dowpharma Paper: Org. Lett. 2003, 5, 1273
Fast Reaction Rates with Ph-BPE Ligand
Rates of asymmetric hydrogenation of methyl acetamidocinnamate
100
90
Ph-BPE
99% e.e.
80
Conversion (%)
70
60
Me-BPE
97% e.e.
Et-BPE
98% e.e
50
40
30
i -Pr-BPE
97% e.e.
20
10
Time
0
00:00:00
00:28:48
00:57:36
01:26:24
01:55:12
02:24:00
02:52:48
03:21:36
03:50:24
04:19:12
Optimizing the catalysis: Argonaut Endeavor
A New Approach to Acyl Enamides
NHAc
OTf
NHAc
Catalyst
Et3N, DMF, Pd(OAc)2 NC
NC
NHAc
H2 (10 bar), MeOH
o
NC
40 °C, S/C 1,000
DPPP, 100 C
Ref: J. Org. Chem., 1992, 57, 3558
BF4
Ph
NHAc
NHAc
NHAc
Ph
P
Rh
Ph
P
NC
Ph
Cl
CO2Me
(S,S)-Ph-BPE
Et
P
Et
99.4% ee
99.1% ee
NHAc
BF4-
98.3% ee
NHAc
Cl
Rh
Et
P
Et
Cl
O
(S,S)-Et-DuPhos
97.9% ee
97.5% ee
4-Amino-2-methyl butanol and 4-hydroxy-3-methyl-butyronitrile
*
OH
*
or
NH2
OH
CN
O
N
H
N
N
N
O
CF3
HN
N
H
N
N
H
O
N
CF3
Takeda Pharmaceuticals
ONO Pharmaceuticals
Merck
• Chiral building blocks for several biologically active compounds
Substrate Synthesis: Methylenesuccinamic acid
O
O
1. 28 % NH4OH
OH
O
NH2
2. HCl
O
O
O
H2
*
OH
NH2
Cat.
O
 Substrate synthesis from readily available materials
 Scaleable process
 Substrate contains ~ 1 mol % of a chloride containing impurity
*
OH
NH2
Asymmetric Hydrogenation of Methylenesuccinamic acid
Ru Precatalyst
(S/C 100)
O
HO2C
NH2
+NEt3
Entry
1
2
3
4
5
6
7
8
9
10
11
MeOH (0.1 - 0.2 M), r.t.
16 h, 60 psi H2
Precatalyst
[(S)-HexaPHEMP Ru Cl2]2 NEt3
[(S)-HexaPHEMP Ru (CF3CO2)2]
[(R)-BINAP Ru (CF3CO2)2]
[(R,R)-Me-DuPhos Ru (CF3CO2)2]
[(R,R)-i-Pr-DuPhos Ru (CF3CO2)2]
[(R,R)-i-Pr-BPE Ru (C4H7)2]
[(R,R)-Me-FerroTANE Ru (C4H7)2]
[(S,S)-i-Pr-FerroTANE Ru (C4H7)2]
[(R,R)-Me-FerroLANE Ru (C4H7)2]
[(R,R)-Et-FerroLANE Ru (CF3CO2)2]
[(R)-(S)-JOSIPHOS Ru (CF3CO2)2]
O
HO2C
*
+NEt3
Conv. (%)
> 98
> 98
> 98
<5
> 98
> 98
~ 10
> 98
> 98
> 98
> 98
e.e. (%)
18 (S)
40 (R)
56 (S)
1 (S)
2 (S)
41 (S)
11 (S)
3 (S)
1 (S)
NH2
Asymmetric Hydrogenation of Methylenesuccinamic acid
Rh precatalyst
(S/C 100)
O
HO2C
100
90
NH2
HO2C *
MeOH (0.1 - 0.2 M), r.t.
16 h, 60 psi H2
NH2
R
Me Et i-Pr
Et i-Pr
Me
O
Me
Me Et
80
Et
P
R
R
i-Pr
P
70
%ee
60
50
40
R
i-Pr MeOXyl
i-Pr
t-Bu
DuPhos
Xyl
30
R
20
P
10
R
Fe
R
0
FerroTANE
5-Fc6
DuPhos
BPE
R
PhanePhos
HexaPHEMP
Chloride containing substrate
P
Chloride free substrate
FerroTANE
Substrate to Catalyst Ratio (S/C)
O
HO2C
O
Rh precatalyst
NH2
HO2C
*
MeOH (0.1 - 0.2 M),
r.t., 60 psi H2
Entry
Precatalyst
S/C
Conv. (%)
ee (%)
1
2
[(R,R)-Me-DuPhos Rh COD]BF4
[(R,R)-Me-DuPhos Rh COD]BF4
100
1,000
> 98
> 98
94 (S)
87 (S)
3
[(S,S)-Et-DuPhos Rh COD]BF4
100
> 98
95 (R)
4
[(S,S)-Et-DuPhos Rh COD]BF4
1,000
> 98
94 (R)
5
[(S,S)-Et-FerroTANE Rh COD]BF4
100
> 98
93 (R)
6
[(S,S)-Et-FerroTANE Rh COD]BF4
1,000
> 98
87 (R)
7
[(S,S)-i-Pr-FerroTANE Rh COD]BF4
100
> 98
91 (S)
8
[(S,S)-i-Pr-FerroTANE Rh COD]BF4
1,000
> 98
83 (S)
•
Performance of Et-DuPhos holds at higher S/C
NH2
Temperature and Pressure
Rh Precatalyst
S/C = 1,000
O
HO2C
NH2
Entry
Precatalyst
1
2
O
HO2C
MeOH (0.3 M), H2
NH2
Temp
(ºC)
H2 Pressure
(psi)
Time
(min)
Conv.
(%)
ee
(%)
[(S,S)-Et-DuPhos Rh COD]BF4
“
0
20
60
60
>18 h
240
33
> 98
93 (R)
94 (R)
3
“
45
60
140
> 98
96 (R)
4
“
20
140
120
> 98
97 (R)
5
“
45
140
90
> 98
95 (R)
6
[(S,S)-Et-FerroTANE Rh COD]BF4
20
60
120
> 98
87 (R)
7
“
20
140
45
> 98
72 (R)
8
“
45
140
20
> 98
86 (R)
•
Enantioselectivity is retained at higher temperatures and pressures
Concentration and Effect of NEt3
[(S,S)-Et-DuPhos Rh COD]BF4
S/C = 1,000
O
HO2C
NH2
Entry
1
2
3
4
5
6
7
8
•
HO2C
MeOH, r.t., H2
H2 Pressure
Conc.
Time
(psi)
(M)
(h)
60
60
60
60
140
140
0.3
0.3
1.0
1.0
0.3
0.3
4
2.5
<10
5
2
2
140
140
1.0
1.0
<8
5
O
Additive
NH2
Conv.
ee
(%)
(%)
NEt3
NEt3
NEt3
> 98
> 98
> 98
> 98
> 98
> 98
94 (R)
74 (R)
94 (R)
69 (R)
97 (R)
72 (R)
NEt3
> 98
> 98
97 (R)
68 (R)
NEt3 increases the reaction rate, but reduces enantioselectivity
Solvent Screen
[(S,S)-Et-DuPhos Rh COD]BF4
S/C = 1,000
O
HO2C
NH2
O
HO2C
Solvent (0.3 M), 25 ºC
16 h, 140 psi H2
NH2
Conv. (%)
ee (%)
MeOH
EtOH
> 98
37
97 (R)
84 (R)
3
i-PrOH
87
97 (R)
4
5
CF3CH2OH
5
-
6
THF
EtOAc
24
21
17 (S)
-
7
CH2Cl2
2
-
8
9
Acetone
Toluene
9
0
-
10
aaa-Trifluorotoluene
0
-
Entry
Solvent
1
2
Effect of Chloride Contaminant
O
HO2C
NH2
Entry
O
[(S,S)-Et-DuPhos Rh COD]BF4
HO2C
MeOH (1.0 M)
45 ºC, 140 psi H2
NH2
S/C
Substrate
Input
Time
1
2
3
1,000
1,000
5,000
15 g
15 g
15 g
1 h 57 min
4 min
24 min
> 98
> 98
> 98
97 (R)
96 (R)
97 (R)
4
10,000
15 g
46 min
> 98
96 (R)
5
6
20,000
15 g
1 h 42 min
> 98
97 (R)
50,000
100,000
40 g
40 g
4 h 2 min
7 h 27 min
> 98
> 98
97 (R)
96 (R)
7
•
Conv. (%) ee (%)
Removal of Cl- increases rate by a factor of 30
Asymmetric Hydrogenation of Methylenesuccinamic acid
[(S,S)-Et-DuPhos Rh COD]BF4
S/C 100,000
O
HO2C
NH2
MeOH (1.0 M), 45 ºC
~8 h, 140 psi H2
O
HO2C
NH2
96% ee
>99.5% ee after
crystal digestion
 Complete conversion with 96 % e.e. at S/C 100,000:1 (w/w ~21,400)
 Chloride impurity identified that limited S/C to 1000:1
 Upgraded to 99.5 % e.e. with a single reslurry (MeOH)
 Rh content reduces from 9.0 ± 0.4 ppm to 0.88 ± 0.05 ppm
(36 ± 1 ppm to 9.8 ± 0.4 ppm for S/C 20,000)
Dowpharma paper: Org. Process Res. Dev. 2003, 7, 407.
Pfizer’s Candoxatril for Congestive Heart Failure
MeO
O
t-BuO2C
1. Asymmetric H2
CO2Na
MeO
2. Cyclohexylamine
O
t-BuO2C
-+
CO2
H3N
MeO
H
O
O
O
H
N
O
CO2H
Candoxatril
Substrate Synthesis: Tetrahedron Letts. 1999, 40, 2187
Pfizer’s Candoxatril: Original Route
CO2H
HO2C
Br
H2SO4
i-Pr2NLi
Br
t-BuO2C
97%
t-BuO2C
THF, -10 oC
CO2H
40%
t-BuOH
(i) i-Pr2NLi, MEMCl
THF, -78 oC
(ii) (1S,2S)-(+)-pseudoephedrine
MeO
n-hexane
O
O
MeO
H
O
H
N
O
Candoxatril
O
CO2H
H
t-BuO2C
CO2H
33%
13% overall yield from 3-bromopropionic acid
Pfizer Patent: EP 0342850
New Asymmetric Hydrogenation Route
O
MeO
(R)-BINAP-Ru
t-BuO2C
CO2Na
H2
MeO
O
A
t-BuO2C
CO2Na
94% ee
+
MeO
O
B
t-BuO2C
25% Isomerised substrate - Inert to H2 conditions
SIPSY Conditions
MeO
(R)-MeOBIPHEP-Ru
S/C = 1,000
O
t-BuO2C
CO2Na
CO2Na
60 Psi, H2
50oC, THF/Water
MeO
O
t-BuO2C
CO2Na
99% ee, 92: 8 (A:B)
M. Bulliard et al. Org. Process Res. Dev. 2001, 5, 438
Screen for Asymmetric Hydrogenation Catalyst
MeO
MeO
H2, Chiral Catalyst
O
t-BuO2C
CO2Na
O
t-BuO2C
H
Catalyst System
[((+)-DIOPRh(COD)]Cl
[((R)-PROPHOS)Rh(COD)]Cl
[((S,S)-BPPM)Rh(COD)]Cl
[((S)-BINAP)Rh(COD)]Cl
[((R)-BINAP)Rh(COD)ClO4
[((S)-BINAP)2RuHCl]
[(R)-BINAP](p-cymene)RuCl]Cl
[((S,S)-Me-BPE)Rh(COD)]BF4
[((S,S)-Et-BPE)Rh(COD)]BF4
[((R,R)-i-Pr-BPE)Rh(COD)]BF4
[((R,R)-Me-DuPHOS)Rh(COD)]BF4
[((S,S)-Et-DuPHOS)Rh(COD)]BF4
MeO
H
CO2Na
O
t-BuO2C
CO2Na
H
H
A
B
Conf. ee[%] A:B
R
24
100:0
S
8
100:0
S
22
100:0
S
78
100:0
R
80
100:0
R
82
92:8
S
94
75:25
R
80
100:0
R
97
100:0
R
92
100:0
S
>99 100:0
R
99
100:0
Candoxatril: Me-DuPHOS-Rh-Catalysed Process
MeO
O
+
[(R,R)-Me-DuPHOS-Rh(COD)]
t-BuO2C
CO2Na
H2 (30-60 psi)
o
20 C
BF4-
MeO
O
t-BuO2C
CO2Na
>99 % ee
No Isomerization
MeOH
• Cationic (R,R)-Me-DuPHOS-Rh Found to be Superior
• S/C Ratio = 3500/1 (5000/1 readily obtainable)
• Reaction Time = 3 h
• Conversion = 100% (No Isomerization)
• Isolated Crude Yield = 97%
• Demonstrated on 12 kg Scale in Pfizer Pilot Plant
Joint Publication: J. Org. Chem. 1999, 64, 3290
Asymmetric Hydrogenation Route to Pregabalin
NH2
CO2H
Pregabalin
CN
Asymmetric Hydrogenation
CO2Et
CN
CO2X
CN
CO2Et
Asymmetric Hydrogenation
CN
CO2X
Pregabalin is a potent anticonvulsant in late stage clinical trials
A resolution route, that uses (S)-mandelic acid, has been reported
(Org. Process Res. Dev. 1997, 1, 26).
Classical Resolution Route to Pregabalin
CO2Et
CHO
+
CO2Et
CO2Et
CO2Et
HOAC
CN
KCN
n-Pr2NH
79-88%
EtO2C
CO2Et
Pregabalin Cyanodiester
CN
KOH
RaNi, H2
CO2K
NH+ -O2C
CO2H
NH2
72-83%
(S)-Mandelic Acid
CO2H
60-70% of Theory
30-35% actual wt
Ph
then recryst
NH2
CO2H
• 15 MT made for clinical trials
• Overall yield of 25% at best
• 4 isolated solids, 2 for resolution
(Org. Process Res. Dev. 1997, 1, 26).
Pregabalin – Substrate Synthesis
OH
O
+
DABCO, H2O
CN
CN
2,6-di-tert-butyl-4-methyphenol
97%
O
O
ClCO2Et, py
OEt
CN
CH2Cl2
Pd(OAc)2, PPh3
CN
EtOH, CO (300 psi)
CO2Et
o
50 C
95%
i) LiOH, H2O, THF
ii) HCl
iii) tert-BuNH2, EtOAc
83%
CN
CO2- +H3NtBu
89%
J. Org. Chem. 2003, 68, 5731
Successful Hydrogenation: Pregabalin
+
-
[(R,R)-Me-DuPHOS-Rh(COD)] BF4
S/C = 2,700
CN
CO2
- +
t
H3N Bu
H2 (50-60 psi), MeOH, 4 h
o
45 C
CN
CO2
- +
t
H3N Bu
>97 % ee
CN
CO2- +H3NtBu
>97 % ee
Ni, KOH, H2 (45 psi)
NH2
MeOH, H2O
CO2H
73% yield, 99.7 % ee
Pregabalin
•
•
•
•
Reduction in cost of goods and waste over resolution route
Improvement in throughput (Bill Kissel MPPCC, 2001)
Resolution route 25% yield, hydrogenation 50% overall yield
Collaborative Project Carried out with Pfizer, Holland, Michigan
Joint Paper J. Org. Chem. 2003, 68, 5731
Alternative Substrates: Pregabalin
CN
CO2- K+
[(R,R)-Me-DuPHOS-Rh(COD)]+BF4H2 (45 psi), MeOH
CN
-
+
CO2 K
97.5 % ee
CN
CO2Et
[(R,R)-Me-DuPHOS-Rh(COD)]+BF4H2 (45 psi), MeOH
CN
CO2Et
23 % ee
CN
CO2H
S/C = 3,200/1
2.5 hours
[(S,S)-Et-DuPHOS-Rh(COD)]+BF4-
S/C = 1,000/1
3 hours
CN
H2 (45 psi), MeOH
CO2H
56% ee
S/C = 100/1
100 hours
Noyori / Ikariya Hydrogenation Technology
K. Matsamura, S. Hashiguchi, T. Ikariya, R. Noyori et al, J. Am. Chem. Soc., 1997, 119, 8738
Ts
N
TRANSFER
HYDROGENATION
O
Ru
Cl
N
H2
(S/C 200/1)
OH
98% ee,
70% yield
KOH, iPrOH
T. Ohkuma, ... T. Ikariya, R. Noyori et al, J. Am. Chem. Soc., 1998, 120, 13529
OMe
Xyl Xyl
P Cl
H2
N
OMe
Ru
PRESSURE
HYDROGENATION
O
P Cl
Xyl Xyl
N
H2
(S/C 100,000/1)
(80 atm H2, 43h)

OH
97% ee,
100% yield
K2CO3, iPrOH
Licensed obtained in Dec 2000 from the Japan
Science and Technology Corporation
Mechanism of Noyori Hydrogenation
H2
P
Cl
H2
N
base
H2
P
Cl
N
H2
precatalyst
P

N
HH
R1
R

P
Ru
H
2
H2
N
H
Ru
Ru
P
H2
N
H
O
P
N
H
+
R1
R2
* H
OH
The substrate does not bind to the metal
Chiral environment created by both diphosphine and diamine
R. Noyori et al. J. Am. Chem. Soc. 2003, 125, 6510
Kilogram Scale Reactions
Xyl Xyl
P
Cl
H2
N
Ph
Ru
P
O
Cl
N
H2
Xyl Xyl
Ph
OH
109 mg
(S)-(R,R)-precatalyst,
S/C = 100,000/1
F
i-PrOH, 1 mol% t-BuOK
H2 30 - 100 psi
2h
1.38 Kg





F
1.31 Kg after distillation
Purity 99.3% by GC
98.3 % e.e.
PhanePhos-based ligand best
Substrate distilled before use
S/C 100,000 : 1 achieved
Catalyst removed by short path distillation
Another example at 100s kgs scale
Org. Lett. 2000, 2, 4173 and Org. Process Res. Dev. 2003, 7, 89
Dynamic Ketone Hydrogenation
MeO
MeO
O
Ar2
P
Cl
H2
N
Ph
Ru
P
Ar2
Cl
N
H2
Ph
OH
(S)-(R,R)-precatalyst,
N
HCl
S/C = 100,000/1
N
i-PrOH, t-BuOK
H2 600 psi
20h, rt
cis/trans 99:1, 97% ee





Catalyst loading of 200,000 demonstrated
Xyl-MeOBIPHEP gave 79% ee at S/C 1,000,000
9 Kg of product produced
Overall yield of route using asymmetric hydrogenation was 53%.
Discovery synthesis 3.5% overall yield
Roche, Org. Process Res. Dev. 2003, 7, 418
Asymmetric Hydrogenation of 2-Methylquinoxaline
N
N
i
H2, 30 bar, 50°C, PrOH, ca. 20 h,
t
t
0.05 eq. 1M BuOK in BuOH
Pre-catalysts (S/C 1000/1):
H
N
*
N
H
Me
Me
Ph2
P
Me
Cl
H2
N
Ru
Me
P
Ph2
Cl
N
H2
Me
Me
[(S)-HexaPHEMP.RuCl2.(S,S)-DACH]: 69% ee, >99% Conv.
[(S)-BINAP.RuCl2.(S,S)-DACH]:
61% ee, >99% Conv.
Patent: US 652868 and Adv. Synth. Catal., 2003, 345, 195-201.
Reduction of Imines
Et
N
P
H
N
Et Cl
Ru
Et
P
94% ee
N
H
Et Cl
H2
N
Cl
N
Tol2
P
P
Tol2
MeO
N
MeO
Ph2
P
Cl
62% ee
N
H2
Cl
H2
N
Ru
P
Ph2
Cl
Ph
Ru
N
H2
Ph
88% ee
Customer Example - Thiadiazine
Ph2 Cl
P
Ru
Cl
P
Ph2
O
O
S
N
N
H2
N
N
H2
Ph
Ph
[(R)-BINAP RuCl2 (R,R)-DPEN]
S/C = 2,500
t-BuOK, i- PrOH, Toluene
O
O
S
NH
N
H2 60 psi, 60 oC
97% Yield, 87% ee
Dowpharma/Oril Joint Publication: Tetrahedron Asymmetry 2003, 14, 3431
Ligands and Catalysts Available from Strem
R
R
R
R
R
P
P
P
Fe
P
P
R
R
R
PPh2
R
R
PPh2
P
R
R
DuPhos
BF4Et
P
Et
BF4Me
P
Rh
Et
P
FerroTANETM
BPE
Me
P
Me
Et
Xyl Xyl
BF4-
P
Rh
Et
Et
PhanePhos
Rh
Fe
Et
P
Cl
Et
Xyl Xyl
O
O
O
O
NH HN
NH HN
PPh2 Ph2P
PPh2 Ph2P
H
N
Ph
Ru
P
Me
Cl
P
O
O
NH HN
N
N
Trost Ligands
Many Dowpharma ligand and catalyst systems are available from
the Strem Chemical Catalogue for Research use only.
N
H
Ph
Conclusions
 A number of asymmetric hydrogenation processes have been
carried out on a manufacturing scale over the last 30 years
 Despite these successes, the technology is still not routinely used
for the manufacture of pharmaceutical intermediates
 With a greater number of catalyst systems available and a better
understanding of the process issues surrounding asymmetric
hydrogenation technology, we are starting to see increased
applications for this technology
 In this talk we have reviewed several case studies of successful
applications of asymmetric hydrogenation
 With a good understanding of catalyst selection, substrate purity,
solvent, temperature and pressure variables, it is relatively
straightforward to develop a successful process
 Security of supply of the catalyst is of paramount importance
Acknowledgements
Ulrich Berens
Frank Bienewald
Mark Burk
David Chaplin
Lee Boulton
Guy Casy
Chris Cobley
Will Hems
Julian Henschke
Daniela Herzberg
Nick Johnson
Pieter de Koning
Ray McCague
Christophe Malan
Graham Meek
Paul Moran
Justine Peterson
Chris Pilkington
Jim Ramsden
Simon Watkins
Andy Wildsmith
Antonio Zanotti
Analytical Team
Natasha Cheeseman
Paul Harrison
Catherine Hill
Jon Hill
Brendan Mullen
Pfizer
Steve Challenger
Nick Thomson
Tom Mulhern
Bill Kissel
Oril
Jean-Pierre Lecouve