Efficient synthesis of valsartan, a nonpeptide angiotensin II receptor antagonist

Article abstract of DOI:10.1055/s-2006-926234

A highly efficient and convergent approach to the synthesis of the angiotensin II receptor antagonist valsartan (1), one of the most important agents used in antihypertensive therapy today, is described. Directed ortho-metalation of 4-bromotoluene provides the key boronic acid intermediate 11 which was subjected to palladium-catalyzed Suzuki coupling. This method overcomes many of the drawbacks associated with the previously reported syntheses. The saponification of the methyl ester in valsartan was realized in a convenient and economical manner, which is more suitable for industrial production. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926234

LETTER
475
Efficient Synthesis of Valsartan, a Nonpeptide Angiotensin II Receptor
Antagonist
Synthesis of the
V
h
alsarta
n
en Zhang,a Guojun Zheng,b Lijing Fang,a Yulin Li*a
a
State Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000,
P. R. of China
Fax +86(931)8912283; E-mail: liyl@lzu.edu.cn
b
Zhejiang Hisun Pharmaceutical Co., Ltd, 46 Waisha Road, Taizhou 318000, P. R. of China
Received 28 October 2005
A-II antagonists (except the second kind) is the aryl–aryl
coupling reaction to form the biphenyl moiety. Previous
approaches to the synthesis of the requisite substitution
pattern have employed the Ullmann coupling between 4-
Abstract: A highly efficient and convergent approach to the syn-
thesis of the angiotensin II receptor antagonist valsartan (1), one of
the most important agents used in antihypertensive therapy today, is
described. Directed ortho-metalation of 4-bromotoluene provides
the key boronic acid intermediate 11 which was subjected to palla- iodotoluene and 2-iodobenzoate,6 nucleophilic aromatic
dium-catalyzed Suzuki coupling. This method overcomes many of
substitution at the ortho-position of a suitably activated
benzoic acid derivative,6,7 and Ni-catalyzed coupling of
the drawbacks associated with the previously reported syntheses.
The saponification of the methyl ester in valsartan was realized in a
(4-methylphenyl)magnesium bromide and 2-bromo-
convenient and economical manner, which is more suitable for
benzonitrile.8 The syntheses were then completed by the
industrial production.
conversion of carboxy equivalent to the tetrazole and
Key words: valsartan, antihypertensive therapy, directed ortho-
subsequent free-radical bromination of methyl group for
metalation, palladium-catalyzed Suzuki coupling, methyl ester
alkylation by the heterocycle. Problems with these
saponification
approaches have been (1) the need for highly toxic tri-
alkyltin azide in the conversion of the benzonitrile inter-
mediate to the tetrazole,9 (2) the nonselective and
Angiotensin II (A-II) is the principle pressor agent of the
moderately yielding free-radical bromination of a late
renin angiotensin system (RAS), which plays a critical
intermediate, (3) the use of expensive metallic species that
role in the regulation of blood pressure.1 Prevention of the
generate extremely dangerous metallic residues not only
formation of A-II, via inhibition of angiotensin converting
harmful to human health but also to the environment.
enzyme (ACE),2 has confirmed the therapeutic benefit of
inhibiting the RAS in hypertension and congestive heart
In designing an alternative synthesis of valsartan (1),10 our
goal was to minimize the use of expensive and hazardous
metals and increase the overall efficiency of the synthesis.
This was accomplished by reversing the order of the
major bond disconnections. We would now like to dis-
close this highly efficient and convergent synthesis of the
valsartan 1 in four linear steps with high overall yield
from the 4-bromotoluene.
failure. This has led to the design and discovery of the
nonpeptide A-II receptor antagonist valsartan 1.3
O
N
COOH
The first segment in our synthesis was the construction of
the 5-(2¢-bromophenyl)-2-triphenylmethyl-2H-tetrazole 4
(Scheme 1), which can be prepared from 2-bromo-
benzonitrile and sodium azide.11 A solution of 2-bromo-
benzonitrile, NH4Cl, NaN3 and LiCl in DMF was heated
and stirred for ten hours at 100 °C to afford the adduct 3
in 90% yield. Protection of the tetrazole was necessary
since the free tetrazole group acted as a potential ligand to
palladium reagents. The triphenylmethyl (trityl) group
was the best for a number of reasons: it can be easily
added and removed under mild conditions, it forms spe-
cifically one isomer at the N-2 position, and is inert to the
basic conditions of the coupling reaction. The tritylation
was carried out by addition of trityl chloride to a mixture
of 3 and Et3N in CH2Cl2 at 0 °C and then the reaction
mixture was stirred at room temperature for three hours
to produce the 5-(2¢-bromophenyl)-2-trityl-2H-tetrazole
(4, 90%).
N
N
NH
N
1
Figure 1 The structure of valsartan (1).
A-II antagonists have been divided into three categories,
a biphenyl imidazolylmethyl such as candesartan;4
a
monophenyl imidazolylmethyl such as eprosartan;5 and a
biphenyl without a heterocycle at the 4-position, such as
valsartan which is substituted with an N-(1-oxopentyl)-L-
valine and a tetrazole group at the 4-position and 2¢-posi-
tion, respectively. The key step in the syntheses of these
SYNLETT 2006, No. 3, pp 0475–0477
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926234; Art ID: W07405ST
© Georg Thieme Verlag Stuttgart · New York
1
5.
0
2.
2
0
0
6

476
C. Zhang et al.
LETTER
N
NCPh3
N
N
NH
N
2¢-yl)benzyl]-L-valine methyl ester (10, 82%). Second,
acylation of 10 with valeroyl chloride was conducted in
the presence of pyridine in CH2Cl2 at 0 °C to produce
the key intermediate N-pentanoyl-N-[4-(4¢,4¢,5¢,5¢-tetra-
methyl-1¢,3¢,2¢-dioxaborolan-2¢-yl)benzyl]-L-valine methyl
ester (11) for Suzuki coupling in 90% yield.
N
N
CN
Br
Br
Br
a
b
4
3
2
The last part is the biaryl coupling, which was conducted
with the borate ester 11 and the 5-(2¢-bromophenyl)-2-
trityl-2H-tetrazole (4) in the presence of Na2CO3 and
Pd(PPh3)4 at 80 °C for ten hours to afford the coupling
product 12 in 80% yield (Scheme 4). Deprotection of
tritylvalsartan (12) and the methyl ester saponification of
valsartan could be carried out with NaOH in one-pot man-
ner without isolation of intermediate to achieve the anti-
cipated product, valsartan (1) in almost 100% yield. To
our delight, hydrolysis of valeroyl amide functionality did
not occur during the saponification of the methyl ester by
carefully controlling the reaction conditions, by varying
the reaction temperature, the concentration of NaOH and
heating time.13
Scheme 1 Reagents and conditions: (a) NH4Cl, NaN3, LiCl, DMF,
100 °C, 90%; (b) Ph3CCl, Et3N, CH2Cl2, 90%.
The second segment of our synthesis was the construction
of
2-[4¢-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (8, Scheme 2). First, magnesium,
iodine and 1,2-dibromoethane were added sequentially to
the 4-bromotoluene (5) in THF and the mixture was re-
fluxed for one hour. Then trimethyl borate ester was add-
ed at –78 °C and stirred for two hours at the same
temperature to afford the 2,4,6-tris(tolyl)-1,3,5,2,4,6-tri-
oxatriborinane (6, 80%). Second, the mixture of 6 and pi-
nacol in cyclohexane was refluxed for ten hours to remove
water and then the 4,4,5,5-tetramethyl-2-p-tolyl-1,3,2-di-
oxaborolane (7) was obtained in 84% yield. Third, com-
pound 7, NBS and AIBN in cyclohexane were refluxed
for five hours to provide the key intermediate 8 (86%).
O
a
b
+
4
11
1
N
COOCH3
Br
N
N
N
c
a
b
Ph3CN
B
B
B
12
O
B
O
B
O
O
O
O
Br
Scheme 4 Reagents and conditions: (a) Na2CO3, Pd(PPh3)4, tolu-
ene, H2O, 80 °C, 80%; (b) (i) 1 N NaOH (or p-TsOH), MeOH, reflux;
(ii) 3 N NaOH, MeOH, reflux, 98%.
O
8
5
6
7
Scheme 2 Reagents and conditions: (a) Mg, I2, 1,2-dibromoethane,
THF, reflux, then –78 °C, B(OCH3)3, 80%; (b) pinacol, cyclohexane,
reflux, 84%; (c) NBS, AIBN, cyclohexane, reflux, 86%.
In summary, a greatly efficient and convergent approach
to the biphenyltetrazole structure of the A-II antagonists
has been developed by employing a combination of the di-
rected ortho-metalation and Suzuki coupling methods.
Application of this approach provided a practical proce-
dure to the synthesis of valsartan, which is a potent, orally
active, nonpeptide antagonist of the angiotensin II AT1-
receptor subtype.
The third part is the preparation of the key intermediate 11
for Suzuki coupling (Scheme 3).12 First, L-valine methyl
ester hydrochloride (9), K2CO3 and 2-[4¢-(bromometh-
yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8) in
DMF were allowed to heated at 80 °C for three hours to
give N-[4-(4¢,4¢,5¢,5¢-tetramethyl-1¢,3¢,2¢-dioxaborolan-
a
O
b
N
COOCH3
HClH2N
COOCH3
HN
COOCH3
O
O
B
B
O
O
9
10
11
Scheme 3 Reagents and conditions: (a) K2CO3, compound 8, DMF, 80 °C, 82%; (b) valeroyl chloride, pyridine, CH2Cl2, 0 °C, 90%.
Synlett 2006, No. 3, 475–477 © Thieme Stuttgart · New York

LETTER
Synthesis of the Valsartan
477
(13) Experimental Procedure and Spectroscopic Data of the
Key Compounds: N-Pentanoyl-N-{[2¢-(2N-trityl-
tetrazole-5-yl)(1,1¢-biphenyl)-4-yl]methyl}-L-valine
Methyl Ester (12).
Acknowledgment
We are grateful for the financial support of the National Natural
Science Foundation of China (Grant No. 20272021).
A mixture of toluene (4.5 mL) and H2O (2 mL) was degassed
by vacuum/nitrogen purges (3×). N-pentanoyl-N-[4-
(4¢,4¢,5¢,5¢-tetramethyl-1¢,3¢,2¢-dioxaborolan-2¢-yl)benzyl]-
L-valine methyl ester (11) (1.03 g, 2.4 mmol), 5-(2¢-
bromophenyl)-2-trityl-2H-tetrazole (4, 934 mg, 2 mmol),
Na2CO3 (424 mg, 4 mmol) and Pd(PPh3)4 (115 mg) were
added. This mixture was degassed (3×) and the reaction
mixture was heated at 80 °C under a nitrogen atmosphere for
10 h. Then the resulting mixture was extracted by EtOAc
(3 × 50 mL), washed with H2O and brine, dried over anhyd
Na2SO4 and filtered. Evaporation of the solvent followed by
flash column chromatography on silica gel (hexane–Et2O,
2:1) to obtain the coupling product 12 as a colorless oil (1.32
g, 80%). [a]D24 –35 (c 8, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 0.79–0.99 (m), 1.16–1.78 (m), 2.13–2.35 (m),
3.28 (s), 3.35 (s, 3H, OCH3), 4.00 (d, J = 11 Hz), 4.19 (d,
J = 15 Hz), 4.52 (s, 2 H, CH2Ar), 4.81–4.90 (m), 6.97–7.52
(m), 7.81–7.87 (m). 13C NMR (75 MHz, CDCl3): d = 13.87,
18.77, 19.98, 22.36, 27.49, 27.71, 33.33, 45.34, 48.44,
51.53, 61.90, 65.80, 82.85, 125.57, 126.29, 127.63, 128.22,
128.91, 129.42, 130.18, 130.44, 130.73, 135.70, 136.73,
140.08, 141.24, 141.53, 164.16, 170.28, 170.99, 174.47. MS
(FAB): m/z calcd [M+]: 691; found: 714 [M + Na+]. IR
(film): nmax = 3061, 2961, 2872, 2246, 1740, 1651, 1468,
1448, 1204, 1029, 1006, 910, 733, 701, 641 cm–1.
References and Notes
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N-Pentanoyl-N-{[2¢-(1H-tetrazole-5-yl)(1,1¢-biphenyl)-4-
yl]methyl}-L-valine (1)
N-Pentanoyl-N-{[2¢-(2N-trityl-tetrazole-5-yl)(1,1¢-
biphenyl)-4-yl]methyl}-L-valine methyl ester (12) (150 mg,
0.22 mmol) was added 1 N NaOH (1 mL) or p-TsOH (10
mg) in MeOH (3 mL) and refluxed for 1 h to remove the
protecting trityl group, then 3 N NaOH (1 mL) was added to
the reaction and the mixture continued to reflux for another
8 h. Subsequently, the MeOH was removed under reduced
pressure and the residue was diluted with EtOAc (100 mL)
and distilled H2O (20 mL). Concentrated HCl was added
dropwise into the mixture until the pH reached to 3.0. Then
the organic phase was separated and the aqueous phase was
extracted by EtOAc (3 × 50 mL). The combined organic
extracts were dried over anhyd Na2SO4 and filtered.
Evaporation of the solvent gave the crude product (92 mg,
98%) and the anticipated product, valsartan (1) was
recrystallized from EtOAc; mp 116–117 °C; [a]D24 –63 (c 3,
MeOH). 1H NMR (400 MHz, CD3OD): d = 0.77–0.90 (m,
CH3), 0.92–0.99 (m, CH3), 1.00–1.12 (m, CH3), 1.21–1.33
(m, CH2), 1.35–1.43 (m, CH2), 1.44–1.59 (m, CH2), 1.63–
1.67 (m, CH2), 2.14–2.37 (m), 2.49–2.55 (m), 2.60–2.68
(m), 3.30–3.34 (m), 4.11–4.13 (m), 4.57–4.79 (m), 7.00–
7.24 (m, 4 H, Ar), 7.50–7.62 (m, 2 H, Ar), 7.63–7.65 (m, 2
H, Ar). 13C NMR (100 MHz, CD3OD): d = 14.17, 19.29,
19.43, 20.03, 20.59, 23.28, 23.35, 28.40, 28.51, 29.13,
34.35, 34.44, 47.35, 50.59, 64.95, 67.88, 124.09, 124.26,
127.75, 128.63, 128.81, 128.94, 129.77, 130.29, 131.58,
131.76, 132.45, 138.66, 138.85, 139.41, 139.61, 143.01,
143.14, 156.56, 156.68, 172.88, 173.51, 176.91, 177.12.
MS (FAB): m/z calcd [M+]: 435; found: 436 [M + H+], 458
[M+ + Na]. IR (KBr): nmax = 3430, 3116, 2963, 2933, 2873,
2745, 2615, 1733, 1602, 1472, 1410, 1274, 1205, 1163,
1106, 1054, 998, 938, 853, 814, 759, 683, 623, 561,
519 cm–1.
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Synlett 2006, No. 3, 475–477 © Thieme Stuttgart · New York