Synthesis of enantiopure (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid-a key intermediate for the preparation of Aliskiren

Article abstract of DOI:10.1016/j.tetlet.2008.07.150

The enantioselective hydrogenation of (E)-2-(4-methoxy-3-(3-methoxypropoxy)-benzylidene)-3-methylbutanoic acid (1) to (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid (2)-a key intermediate in the synthesis of the pharmacologically important renin inhibitor Aliskiren-is described. The stereochemistry of the catalytic transformation has been studied using a number of homogeneous chiral Rh(I) and Ru(II) complexes bearing ferrocene-based phosphine ligands. The highest enantioselectivity for the homogeneous hydrogenation of 1 (up to 95% ee) was achieved with a [Rh(NBD)₂]BF₄ pre-catalyst (substrate/catalyst ratio 100:1, 10 bar H₂, 40 °C, in MeOH). To bring the enantioselectivity to perfection an effective method for the isolation of the enantiopure carboxylic acid is suggested likewise.

Full text of DOI:10.1016/j.tetlet.2008.07.150

Tetrahedron Letters 49 (2008) 5980–5982
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of enantiopure (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-
methylbutanoic acid—a key intermediate for the preparation of Aliskiren
a,*
a
b
c
a,d,*
Natalia Andrushko , Vasyl Andrushko , Thomas Thyrann , Gerd König , Armin Börner
a
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Ratiopharm Schweiz AG, Pelikanweg 2, 4054 Basel, Switzerland
Ratiopharm GmbH, Graf-Arco-Str. 3, 89070 Ulm, Germany
Institut für Chemie der Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective hydrogenation of (E)-2-(4-methoxy-3-(3-methoxypropoxy)-benzylidene)-3-meth-
ylbutanoic acid (1) to (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid (2)—a
key intermediate in the synthesis of the pharmacologically important renin inhibitor Aliskiren—is
described. The stereochemistry of the catalytic transformation has been studied using a number of homo-
geneous chiral Rh(I) and Ru(II) complexes bearing ferrocene-based phosphine ligands. The highest
enantioselectivity for the homogeneous hydrogenation of 1 (up to 95% ee) was achieved with a
Received 25 June 2008
Revised 28 July 2008
Accepted 29 July 2008
Available online 5 August 2008
2 4 2
[Rh(NBD) ]BF pre-catalyst (substrate/catalyst ratio 100:1, 10 bar H , 40 °C, in MeOH). To bring the
enantioselectivity to perfection an effective method for the isolation of the enantiopure carboxylic acid
is suggested likewise.
Ó 2008 Elsevier Ltd. All rights reserved.
Ò
Ò
Aliskiren (trade-names Tekturna , Rasilez ) represents the first
drug on the market being constituent of a novel class of renin
inhibitors with a huge potential for treatment of hypertension
and related cardiovascular diseases.1 Renin is an important en-
zyme at the beginning of the renin angiotensin system (RAS), one
of the key regulators of blood pressure. Efficient renin inhibitors
decrease the plasma renin activity and reduce the production of
angiotensin I from angiotensinogen. In this view, Aliskiren is a
highly efficient, nonpeptidic, orally administered drug. Currently,
the development of more efficient and alternative methods for
the synthesis of this compound is in the focus of several pharma-
ceutical companies. One of the key steps is the stereoselective
generation of the enantiopure building block A.
In this connectivity, herein we describe our results for the
production of enantiopure (R)-2-(4-methoxy-3-(3-methoxyprop-
oxy)-benzyl)-3-methylbutanoic acid (2) by asymmetric hydro-
genation of (E)-2-(4-methoxy-3-(3-methoxypropoxy)-benzylidene)-
3-methylbutanoic acid (1) (Scheme 1). The chiral acid can be
employed for the synthesis of Aliskiren. The hydrogenation was
already investigated by some other research groups. In best cases
up to 95% ee at S/C ratios of >5000 were reported. However, the
broad application of these protocols is hampered by the inaccessi-
bility of some chiral ligands used. Moreover, the frequently faced
problem how to proceed with hydrogenation products of low
enantioselectivity is not clear.
In order to identify efficient hydrogenation conditions we
screened the reaction in the presence of a set of rhodium and
ruthenium catalysts bearing several commercially available chiral
ferrocene-based phosphine ligands (I–XII). The results of the
hydrogenation are summarized in Table 1. Most reactions were
2
,3
OH
H
H N
2
N
NH2
O
O
O
O
O
2 4
conducted by using a commercially available [Rh(NBD) ]BF com-
plex as a precursor. It was mixed with 1.2 equiv of the chiral
diphosphine prior to the hydrogenation.
A
Aliskiren
The hydrogenation catalyzed by these Rh-catalysts proceeded
smoothly at 40 °C in MeOH with an initial H
2
-pressure of 10 bar.
or related
Remarkably, other Rh-precursors like [RhI (p-cymene)]
2
2
Ru-complexes provided low ee (<42%). Moreover, catalysts were
less active. The most efficient system for the production of
optically pure (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-
*
Corresponding authors. Tel.: +49 381 1281 192 (N.A.); tel.: +49 381 1281 202;
fax: +49 0381 1281 5202 (A.B.).
E-mail addresses: natalia.andrushko@catalysis.de (N. Andrushko), armin.
boerner@catalysis.de (A. Börner).
3
-methylbutanoic acid was noted in the reaction with a Rh-
complex based on (R)-(R)-PPPhFCHCH P((3,5-CF Ph) (I) as chiral
3
3
)
2
2
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.150

N. Andrushko et al. / Tetrahedron Letters 49 (2008) 5980–5982
5981
1
. (S)-(-)-α-methyl-
O
H , Ligand,
O
benzylamine, Et2O,
one crystallization
O
2
Rh complex
RO
RO
RO
OH
OH
OH
4
0ºC, MeOH,
2. HCl (1N), Et O
2
MeO
overnight
MeO
MeO
1
2 (95% ee)
(R)-2 (>99% ee)
R =(CH ) OMe
2
3
Scheme 1. Asymmetric hydrogenation and kinetic resolution.
MeO
OMe
F3C
CF3
CF3
F3C
F3C
CF3
F3C
CF3
CF3
P
P
P
P
P
P
OMe
MeO
Me
Fe
Fe
Me
Fe
Me
H
H
H
F3C
CF3
)-PPPhFCHCH P((3,5-CF ) Ph)
2
CF3
(
(
S )-(S
)-(3,5-Me-4-MeOPh) PPhFCHCH P-
3,5-CF Ph)2
(
R)-(R
(R)-(R
)-(3,5-Me-4-MeOPh)2PPhFCHCH3P(3,5-CF3Ph)2
2
3
3
3 2
3
I
II
III
F3C
CF3
NMe2
F3C
P
NMe2
NMe2
H
P
P
H
H
Fe
F3C
Fe
P
Fe
CF3
H
H
H
NMe2
P
NMe2
NMe2
P
F3C
CF3
CF3
(R)-(S
)-NMe -PPh -Mandyphos
(R)-(
S
)-NMe -PCy -Mandyphos
2
2
2
2
(
R)-(S)-NMe -P(3,5-CF Ph) -Mandyphos
2
3
2
IV
V
VI
OMe
F3C
CF3
CF3
NMe2
NMe2
H
NMe2
H
MeO
P
P
P
H
Fe
P
Fe
P
CF3
Fe
F3C
F3C
H
H
NMe2
H
NMe2
NMe2
P
OMe
CF3
F3C
MeO
(S )-(
R
)-NMe -P(3,5-CF Ph) -Mandyphos
(R)-(S
)-NMe -P(3,5-Me-4-MeOPh) -Mandyphos
2
2
(R)-(S
)-NMe2-PXyl2-Mandyphos
2
3
2
VII
VIII
IX
Me N
H
Me2N
H
2
MeO
P
P
Fe
Fe
P
P
P
Fe
H
Me
P
H
H
Me N
Me N
2
2
MeO
(
S)-(R)-NMe -PXyl -Mandyphos
(R)-(S
)-(3,5-Me -4-MeOPh) PFPXyl
2
2
(S)-(R
)-NMe -P(
o
-Tol) -Mandyphos
2
2
2
2
2
X
XII
XI

5
982
N. Andrushko et al. / Tetrahedron Letters 49 (2008) 5980–5982
Table 1
Asymmetric hydrogenation of (E)-2-(4-methoxy-3-(3-methoxypropoxy)-benzylidene)-3-methylbutanoic acid according to Scheme 1
Ligand
Metal complex
Metal:ligand:substrate ratio
Pressure (bar)
Conc. (mol/l)
Conv.a (%)
eeb (%), Conf.
I
I
I
I
I
I
II
III
IV
V
VI
VII
VIII
VIII
IX
X
XI
XII
VIII
VIII
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
[Rh(NBD)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
1:1.2:25
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
50
0.1
0.1
0.1
0.2
0.5
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
100
100
100
100
100
72
100
100
66
100
24
22
100
24
100
100
100
24
62
100
91(R)
94(R)
94(R)
95(R)
90(R)
77(R)
90(R)
94(S)
27(R)
3(R)
68(R)
49(S)
69(R)
61(R)
66(R)
65(S)
61(R)
8(R)
1:1.2:100
1:1.2:500
1:1.2:100
1:1.2:100
1:1.2:500
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:100
1:1.2:25
c
c
[RhI
[RhI
2
(p-cymene)]
(p-cymene)]
2
16(S)
42(S)
2
2
1:1.2:25
a
Conversion was detected by 1H NMR.
Ratio of enantiomers was estimated by using HPLC.
The reaction was completed within 1 h.
b
c
Table 2
(E)-2-(4-methoxy-3-(3-methoxy-propoxy)-benzylidene)-3-meth-
ylbutanoic acid.
Enantiomeric enrichment of acid 2
ee of the crude hydrogenation
product (%)
Times of
recrystallization
Yield after
recrystallization (%)
a
References and notes
9
9
7
5
0
0
1
2
3
90
75
38
1
.
(a) Uresin, Y.; Mehtar Bozkurt, M.; Sabirli, S.; Ozunal, Z. G. Expert Rev. Cardiovasc.
Ther. 2007, 5, 835–849; (b) Lam, S.; Choy, M. Cardiol. Rev. 2007, 15, 316–323; (c)
Frampton, J. E.; Curran, M. P. Drugs 2007, 67, 1767–1792; (d) Gradman, A. H.;
Traub, D. Rev. Cardiovasc. Med. 2007, 8, S22–S30.
(a) Chen, W.; McCornack, P. J.; Mohammed, K.; Mbafor, W.; Roberts, S. M.;
Whittall, J. Angew. Chem., Int. Ed. 2007, 46, 4141–4144; (b) Sturm, T.;
Weissensteiner, F.; Spindler, F. Adv. Synth. Catal. 2003, 345, 160–164; (c)
McCormack, P.; Chen, W.; Mohammed, K. WO 2006075177 A1, 2006; Chem.
Abstr. 2006, 145, 166866; (d) McCormack, P.; Chen, W.; Whittall, J. WO 2006/
a
In order to achieve >99% ee.
2
.
ligand. At a preparative substrate/catalyst ratio of 100:1 an ee by
up to 95% was achieved, and the reaction was complete within
1
075166 A1, 2006; Chem. Abstr. 2006, 145, 167412; (e) Hettche, F.; Völkert, M.;
4
Jäkel, C. WO 2006/097314 A1, 2006; Chem. Abstr. 2006, 145, 377060.
h.
3
4
.
.
(a) Boogers, J. A. F.; Felfer, U.; Kotthaus, M.; Lefort, L.; Steinbauer, G.; De Vries, A.
H. M.; De Vries, J. G. Org. Process Res. Dev. 2007, 11, 585–591; (b) De Vries, J. G.;
Lefort, L. Chem. Eur. J. 2006, 12, 4722–4734; (c) Jackson, P. M.; Lennon, I. C.; Fox,
M. E. WO 2007123957 A2, 2007; Chem. Abstr. 2007, 147, 486549.; (d) Chen, W.;
Spindler, F.; Pugin, B. WO 2007116081 A1, 2007; Chem. Abstr. 2007, 147,
469465; (e) Herold, P.; Stutz, S. WO 2002002500 A1, 2002; Chem. Abstr. 2002,
In order to enhance the optical purity of the reaction product
the crude hydrogenation product was recrystallized with (S)-(À)-
-methyl benzylamine as a base.5 Already one crystallization is
a
sufficient to provide the free carboxylic acid 2 with >99% ee (Table
2
uct of 95% ee. Two crystallizations are required for a mixture of 90%
ee of stereoisomers 2 in order to obtain perfect enantioselectivity,
for a hydrogenation product of 60–70% ee three crystallizations
were required. The acidification reaction with hydrochloric acid
proceeded fast, smoothly, and without prior purification of the
salt.
In conclusion a new protocol for the preparation of enantio-
meric pure (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-
methylbutanoic acid was found based on the enantioselective
Rh-catalyzed hydrogenation or/and the subsequent enantiomeric
enrichment of a product with poor enantioselectivity.
1
36, 85662.
Under argon
.008 mmol), 4 ml of methanol, and (R)-(R)-PPPhFCHCH
) after acidification of the salt derived from a hydrogenation prod-
a
25 ml flask was charged with [Rh(NBD)
2
]BF
4
(3.0 mg,
Ph)
2
0
3
P((3,5-CF
3
)
2
(8.96 mg, 0.0096 mmol). The resulting mixture was vigorously stirred for
30 min at room temperature and then was added to a solution of (E)-2-(4-
methoxy-3-(3-methoxypropoxy)-benzylidene)-3-methylbutanoic acid. (246.7 mg,
6
0
.8 mmol) in 4 ml of methanol. The reaction mixture was placed into a 12 ml
autoclave equipped with a magnetic stirring bar. The autoclave was flushed 3
times with H and pressurized to 10 bar. The reaction mixture was stirred at
0 °C for 1 h. After cooling to rt and releasing of the excess H , the solvent was
7
2
4
2
evaporated and 2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic
acid (95% ee) was obtained.
5. A similar method was applied in a preparative scale for the purification of R-(À)-
ibuprofen: Trung, T. Q.; Kim, J. M.; Kim, K. H. Arch. Pharm. Res. 2006, 29, 108–111.
6
.
.
To the solution of acid 2 (95% ee) (235 mg, 0.76 mmol) in 3 ml of diethyl ether
was added at room temperature dropwise -methyl
a
solution of (S)-(À)-a
benzylamine (96.3 mg, 0.8 mmol) in 2 ml of diethyl ether. The solution was
cooled and allowed to stand in the fridge overnight. Crystals formed were
filtered off and dried.
Acknowledgments
7
To the salt (100 mg, 0.23 mmol) in 4 ml of diethyl ether was added 1 N aqueous
HCl, and the mixture was vigorously shaken. Then the organic layer was
separated and three times extracted with diethyl ether. Combined organic
The authors are grateful to ratiopharm GmbH (Ulm) for finan-
cial support of this work and Ratiochem Ltd (Brno) for providing
4
extracts were dried with MgSO , filtered off, and evaporated.