A practical synthesis of 5-(4′-methylbiphenyl-2-yl)-1H-tetrazole

Article abstract of DOI:10.1002/jhet.5570430532

Practical synthesis of 5-(4′-methylbiphenyl-2-yl)-1H-tetrazole, key intermediate in several angiotensin II receptor antagonists from 2-fluorobenzonitrile in excellent yields and very high purity is described.

Full text of DOI:10.1002/jhet.5570430532

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A Practical Synthesis of 5-(4'-Methylbiphenyl-2-yl)-1H-tetrazole
Srinivas Kantevari*, C. K. Snehalatha Nair and M. Pardhasaradhi
Organic-II Division, FCL Building,
Indian Institute of Chemical technology, Uppal road,
Hyderabad-500 007. INDIA.
E-mail: kantevari@yahoo.com
Received October 20, 2005
N
N
N
N
N
N
O
N
NH
N
N
N
NH
Mg
H3C
MgBr
H3C
MgBr
O
F
F
Br
Practical synthesis of 5-(4'-methylbiphenyl-2-yl)-1H-tetrazole, key intermediate in several angiotensin II
receptor antagonists from 2-fluorobenzonitrile in excellent yields and very high purity is described.
J. Heterocyclic Chem., 43, 1353 (2006).
Introduction.
another class of potential drugs I-VIII, for treatment of
hypertension [1]. The major structural feature common in
all these drug molecules is a biphenyl moiety with acidic
tetrazole group in 2-position (Figure-1) [2-4]. The key
steps involved in the synthesis of the biphenyl tetrazoles
Inhibition of renin angiotensin system (RAS) is the
topic of pharmaceutical research for the last decade.
Recently the discovery of heterocyclic agents that are
angiotensin II receptor antagonists has produced yet
Cl
N
N
N
HO
O
N
N
N
O
OHC
N N
N
OH
N
N
N-K+
N
NH
N
N
N
NH
N
N
O
N
NH
O
Valasartan (IV)
Irbesartan (II)
Olmesartan (III)
LOSARTAN-K (I)
N
CH3
CH3 OH
O
N
N
N-K+
N
N
O
N
O
O
N
N
N
H3C
N
O
N N
H3C
N
O
N N
O
N
NH
N
NH
N
NH
OH
O
O
O
Enoltasartan (VIII)
Tososartan (VII)
Candesartan (VI)
Cilexitill (V)
O
HO
N
O
S
N
O
NH2
N
N
N
N
N
NH
N
N
N
N
NH
NH
N
N
O
N
N
N
N
O
N
NH
N
NH
O
CF3
HN
O
S
HN
X
XII
XI
IX
Figure I. Examples of pharmaceutically relevant biphenyl tetrazoles I-XII

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S. Kantevari, C. K. S. Nair and M. Pardhasaradhi
Vol 43
at 98-100 °C, we now concentrated our efforts in the
preparation of Grignard reagent and its coupling in
suitable solvent to give XIV (Scheme-I). For better
recoverability and reusability of solvent, we initially used
single solvent for the preparation of p-toluene magnesium
bromide and its coupling with 5-(2-fluorophenyl)-1H-
tetrazole.
Our preliminary experiments using ether and THF as
single solvent did not give fruitful results and ended with
only poor yields of biphenyl tetrazole XIV (entry 1 & 2,
Table-I). As observed in the literature [11], when we
are (1) aryl-aryl coupling reaction to form the biphenyl
moiety and (2) conversion of nitrile group in the 2-
position to tetrazole. Methods generally employed are
Ullmann coupling between two iodoaryl derivatives [5] or
nickel [6], manganese [7] or palladium [8] catalyzed
coupling of aryl halides with 2-halobenzonitrile. In the
subsequent reaction, nitrile group at 2-position was
converted to tetrazole using either trialkyltin azide [9] or
TMS-N3 [10]. Aside from the expense and potential
concerns associated with the recovery of Pd°L4 catalysts
from pilot-scale procedures, it was difficult to satisfacto-
rily remove trace levels of palladium contamination from
products. Moreover, serious problems are also encoun-
tered in the conversion of biphenyl nitrile to biphenyl
tetrazole due to the use of highly toxic trialkyltin azide [9]
or TMS-N3 [10] which make rigorous purification
absolutely necessary in order to obtain the high purity
product as required by pharmaceutical industry.
Scheme II
N
N
N
N
O
N
N
NH
N
H3C
MgBr
H3C
MgBr
Mg
F
O
XIV
F
Br
An alternate approach described by Russel and Murry
[11] involve the tetrazolylation of 2-fluorobenzonitrile by
refluxing with sodium azide in acetic acid. Subsequently
the formed 5-(2-fluorophenyl)-1H-tetrazole is reacted
with p-tolylmagnesium bromide to yield the desired
biphenyl tetrazole. Here in situ generation of poisonous
hydrazoic acid and use of ether solvent in Grignard
reaction for biphenyl formation make this method
unsuitable for large-scale preparations. In our attempts
[12] to develop an efficient process for the preparation of
angiotensin II antagonists such as Losartan-K (I) we
require a suitable procedure for large-scale preparation of
Plausible mechanism for the formation of XIV
carried out the coupling reaction in dimethoxy ethane
(DME) by adding p-toluene magnesium bromide in ether,
XIV was obtained in reasonably good yield (entry 3,
Table-I). This observation made us think that probably
DME solvent is essential for the formation of some sort of
complex with magnesium to facilitate the coupling
reaction. Further when both the Grignard reagent and the
subsequent coupling reaction were carried out in DME,
increasingly good yields of the required compound XIV
with greater purity was obtained (entry 4, Table-I). For
5-(4'-methylbiphenyl-2-yl)-1H-tetrazole XIV.
In this
Scheme I
N
N
N
N
N
NH
N
NH
H3C
CN
CH3
BrMg
X
X
TEA
NaN3
Toluene
XIV
Solvent
XIII
a) X= F
b) X= Cl
c) X= Br
paper we describe a practical and economically viable
synthesis of 5-(4'-methylbiphenyl-2-yl)-1H-tetrazole XIV
from 5-(2-fluorophenyl)-1H-tetrazole XIIIa via Grignard
reaction with p-tolylmagnesium bromide in 93% yield and
99.6% HPLC purity (Scheme-I).
Table I
Effect of solvent and reaction conditions on the yield of the product.
S.No
Solvent for
Grignard
Coupling reaction
Solvent
Reaction
Reaction
Yield of
preparation
Temp. ( oC) Time (h)
XIV (%)
Results and Discussion.
1
2
3
4
5
Ether
THF
Ether
DME
THF
Ether
THF
Reflux
Reflux
Reflux
85
48
48
24
20
12
3
Having developed [13] a suitable high yield and high
purity procedure for the preparation 5-(2-halophenyl)-1H-
tetrazoles XIIIa-c by reacting 2-halobenzonitrile with
sodium azide and triethyl ammonium chloride in toluene
10
67
74
93
DME
DME
DME
80

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A Practical Synthesis of 5-(4'-Methylbiphenyl-2-yl)-1H-tetrazole)
1355
MHz using CDCl3 as internal standard. Mass spectra were
recorded on a VG Micromass 7070H and Finnigan Mat 1020B
mass spectrometers operating at 70 eV. 2-Fluoro phenyltetrazole
XIIIa, 2-chlorophenyl tetrazole XIIIb and 2-bromophenyl
tetrazole XIIIc were prepared according to the reported
procedure [12].
the first time, we achieved highest yield (93%) and best
purity (99.6%) by adding p-toluene magnesium bromide
in THF to 5-(2-fluorophenyl)-1H-tetrazole in DME and
heating the mixture at 80 °C (entry 5, Table-I).
In order to have broader applicability, we carried out
coupling reaction with 5-(2-chlorophenyl)-1H-tetrazole
(XIIIb) in DME by adding p-toluene magnesium bromide
in THF and heating at 80-85 °C. Contrary to our expect-
ation, the reaction did not proceed even after refluxing the
mixture for longer hours (72 h). With bromo derivative
XIIIc, the reaction was sluggish and did not give the
desired product. This observation revealed that, apart
from DME solvent, fluoro group at 2-position on the
phenyl ring containing tetrazole moiety was also essential
for the success of the reaction.
Typical Procedure for the Preparation of 5-(4'-Methylbiphenyl-
2-yl)-1H-tetrazole.
To the suspension of activated magnesium turnings (46.7 g,
1.92 mol) in anhydrous tetrahydrofuran (200 mL), p-
bromotoluene (330 g, 1.92 mol) in tetrahydrofuran (1 L) was
added drop wise in such a way that the reaction temperature is
maintained at 40-50 °C. Following the addition, the mixture was
stirred at 50 °C until the magnesium was entirely dissolved (1
h). The resulting reagent was cooled to room temperature and
added drop wise to the solution of 2-fluorophenyl tetrazole (100
g, 0.61 mol) in dimethoxyethane (1.5 L) at 5-10 °C (1 h) under
N2. After complete addition, the mixture was brought to room
temperature, heated to distill out tetrahydrofuran till the
temperature of reaction mixture reached to 80 °C and then
stirred for 12 h. With ice bath cooling, the mixture was slowly
quenched with 6 N HCl (400 mL), dimethoxyethane was
removed under reduced pressure. The resulting aqueous residue
was extracted with dichloroethane (4x150ml) and the combined
organic layer was washed with 2 N NaOH (3x200mL). The
alkaline portion was acidified to pH 2 with conc. HCl, the
precipitate formed was collected by filtration, washed with water
and dried at 60 °C. Recrystalization from toluene afforded a tan
color solid 5-(4'-methylbiphenyl)-2-yl)-1H-tetrazole XIV (133.2
g) in 93% yield and 99.6% HPLC purity; m.p. 146 °C (Lit. [11]
m.p. 144-148 °C). The product was fully characterized by NMR
and mass spectral analysis and compared with authentic sample.
Based on these observations, we propose that, initial
addition of Grignard reagent to 5-(2-fluorophenyl)-1H-
tetrazole forms an electron rich magnesium tetrazolate
complex that is stabilized by interactions with nucleofugic
fluoro group at 2-position (Scheme-II). The stability of
the complex may be further increases by forming a
binding pocket with dimethoxyethane (DME) [8b]. On
further addition of Grignard reagent, the fluoro group
activated by magnesium tetrazolate undergoes nucleo-
philic displacement reaction (SNAr) to give the required
biphenyl product XIV. In the preparation of Grignard
reagent it is not essential whether we use DME or THF as
solvent [14]. In case of chloro and bromophenyl
magnesium tetrazolates, probably the interactions
involving chloro or bromo groups with magnesium are
not strong enough to facilitate nucleophilic displacement
(SNAr) reaction.
Acknowledgment.
We thank Dr. J.S. Yadav, Director, IICT and Dr. M.Hari
Babu, Head, Organic-II division, IICT, Hyderabad for
encouragement and support.
In conclusion, we described here an efficient and
industrially viable practical procedure for the synthesis of
5-(4'-methylbiphenyl-2-yl)-1H-tetrazole, key intermediate
in several angiotensin II receptor antagonists from 2-
fluorophenyltetrazole 93% yield and 99.6% purity.
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