A short and efficient synthesis of valsartan via a Negishi reaction

Article abstract of DOI:10.3762/bjoc.6.27

An efficient synthesis of the angiotensin-II inhibitor valsartan (Diovan) is presented. Directed ortho-metalation of 5-phenyl-1-trityl-1H- tetrazole (6) and its Negishi coupling with aryl bromide 5 are the key steps of the synthesis. This method overcomes

Full text of DOI:10.3762/bjoc.6.27

A short and efficient synthesis of valsartan via a
Negishi reaction
Samir Ghosh, A. Sanjeev Kumar and G. N. Mehta*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 27.
Applied Chemistry Department, S.V. National Institute of Technology,
Surat-395 007, India
doi:10.3762/bjoc.6.27
Received: 21 January 2010
Accepted: 10 March 2010
Published: 18 March 2010
Email:
G. N. Mehta* - drgnmehta@gmail.com
*
Corresponding author
Associate Editor: I. Marek
Keywords:
© 2010 Ghosh et al; licensee Beilstein-Institut.
License and terms: see end of document.
antihypertensive therapy; aryl bromide; Negishi coupling; tetrazole;
valsartan
Abstract
An efficient synthesis of the angiotensin-II inhibitor valsartan (Diovan®) is presented. Directed ortho-metalation of 5-phenyl-1-
trityl-1H-tetrazole (6) and its Negishi coupling with aryl bromide 5 are the key steps of the synthesis. This method overcomes many
of the drawbacks associated with previously reported syntheses.
Introduction
Valsartan (Figure 1) is a member of a class of compounds
known as angiotensin II (AT-II) receptor antagonists. This class
combines effective anti-hypertensive activity with an excellent
profile of safety and tolerability. Activation of AT-II receptors
in the outer membrane of vascular smooth muscle cells of the
heart and arteries causes the tissues to constrict. AT-II receptors
are activated by the octapeptide AT-II. AT-II helps to maintain
constant blood pressure [1] despite fluctuations in a person’s
state of hydration, sodium intake and other physiological vari-
Figure 1: Valsartan.
ables. AT-II also performs the regulatory tasks of inhibiting the
excretion of sodium by the kidneys, inhibiting norephedrine
re-uptake and stimulating aldosterone biosynthesis.
prevents the increase of blood pressure produced by the
hormone–receptor interactions. Hence, it is used in the treat-
Valsartan [2] is therefore a non-peptide AT-II antagonist. By ment of cardiovascular complaints such as hypertension and
inhibiting the actions of AT-II on its receptors, valsartan heart failure. Comparative trial studies have shown that
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Beilstein Journal of Organic Chemistry 2010, 6, No. 27.
valsartan is as effective as angiotensin-converting enzyme obtained from commercially available benzonitrile. Aryl bro-
(
ACE) [3] inhibitors, calcium-channel blockers and α-blockers, mide 5 could be accessed by several discrete reactions of com-
and is generally better tolerated. Valsartan is marketed as the pound 3 and compound 4 via a nucleophilic substitution reac-
free acid under the trade name Diovan®. In addition, in combin- tion.
ation with diuretics such as hydrochlorothiazide, valsartan
offers specific advantages as an anti-hypertensive agent.
As shown in Scheme 2, inexpensive and commercially readily
available valeryl chloride 1 was coupled with L-valine methyl
The formation of the aryl–aryl bond represents the key step in ester hydrochloride (2) in the presence of triethylamine in
the synthesis of sartans: whilst the synthesis of losartan [4] as dichloromethane at 0 °C to afford methyl N-pentanoyl-L-
described in the literature makes use of Negishi [5,6] and valinate in 95% yield. Compound 3 was N-protected with
Ullmann [7] couplings, the published methods for the prepar- 1-bromo-4-(bromomethyl)benzene in presence of sodium
ation of valsartan utilize Suzuki–Miyaura couplings [8]. Of hydride in tetrahydrofuran to give methyl N-(4-bromobenzyl)-
these, Negishi reactions have proved to be very efficient. N-pentanoyl-L-valinate (5) [9] in 70% yield. Ortho-metalation
However, the use of organozinc compounds provides better of 5-phenyl-1-trityl-1H-tetrazole (6) [10] with n-butyllithium at
transmetalation activity than that obtained by the use of 25 °C followed by treatment with zinc chloride at −20 °C gave
organoboron reagents as well as good chemoselectivity since the desired organozinc chloride compound. Coupling of the
most common functional groups are not attacked by organozinc latter with aryl bromide 5 in presence of a catalytic amount of
species. Although preparations of several biphenyl ring systems Q-phos and palladium acetate in tetrahydrofuran at 75 °C
related to valsartan have been reported, a number of challenges produced methyl N-pentanoyl-N-{[2'-(1-trityl-1H-tetrazol-5-
and some disadvantages - such as tedious reaction conditions, yl)biphenyl-4-yl]methyl}-L-valinate (7) in 80% yield.
low yields and multistep sequences - still exist. Therefore, Hydolysis of 7 with 3 N NaOH in methanol gave valsartan 8
developing an efficient synthetic strategy with fewer steps that [11].
provides diverse access to these bioactive compounds is an
important goal. In this paper, we report a new, concise and effi- Conclusion
cient synthesis of valsartan via Negishi coupling.
In summary, a highly efficient approach to the biphenyltetra-
zole structure of the AT-II antagonists has been developed
which involves Negishi coupling of metalated 5-phenyl-1-trityl-
Results and Discussion
From a retro-synthetic analysis (Scheme 1), compound 8 could 1H-tetrazole. The method is commercially viable and applic-
be constructed via Negishi coupling from aryl bromide 5 and able to plant scale production. This approach provides an indus-
5
-phenyl-1-trityl-1H-tetrazole (6), which in turn could be trial viable procedure for the synthesis of valsartan.
Scheme 1: Retrosynthetic analysis of 8.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 27.
Scheme 2: (a) Et3N, CH2Cl2, 0 °C, 95%; (b) NaH, THF, 70%; (c) n-BuLi, 25 °C, THF, anhyd ZnCl2, −20 °C, Q-phos, Pd(OAc)2, 75 °C, 2 h, 80%; (d)
3
N NaOH, MeOH, reflux, 90%.
Experimental
4
6.51 mmol) was added to a solution of compound 3 (5.0 g,
Materials and instruments
23.25 mmol) and 1-bromo-4-(bromomethyl)benzene (4)
All solvents and reagents were purchased from the suppliers (6.39 g, 25.58 mmol) in tetrahydrofuran (80 mL). The reaction
and used without further purification. All non-aqueous reac- mixture was refluxed for 1 h. After cooling, the mixture was
tions were performed in dry glassware under a dry nitrogen at- diluted with ether (100 mL) and washed successively with
mosphere. Organic solutions were concentrated under reduced saturated aq NH4Cl (50 mL) and water (100 mL). The organic
pressure. Thin layer chromatography was performed on Merck layer was dried over Na2SO4 and concentrated in vacuum. The
precoated Silica-gel 60 F254 plates. 1H and 13C NMR spectra residue was chromatographed on silica gel. Elution with a mix-
were recorded on a Varian Gemini 400 MHz FT NMR spectro- ture of heptanes and ethyl acetate (70:30) yielded the title com-
meter using CDCl3 or DMSO-d6 as solvent. Chemical shifts are pound 5 (6.25 g, 70%) as a colorless oil. Rf = 0.5 (7:3; heptanes/
reported in δ ppm relative to TMS. Mass spectra were recorded EtOAc), 1H NMR (400 MHz, DMSO-d6): δ 7.54 (d, J = 6.8 Hz,
on a Shimadzu LCMS-QP 800 LC-MS and AB-4000 Q-trap 2H), 7.29 (d, J = 8.8 Hz, 2H), 5.01 (s, 2H), 4.13 (m, 1H) 3.31
LC-MS/MS.
(s, 5H), 2.32 (t, J = 14.8 Hz, 2H) 1.50 (m, 2H), 1.93 (m, 1H),
.24 (m, 3H), 1.22 (m, 3H), 0.83 (d, J = 7.6 Hz, 3H); 13C NMR
Methyl N-pentanoyl-L-valinate (3). Triethylamine (8.33 mL, (100 MHz, DMSO-d6): δ 173.9, 136.5, 133.1, 131.3, 121.1,
9.88 mmol) was added to a suspension of L-valine methyl 68.3, 52.5, 49.9, 34.2, 29.5, 27.2, 24.1, 23.2, 22.1, 19.2; ESIMS:
ester hydrochloride 2 (5.0 g, 29.94 mmol) in dichloromethane m/z calcd [M]+: 384; found: 385 [M+H]+. HRMS (ESI): m/z
50 mL). Valeryl chloride 1 (3.95, 32.93 mmol) was then added calcd [M]+: 384.3079; found: 384.3085 [M]+.
1
5
(
at 0 °C and the mixture stirred at 25 °C for 1 h. Water (50 mL)
was added to the reaction mixture and the organic layer separ- Methyl N-pentanoyl-N-{[2'-(1-trityl-1H-tetrazol-5-
ated and concentrated. The solid compound was triturated with yl)biphenyl-4-yl]methyl}-L-valinate (7). To a solution of
heptanes (50 mL) to give an off white solid 3 (6.11 g, 95% 5-phenyl-1-trityl-1H-tetrazole (6) (2.0 g, 5.15 mmol) in THF
yield). Rf = 0.6 (7:3; heptanes/EtOAc), 1H NMR (400 MHz, (20 mL), n-BuLi (2.5 M in hexane) (2.5 mL, 6.18 mmol) was
DMSO-d6): δ 8.01 (s, 1H), 4.12 (m, 1H), 3.59 (s, 3H), 2.48 (m, added at 25 °C under a N2 atmosphere. The reaction mixture
2
0
H), 2.13 (m, 2H), 1.95 (m, 1H), 1.45 (m, 3H), 1.25 (m, 5H), was stirred at 25 °C for 1 h and then cooled to −20 °C. Anhy-
.86 (d, J = 4.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): drous ZnCl2 (1.25 g, 9.27 mmol) was added to the reaction mix-
δ 173.2, 77.4, 56.8, 52.0, 36.2, 34.9, 31.2, 27.7, 22.2, 18.8; ture and then stirred at −20 °C for 30 min. The reaction mixture
ESIMS: m/z calcd [M]+: 215; found: 216 [M+H]+. was allowed to warm to 25 °C. Aryl bromide 5 (2.37 g,
.18 mmol) followed by Q-phos (0.182 g, 0.25 mmol) and
6
Methyl N-(4-bromobenzyl)-N-pentanoyl-L-valinate (5). Pd(II)OAc (0.06 g, 0.25 mmol) was added to the reaction mix-
Sodium hydride dispersion (60%) in mineral oil (1.83 g, ture. The reaction mixture was heated to reflux at 75 °C for 2 h.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 27.
The reaction was monitored by TLC until the starting material References
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The residue was chromatographed on silica gel. Elution with a
mixture of heptanes and ethyl acetate (70:30) gave the title
compound 7 (2.84 g, 80%) as a white solid, mp 45–47 °C, Rf =
1. Duncia, J. V.; Chiu, A. T.; Carini, D. J.; Gregory, G. B.; Johnson, A. L.;
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1
3
2
H), 7.36 (m, 11H), 6.98 (m, 1H), 6.88 (m, 7H), 4.62 (m, 2H),
.25 (s, 3H), 3.17 (s, 1H), 2.23 (m, 2H), 2.01 (m, 1H), 1.34 (m,
H), 1.19 (m, 3H), 1.01(m, 2H), 0.86 (d, 3H), 0.74 (d, 3H);
4
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.
.
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28.0, 127.9, 127.4, 126.2, 82.7, 62.3, 51.7, 48.6, 33.6, 32.6,
7.6, 22.5, 20.3, 19.7, 14.4; ESIMS: m/z calcd [M]+: 691;
1
821–1823. doi:10.1021/jo00430a041
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
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8
N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-
L-valine (8). To a solution of compound 7 (2 g, 2.89 mmol) in
methanol (20 mL), 3 N NaOH (2.85 mL) was added and the
mixture heated under reflux for 6 h. The progress of the reac-
tion was monitored by TLC until the starting material was
absent. The reaction mixture was concentrated under reduced
pressure and the residue was diluted with EtOAc (100 mL) and
distilled H2O (20 mL). Hydrochloric acid (2 N HCl) was added
dropwise to the mixture until the pH reached 4.0. Then the
organic phase was separated and the aqueous phase extracted
with EtOAc (3 × 50 mL). The combined organic extracts were
dried over anhydrous Na2SO4. Evaporation of the solvent gave
the crude product (1.12 g, 90%). Recrystallization from EtOAc
afforded the anticipated product valsartan 8; mp 114–118 °C;
9
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License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
1
H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 7.72 (m, 4H),
.24 (m, 1H), 7.15 (m, 2H), 6.94 (m, 1H), 4.58 (m, 1H), 4.40
m, 1H), 3.33 (m, 1H), 2.25 (m, 1H), 1.52 (m, 6H), 0.9 (m, 3H),
.84 (m, 3H), 0.74 (m, 3H); 13C NMR (100 MHz, DMSO-d6):
δ 174.0, 172.4, 171.8, 141.7, 138.2, 131.54, 131.1, 131.0,
7
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(
0
(http://www.beilstein-journals.org/bjoc)
1
2
29.3,128.8, 128.2, 127.4, 126.7, 70.3, 63.4, 49.9, 32.9, 28.05,
The definitive version of this article is the electronic one
which can be found at:
7.3, 22.2, 20.6, 14.2; ESIMS: m/z calcd [M]+: 435; found: 436
[
M+H]+; HRMS (ESI): m/z calcd [M]+: 435.5187; found:
35.5125 [M]+
doi:10.3762/bjoc.6.27
4
Acknowledgements
We are grateful for the support of the Sardar Vallabhbhai
National Institute of Technology, Surat and Indian Association
for the Cultivation of Science, Jadavpur, W.B. India for analyt-
ical support.
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