Improved synthesis of valsartan via nucleophilic aromatic substitution on aryloxazoline

Article abstract of DOI:10.1080/00397910902840819

A highly efficient approach to the synthesis of the angiotensin II receptor antagonist valsartan (Diovan), one of the most important agents used in antihypertensive therapy today is described. The formation of the aryl-aryl bond represents the key step of its synthesis, which has been done by simple nucleophelic aromatic substitution on aryloxazoline with good yield and purity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910902840819

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Improved Synthesis of
Valsartan via Nucleophilic
Aromatic Substitution on
Aryloxazoline
a
a
Samir Ghosh , A. Sanjeev Kumar , R.
a
a
Soundararajan & G. N. Mehta
a
Applied Chemistry Department , Sardar
Vallabhbhai National Institute of Technology , Surat,
India
Published online: 07 Oct 2009.
To cite this article: Samir Ghosh , A. Sanjeev Kumar , R. Soundararajan & G.
N. Mehta (2009) Improved Synthesis of Valsartan via Nucleophilic Aromatic
Substitution on Aryloxazoline, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:21, 3880-3887, DOI:
10.1080/00397910902840819
To link to this article: http://dx.doi.org/10.1080/00397910902840819
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1
Synthetic Communications , 39: 3880–3887, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902840819
Improved Synthesis of Valsartan via Nucleophilic
Aromatic Substitution on Aryloxazoline
Samir Ghosh, A. Sanjeev Kumar, R. Soundararajan,
and G. N. Mehta
Applied Chemistry Department, Sardar Vallabhbhai National Institute of
Technology, Surat, India
Abstract: A highly efficient approach to the synthesis of the angiotensin II
receptor antagonist valsartan (Diovan), one of the most important agents used
in antihypertensive therapy today is described. The formation of the aryl–aryl
bond represents the key step of its synthesis, which has been done by simple
nucleophelic aromatic substitution on aryloxazoline with good yield and purity.
Keywords: Antihypertensive therapy, nucleophilic aromatic substitution, oxazoline,
valsartan
INTRODUCTION
Angiotensin II (A-II) is the principle pressor agent of the renin angioten-
sin system (RAS), which plays a critical role in the regulation of blood
[
1]
pressure. Prevention of the formation of A-II, via inhibition of angio-
[2]
tensin converting enzyme (ACE), has confirmed the therapeutic benefit
of inhibiting the RAS in hypertension and congestive heart failure. This
has led to the design and discovery of the nonpeptide A-II receptor
[3]
antagonist valsartan 1.
Hypertension is one of the most prevalent diseases in developed
countries, with an estimated 1 billion cases worldwide, conferring to its
treatment enormous social and economic importance. The therapeutic
Received November 12, 2008.
Address correspondence to R. Soundararajan, Applied Chemistry Department,
SVNIT, Surat 395 007, India. E-mail: soundara1959@yahoo.com
3
880

Improved Synthesis of Valsartan
3881
Figure 1. Valsartan (1).
standard was significantly improved in the 1980s by the introduction of
[4]
losartan (Lorzaar, Merck) as the first nonpeptidic A-II receptor
antagonist. An entire therapeutic class, the sartans, has since been devel-
oped, among which valsartan (1; Diovan, Novartis: US $4.2 billion sales
in 2006) (Fig. 1) currently holds the largest market share.
In designing an alternative synthesis for valsartan 1, our goal was to
0
develop a robust and economic route for valsartan 1 and 2 -(4,4-
dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-carbaldehyde 14 by mini-
mizing the use of expensive chemicals and increasing the overall
efficiency of the synthesis. We now disclose this highly efficient and
industrially viable process for the synthesis of valsartan 1, with good overall
yield.
The structural element, a biphenyl unit, is essential for the binding
affinity to the receptor and for oral bioavailability. The formation of
its aryl–aryl bond represents the key step in the synthesis of sartans:
[
5]
[6]
whereas for the synthesis of losartan, the use of Negishi and Ullmann
couplings is described in the literature, but the published methods for the
[
7]
preparation of valsartan make use of Suzuki–Miyaura couplings. The
principal synthetic pathways leading to valsartan are depicted in
Scheme 1. In route A, 2-chlorobenzonitrile (2) and 4-tolylboronic acid
0
(3) are coupled to give 2-cyano-4 -methylbiphenyl (4), which is then bro-
minated and reacted with L-valine methyl ester (5) to give N-
0
[
(2 -cyanobiphenyl-4-yl)methyl]-L-valine methyl ester (6). Alternatively,
can be obtained via the coupling of 4-bromobenzaldehyde (8) with a
6
boronic acid derivative (e.g., 7), followed by reductive amination with
L-valine methyl ester (5) (route B). Route C results from a combination
of both approaches, in which the sensitive formyl group in biaryl 9 is
generated by oxidation of the more robust derivative 4.
DISCUSSION
The main shortcoming common to these syntheses originates from the
use of expensive boronic acid substrates and palladium catalyst in the

3882
S. Ghosh et al.
Scheme 1. Reported synthetic scheme for valsartan. Reagents and conditions: (a)
n
Pd-cat., K CO , H O, TBAB, D, 2 d, 69%; (b) NBS, 70–90%; (c) BuCOCl, Et N,
2
3
2
3
NaN , nBu SnCl, NaOH, 60–85%; (d) NBS, NaOAc=AcOH, NaOH, Swern
3
3
ꢀ
3 2 3
oxidation; (e) NaBH CN, no yield reported; (f) Pd-cat., K CO , 100 C, 73%.
cross-coupling step. We believed that we could overcome this weakness
with the biaryl synthesis recently developed in our group. This method
overcomes many of the drawbacks, such as use of expensive boronic acid
reagent and Pd catalyst as well, which results in the palladium content in
the final active pharmaceutical ingredient (API) associated with the
previously reported synthesis.
In our approach, shown in Scheme 2, inexpensive and commercially
available O-anisic acid (10) was treated with thionyl chloride for the
formation of acid chloride, which was treated with 2-amino-2-methyl
propane-1-ol (11) to get the amide. This was further treated with thionyl
[
8]
chloride to get oxazoline compound (12). This oxazoline compound
12) was treated with [4-(dimethoxymethyl) phenyl] magnesium bromide,
which was prepared from 1-bromo-4-(dimethoxymethyl) benzene (13)
(
using magnesium as a metal and a catalytic amount of I for the initiation
2
of the reaction. The nucleophelic aromatic substitution on aryloxazoline is
the key step of the synthesis. The coupled compound was taken in tetra-
hydrofuran (THF), and 1 N was added HCl and stirred at rt for 4 h to
0
get 2 -(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-carbaldehyde (14).
0
This 2 -(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-carbaldehyde
(14) was taken in methanol, and L-valine methyl ester hydrochloride was
added followed by sodium cyano borohydride at reflux condition for

Improved Synthesis of Valsartan
3883
Scheme 2. Modified synthetic scheme for valsartan. Reagents and conditions: (a)
ꢀ
SOCl
2
, DCM, rt, 95%; (b) Mg, THF, I
ester hydrochloride, NaBH CN, Et N, MeOH, 70 C, 90%; (d) pyridine, DCM,
2
, 70 C, 1(N) HCl, 85%; (c) L-valine methyl
ꢀ
3
3
ꢀ
ꢀ
0
3 3 3
C, 90%; (e) POCl , pyridine, 85 C, 14 h, 90%; (f) NaN , Bu SnCl, NaOH.
0
2
amino}-3-methyl-butyric acid methyl ester (15). The 2-{[2 -(4,4-dimethyl-
h to get 2-{[2 -(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-ylmethyl]-
0
4
acid methyl ester (15) was taken in dichloromethane, and valeryl chlor-
,5-dihydro-oxazol-2-yl)-biphenyl-4-ylmethyl]-amino}-3-methyl-butyric
0
ide followed by pyridine was added to get 2-{[2 -(4,4-dimethyl-4,
-dihydro-oxazol-2-yl)-biphenyl-4-ylmethyl]-pentanoyl-amino}-3-methyl-
5
0
butyric acid methyl ester (16). The 2-{[2 -(4,4-dimethyl-4,5-dihydro-
oxazol-2-yl)-biphenyl-4-ylmethyl]-pentanoyl-amino}-3-methyl-butyric
acid methyl ester (16) was taken in pyridine, and phosphorous oxychlor-
ꢀ
ꢀ
0
ide was added at 0 C and heated at 85 C to get 2-[(2 -cyano-biphenyl-
4
Valsartan can be synthesized by sodium azide and tributyl tin chloride.
-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester (17).
[
9]
In summary, a highly efficient approach to the biphenyltetrazole
structure of the A-II antagonists has been developed by employing a
nucleophelic aromatic substitution on aryloxazoline, which is commer-
cially viable and suitable to plant scale. Application of this approach
provided an industrial viable procedure for the synthesis of valsartan,
which is a potent, orally active, nonpeptide antagonist of the angiotensin
II AT1-receptor subtype.

3884
S. Ghosh et al.
EXPERIMENTAL
Materials and Instruments
All solvents and reagents were purchased from the suppliers and used
without further purification. All nonaqueous reactions were performed
in dry glassware under an atmosphere of dry nitrogen. Organic solutions
were concentrated under reduced pressure. Thin-layer chromatography
(TLC) was performed on Merck precoated silica-gel 60F
1
plates. H
2
54
1
3
and C NMR spectra were recorded in dimethylsulfoxide (DMSO-d6)
and CDCl3 on a Varian Gemini 400-MHz Fourier transform (FT)
NMR spectrometer. The chemical shifts were reported in d ppm relative
to tetramethylsilane (TMS). The mass spectra were recorded on
Shimadzu LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS=MS
instruments.
0
2
-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-carbaldehyde (14)
An oven-dried flask equipped with an internal thermometer, a dropping
funnel filled with molecular sieves, and a condenser was charged with
magnesium metal (0.7 g, 29.25 mmol), iodine (1 pinch), and 0.5 ml of
1
-bromo-4-(dimethoxymethyl) benzene (13) in dry tetrahydrofuran
ꢀ
(THF; 10 ml). The reaction mixture was heated at 70 C for 30 min. Iodine
color was dispersed, and initiation was observed. Then the rest of the
-bromo-4-(dimethoxymethyl) benzene (5 g, 24.39 mmol) in THF (50 ml)
1
was added slowly dropwise and vigorously refluxed the reaction mass.
The refluxation was continued for another 2 h. The reaction mixture
was cooled down to rt and transferred via cannula to the oxazoline com-
ꢀ
pound (2 g, 9.7 mmol) (12) in THF (40 ml) at 56 C. The reaction mixture
was stirred at the same temperature for 16 h. The reaction mixture was
monitored by thin-layer chromatography (TLC), and no starting material
ꢀ
was left. The reaction mass was cooled down to 0–5 C, and 1.5 N dilute
aq. HCl (20 ml) was added to quench the reaction mixture, which was
stirred for 1 h. The reaction mixture was washed with methyl tert-butyl
ether (MTBE) (2 ꢁ 50 ml) to remove small impurities. The aq. layer
was basified to pH ꢂ7 with 10% aq. NaHCO solution, extracted with
3
ethyl acetate (2 ꢁ 50 ml), and washed with water. Removal of the solvent
0
10]
afforded the 2 -(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-carbal-
dehyde (14)
[
1
as an oil (2.3 g, 85% yield). H NMR (400 MHz,
DMSO-d ) d 10.00 (s, 1H) 7.42–7.91 (m, 8H), 3.76 (s, 2H), 1.12 (s,
6
1
3
6
H). C NMR (DMSO-d ) d 28.09, 68.06, 78.95, 128.05, 128.51,
6
1
29.53, 129.69, 130.41, 130.57, 131.22, 135.38, 140.29, 147.00, 161.88,

Improved Synthesis of Valsartan
3885
1
93.28. ESIMS: m=z calcd. [Mþ]: 279; found: 280 [M þ Hþ]. HRMS
(
ESI): m=z calcd. [Mþ]: 279; found: 280.07 [M þ Hþ].
0
2
-{[2 -(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-ylmethyl]-
amino}-3-methyl-butyric Acid Methyl Ester (15)
L-Valine methyl ester hydrochloride (0.65 g, 3.93 mmol), followed by
Et N (0.65 ml, 5.37 mmol) and sodium cyanoborohydride (0.292 g,
3
0
4
.6 mmol), was added to a solution of compound 2 -(4,4-dimethyl-4,
-dihydro-oxazol-2-yl)-biphenyl-4-carbaldehyde (14) (1 g, 3.58 mmol) in
5
methanol (15 ml). The reaction mixture was heated at 70 C for 2 h under
ꢀ
an N atmosphere. The reaction was monitored by TLC, and no SM was
2
left. The reaction mixture was cooled down to rt, quenched with water,
and extracted with ethyl acetate. The organic layer was concentrated
under vacuum to get a crude residue. The crude was purified by column
chromatography (SiO , ethyl acetate=hexane 3:7), yielding compound 2-
2
0
{
[2 -(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-ylmethyl]-amino}-
-methyl-butyric acid methyl ester (15) as an pale yellow oil (1.3 g, 90%
3
1
yield). H NMR (400 MHz, DMSO-d ) d 7.23–7.58 (m, 8 H), 3.74–3.79
6
(
(
m, 2 H), 3.65–3.72 (m, 2 H) 3.61 (s, 3 H), 2.85–2.86 (d, 1 H), 1.79–1.81
m, 1 H), 1.22 (s, 3 H), 1.14 (s, 3 H), 0.86–0.88 (3 H, d), 0.81–0.84 (3 H,
1
3
d). C NMR (DMSO-d ) d 19.21, 19.66, 28.14, 31.39, 51.38, 51.60,
6
6
1
6.24, 67.89, 78.94, 127.45, 128.05, 128.24, 128.37, 130.26, 130.40,
30.95, 139.20, 139.79, 141.24, 162.54, 175.39. ESIMS: m=z calcd.
[
Mþ]: 394; found: 395 [M þ Hþ], 417 [M þ þ Na]. HRMS (ESI): m=z
calcd. [Mþ]: 394; found: 395.04 [M þ Hþ], 417.08 [Mþ þNa].
0
2
-{[2 -(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-ylmethyl]-
pentanoyl-amino}-3-methyl-butyric Acid Methyl Ester (16)
0
An oven-dried flask was filled with compound 2-{[2 -(4,4-dimethyl-4,5-
dihydro-oxazol-2-yl)-biphenyl-4-ylmethyl]-amino}-3-methyl-butyric acid
methyl ester (15) (1.0 g, 2.53 mmol) dissolved in dichloromethane
ꢀ
(
20 mL) and pyridine (0.26 g, 3.29 mmol) and then cooled to 0 C.
Afterward valeroyl chloride (0.397 g, 3.29 mmol) in dichloromethane
was added slowly drop by drop under stirring, and the reaction mixture
was stirred overnight. The reaction was diluted with water, and the
dichloromethane layer was separated and washed with saturated aqueous
NaHCO and brine. The organic layer was concentrated under vacuum
3
and purified through column chromatography (SiO , ethyl acetate=
2
0
hexane 3:7), yielding compound 2-{[2 -(4,4-dimethyl-4,5-dihydro-
oxazol-2-yl)-biphenyl-4-ylmethyl]-pentanoyl-amino}-3-methyl-butyric acid

3886
S. Ghosh et al.
1
methyl ester (16) as a colorless oil (1.1 g, 90% yield). H NMR (400MHz,
DMSO-d ) d 7.09–7.59 (m, 8 H), 4.52–4.74 (m, 2 H), 4.18–4.20 (d, 1 H)
6
3
2
.71–3.77 (q, 2 H), 3.31–3.36 (d, 3 H), 2.25–2.33 (m, 2 H), 1.90–2.20 (m,
H), 1.55–1.6 (m, 1 H), 1.40–1.45 (2 H, m), 1.00–1.20 (6 H, m), 0.88–0.91
1
3
(3H, t), 0.76–0.80 (6 H, m). C NMR (DMSO-d ) d 14.14, 18.63, 19.69,
6
2
1
1
2.20, 27.35, 27.67, 28.12, 32.76, 48.52, 51.81, 62.25, 67.91, 78.91, 126.18,
27.58, 128.17, 128.68, 130.28, 130.47, 130.97, 137.23, 139.59, 141.05,
62.37, 170.96, 173.81; ESIMS: m=z calcd. [Mþ]: 478; found: 479 [M þ Hþ].
HRMS (ESI): m=z calcd. [Mþ]: 478; found: 479.17 [M þ Hþ].
0
2-[(2 -Cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric
Acid Methyl Ester (17)
Phosphorus oxychloride (0.64 g, 4.18 mmol) was added dropwise to a solu-
0
tion of compound 2-{[2 -(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-
4-ylmethyl]-pentanoyl-amino}-3-methyl-butyric acid methyl ester (16) (1g,
ꢀ
2
.09 mmol) in dry pyridine (5 ml) at 0 C. The resulting solution was stirred
ꢀ
at 85 C (bath temperature under nitrogen for 14 h and, after being cooled to
room temperature, was poured into a cold saturated solution of sodium car-
bonate (100 ml). After being cooled to room temperature, the mixture was
quenched by addition of water, and the resulting emulsion was extracted
with ethyl acetate. The combined organic phases were washed with water,
10% aqueous cupric sulfate solution, and brine. The solution then was dried
over anhydrous magnesium sulfate, filtered, concentrated under vacuum,
and purified by column chromatography (SiO , ethyl acetate=hexane 3:7),
2
0
yielding compound 2-[(2 -cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-
[11]
methyl-butyric acid methyl ester (17) as a yellow oil (0.75 g, 90% yield).
1
H NMR (400 MHz, DMSO-d ) d 7.17–7.86 (m, 8 H), 4.53–4.87 (m, 2 H),
6
4
1
.13–4.18 (m, 1 H), 3.25–3.33 (d, 3 H), 2.24–2.35 (m, 2 H), 2.00–2.13 (m,
H), 1.41–1.53 (2H, m), 1.10–1.31 (2 H, m), 0.86–1.08 (3H, m), 0.68–0.79
1
3
(6 H, m). C NMR (DMSO-d ) d 14.16, 18.45, 19.59, 22.21, 27.56, 32,76,
6
48.39, 52.07, 62.17, 65.09, 110.46, 119.03, 126.72, 127.54, 128.51, 128.63,
130.66, 134.22, 136.86, 139.19, 144.72, 170.59, 174.13; ESIMS: m=z calcd.
[
Mþ]: 406; found: 407 [M þ Hþ], 429 [M þ þNa]. HRMS (ESI): m=z calcd.
[Mþ]: 406; found: 407.06 [M þ Hþ], 429.04 [Mþ þ Na].
ACKNOWLEDGMENTS
We are grateful for the support of the Sardar Vallabhbhai National
Institute of Technology Surat and Indian Association for the Cultivation
of Science, Jadhavpur, India.

Improved Synthesis of Valsartan
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