An improved synthesis of telmisartan: Via the copper-catalyzed cyclization of o -haloarylamidines

Article abstract of DOI:10.1039/d0ra00886a

A concise synthetic route was designed for making telmisartan. The key bis-benzimidazole structure was constructed via the copper-catalyzed cyclization of o-haloarylamidines. By adopting this approach, telmisartan was obtained in a 7-step overall yield of 54% starting from commercially available 3-methyl-4-nitrobenzoic acid, and the use of HNO₃/H₂SO₄ for nitration and polyphosphoric acid (PPA) for cyclization in the reported literatures were avoided.

Full text of DOI:10.1039/d0ra00886a

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An improved synthesis of telmisartan via the
copper-catalyzed cyclization of
Cite this: RSC Adv., 2020, 10, 13717
o-haloarylamidines†
c
c
ab
Junchi Zhang,ab Rui Li,ab Fuqiang Zhu, Changliang Sun and Jingshan Shen
*
*
A concise synthetic route was designed for making telmisartan. The key bis-benzimidazole structure was
constructed via the copper-catalyzed cyclization of o-haloarylamidines. By adopting this approach,
telmisartan was obtained in a 7-step overall yield of 54% starting from commercially available 3-methyl-
4-nitrobenzoic acid, and the use of HNO3/H2SO4 for nitration and polyphosphoric acid (PPA) for
cyclization in the reported literatures were avoided.
Received 30th January 2020
Accepted 21st March 2020
DOI: 10.1039/d0ra00886a
rsc.li/rsc-advances
which might cause enhanced difficulty with purication and
lose on yield.
1. Introduction
Several routes with different synthetic strategies have been
reported.2,10–13 Wang et al. adopted a PPA-free method to con-
structed the methylbenzimidazole ring by employing the
cyclocondensation between aromatic aldehyde and o-phenyl-
enediamine.2 In addition, Goossen et al. developed a reductive
amination–condensation sequence to build the central benz-
imidazole moiety,10 completely avoided the regioisomer impu-
rity. However, the problem of the excess use of nitration reagent
still remains in the above two routes. Martin et al. reported
a convergent approach to the synthesis of telmisartan via
Telmisartan 1, a potent and selective angiotensin II type 1 (AT1)
receptor antagonist, is one of the top-selling drugs for the treat-
ment of essential hypertension.1,2 This drug is marketed under the
brand name of Micardis®, and is characterized by excellent AT1
receptor binding affinity, long half-life, and good tolerability.1–3
Take a brief look at the structure of telmisartan, it is assembled
from two different benzimidazole subunits and a biphenyl-2-
carboxylic acid fragment. The original approach was reported by
Ries et al. in 1993 (Scheme 1),4 in which, the central benzimid-
azole ring was initially constructed stepwise from 4-amino-3-
methylbenzoic acid methyl ester 2. Subsequently, aer the
saponication of 3, the bis-benzimidazole intermediate 5 was
formed via the condensation between the free carboxyl group of
the central benzimidazole moiety and N-methyl-1,2-
benzenediamine 4. Finally, alkylation of 5 with the substituted
biphenyl fragment 6 was followed by hydrolysis, and afforded the
nal product 1 in an eight-step overall yield of 21%.
However, excess amount of nitration reagent HNO3/H2SO4
was utilized among the formation of the central benzimidazole
moiety, which might bring concerns to safety and wastewater
disposal.5–8 In addition, the crucial intermediate 5 was built
using the viscous PPA as the solvent, increased the difficulty of
production operation and sewage treatment.9 Moreover,
regioisomer impurity was inevitable in the alkylation of 5 with 6,
a
Suzuki cross-coupling, which is direct and efficient.13
However, considering the fact that palladium catalysts were
utilized in two steps of the route, the price element might be
taken into account.
Transition-metal-catalyzed cross-coupling reactions belong
to the frontier areas in modern organic chemistry, among
which, the copper-catalyzed Ullmann-type reaction are widely
utilized in C–N bond formation due to the high efficiency, low
cost, and low toxicity of copper catalysts.14–17 Considerable
efforts have been devoted to the copper-catalyzed synthesis of
benzimidazole derivatives,18–22 in which the cyclization of o-
haloarylamidines has drawn much attention.23–29 Herein, we
explored the idea to build the key bis-benzimidazole structure
of telmisartan via the copper-catalyzed cyclization of o-haloar-
ylamidines,30,31 which were accessible to be obtained from o-
haloarylamines (Scheme 2). This approach was suitable to
produce telmisartan with good overall yield while avoiding the
shortcomings associated with the reported routes.
aCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences (CAS), 555 Zuchongzhi Road, Shanghai 201203,
People's Republic of China. E-mail: shenjingshan@simm.ac.cn
bUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049,
People's Republic of China
2. Results and discussion
2.1 Synthesis of o-haloarylamidines 12a–c and 14
cTopharman Shanghai Co., Ltd, Building 1, No. 388 Jialilue Road, Zhangjiang Hitech
Park, Shanghai 201203, People's Republic of China. E-mail: changliang.sun@
topharman.cn
Initially, the o-haloarylamines 10a–c were formed in three steps
starting from commercially available 3-methyl-4-nitrobenzoic
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra00886a
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Scheme 1 Original approach for the synthesis of telmisartan. Reagents and conditions: (a) n-PrCOCl, C6H5Cl, 100 ꢀC; (b) HNO3/H2SO4, 0 ꢀC; (c)
Pd/C, 5 bar H2, MeOH; (d) AcOH, reflux; (e) NaOH, MeOH/H2O, reflux; (f) 4, PPA, 150 ꢀC; (g) 6, t-BuOK, DMF, rt; (h) TFA, DCM, rt.
Scheme 2 Retrosynthetic analysis of telmisartan.
acid 7 (Scheme 3). An amidation–condensation sequence was NH3 solution in methanol or 40-(aminomethyl)-[1,10-biphenyl]-2-
conducted from compound 7 with 4, afforded 8 in the yield of carbonitrile 13 (commercially available and is easy to obtain via
85%. Aerwards, reduction of nitro group was easy to occur reported methods33,34), afforded N-monosubstituted o-haloar-
under Pd/C–H2 condition, and the downstream selective halo- ylamidines 12a–c and N,N0-disubstituted o-haloarylamidine 14
genation of 9 was amenable to be carried out by N-hal- with high yields. Furthermore, based on the construction of the
osuccinimides, gave the o-haloarylamines 10a–c with N,N0-disubstituted o-haloarylamidine 14, the biphenyl moiety
satisfactory regioselectivity and yields, probably due to the was introduced prior to the cyclization of the central benz-
higher reactivity on ortho-amino position of 9. Furthermore, the imidazole ring, circumvented the generation of undesirable
isolated yields of both o-bromoarylamine 10b (86%) and o- regioisomer caused by the N-alkylation of the benzimidazole
iodoarylamine 10c (89%) were higher than o-chloroarylamine ring in the previously reported method.10
10a (70%).
Subsequently, with the o-haloarylamines 10a–c in hand,
2.2 Optimization of the reaction conditions for the
cyclization of o-haloarylamidines
efforts were focused on the construction of the o-haloar-
ylamidines 12a–c and 14 (Scheme 3). Firstly, 12a–c were directly
prepared from 10a–c with n-butyronitrile in the presence of
Lewis acids or Brønsted acids,32 however, yields of 12a–c in this
method were low (<50%), probably due to the steric hindrance
and electronic effect of the ortho-halogen in primary arylamines
10a–c. Hence, we adopted the approach to construct 12a–c and
14 from the arylamides 11a–c, which could be easily prepared
from 10a–c through a base-free acylation reaction. The classic
method for preparing arylamidines from arylamides usually
requires oxalyl chloride/thionyl chloride/phosphorus chloride
and so on, however, we attempted herein to introduce tri-
phosgene (also named bis(trichloromethyl)carbonate), regar-
ded broadly as a cleaner alternative, in our synthetic route.
Direct reaction of compound 11a–c as free bases with tri-
phosgene resulted in a rapid decomposition of triphosgene,
while the monohydrochloride salts of 11a–c facilitated the
chlorination step greatly, and the following quenching with
The nal cyclization of 12a–c and 14 was conducted via the
Ullmann-type cross-coupling reaction. Since the copper-
catalyzed cyclization of o-haloarylamidines were the key steps
in our research, efforts were devoted to the optimization of
reaction conditions for the o-bromoarylamidine 12b (Table 1).
As shown in entries 1–10, the impact of solvents was enor-
mous according to the results of HPLC. DMSO exhibited a better
result than DMF, dioxane, or toluene, indicating a favored
solvent circumstance with higher polarity (Table 1, entries 1–2,
entries 4–5), and also a favored condition of higher temperature
(Table 1, entries 3). But pure water as solvent worked not
effectively due to the low solubility of organic compounds (entry
6). Therefore, biphasic system of water and hydrosoluble
solvents instead of DMSO provided a potential solution for the
contradiction of polarity and solubility as described above
(entries 7–10). The level of 5 reached 91.8% in 1,4-dioxane/H2O
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Scheme 3 Synthesis of o-haloarylamidines 12a–c and 14. Reagents and conditions: (a) (i) oxalyl chloride, DMF, DCM, 0 ꢀC, rt; (ii) 4, DIPEA, DCM,
0 ꢀC, rt; (iii) TsOH$H2O, toluene, reflux; (b) Pd/C, 5 bar, MeOH, THF, 50 ꢀC; (c) N-halosuccinimide; (d) n-PrCOCl, MeCN, reflux; (e) (i) triphosgene,
DMF, MeCN, reflux; (ii) NH3 (7.0 M solution in MeOH); (f) (i) triphosgene, DMF, MeCN, reflux; (ii) 13, Et3N, DCM.
Table 1 Optimization of the reaction conditions for the cyclization of 12ba
HPLC results in reaction mixtureb
(%)
Entry
Solvent
Temp. (ꢀC)
Catalyst
Ligand (0.1 equiv.)
Base
5
12b
11b
10b
1
2
3
4
5
6
7
8
DMF
DMSO
DMSO
Toluene
1,4-Dioxane
H2O
110
110
130
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
79.4
91.0
98.5
12.6
32.0
4.1
91.8
63.6
71.9
87.9
1.4
97.8
97.6
96.7
96.4
82.0
83.1
61.3
71.4
83.3
97.0
16.9
6.2
1.2
0.9
0.2
0.8
<0.1
1.5
<0.1
1.3
1.9
0.4
1.2
0.3
0.6
1.0
0.8
1.2
1.2
1.1
1.3
1.5
0.5
2.5
1.9
1.3
—–c
2.0
0
<0.1
86.6
66.0
94.4
7.6
34.5
26.1
10.8
44.0
0.3
0
0.5
0
10.7
10.5
17.7
21.7
12.8
0
Reux
Reux
Reux
Reux
Reux
Reux
Reux
130
130
130
130
130
130
130
130
130
130
130
1,4-Dioxane/H2Od
MeCN/H2Od
2-Me-THF/H2Od
DME/H2Od
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0.5
0.6
<0.1
0.9
53.4
1.5
1.9
1.8
2.8
6.0
5.2
19.9
5.6
2.4
2.5
9
10
11
12
13
14
15
16
17
18
19
20
21
e
e
—
CuI
—
e
—
e
CuBr
CuCl
Cu2O
CuBr2
CuCl2
CuO
Cu(OAc)2
CuI
CuI
—
e
—
e
—
e
—
e
—
e
—
e
—
e
—
e
—
KOH
a
The reactions were performed on the scale of 0.5 mmol of 12b under the conditions: 0.1 equiv. of copper catalyst, 3.0 equiv. of base, 12 ml mmolꢁ1
of solvent, heat for 8 h. b Calculated for the reaction mixture from the HPLC area percentage at 220 nm. c Not detected. d The ratio of mixed solvents
was 2 : 1 by volume. Not added.
e
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Scheme 4 Synthesis of bis-benzimidazole intermediates and telmisartan.
(entry 7), and the slightly lower efficiency might be derived from similar with that from 12b. However, such yield of the cycliza-
the relative lower boiling point of biphasic solvent systems. tion of 12a was merely 13%, which may be caused by the poor
Taken all together, DMSO was regarded as the optimal solvent leaving group ability of chlorine, while the yield of the impurity
system for further research.
10a could reached the level of 82%, suggesting the competitive
Since several metal-free,35–37 and ligand-free23,26 conditions relationship between cyclization and hydrolysis reactions in
were reported for the cyclization of o-haloarylamidines, the this step.
necessity of copper catalyst and ligand in our route was subse-
The traditional method for the preparation of compound
quently investigated (entries 11 and 12). The copper catalyst was 15, an industrially widely utilized precursor of telmisartan,40–42
proved to be essential, since a signicant decline of 5, along requires the N-alkylation compound of 5 with the 2-cyano-40-
with an obvious augment of impurity 10b were observed in the (bromomethyl)biphenyl, resulting in regioisomer impurities.
absence of copper (entry 11). Moreover, in a ligand-free condi- Herein, the cyclization of N,N0-disubstituted o-haloar-
tion (entry 12), there was almost no change in the levels of 5 and ylamidine 14 was utilized, offering 15 in an isolated yield of
impurities 10b, 11b, and 12b in comparison with the result in 89%. Aerwards, the downstream cyano-group hydrolysis was
entry 3, suggesting additional ligand could be dispensable in able to achieve through reported method,41 leading to the
our method, and the coordination effect between copper cata- formation of the nal product with 97% yield aer simple
lyst and the benzimidazole subunit from substance might play purication.
a very similar role in the reaction system.38,39
Aerwards, a series of commonly utilized copper catalysts
were investigated in DMSO under a ligand-free condition, using
three equivalents of Cs2CO3 as the base (entries 12–19). Cop-
per(I) salts displayed distinct advantages over copper(II) cata-
preparation of telmisartan, featuring a ligand-free copper-
lysts, and CuI (entry 12) was selected as the optimal choice. In
addition, the evaluation of bases was also carried out (entries
12, 20 and 21). Three commonly used bases were employed, and
while the use of HNO3/H2SO4 and PPA in the original route was
the results showed that both Cs2CO3 and KOH displayed higher
3. Conclusions
In conclusion, an improved synthesis was developed for the
catalyzed cyclization of benzimidazolyl-substituted o-haloar-
ylamidines to form the core bis-benzimidazole fragment,
averted. Furthermore, our approach provided a new manner
yields than K2CO3.
for introducing the biphenyl-4-methyl subunit, which avoided
As a consequence, the utilization of CuI (0.1 equiv.) and
the generation of regioisomer impurities in the traditional N-
alkylation method. By adopting this route, telmisartan was
obtained in a 7-step overall yield of 54%, while achieving an
all-around improvement in safety, waste disposal, and opera-
Cs2CO3 (3.0 equiv.) in DMSO (entry 12) was chosen as the
optimal condition for the cyclization of 12b, and the key bis-
benzimidazole intermediate 5 was obtained in an isolated
yield of 92% in such manner (Scheme 4).
bility. In the long run, such copper-catalyzed cyclization
strategy brings a new avenue to the preparation of drugs and
their derivatives containing benzimidazole pharmacophores.
2.3 Synthesis of bis-benzimidazole intermediates and
telmisartan
Based on the screening results of 12b, the cyclization of other o-
haloarylamidines 12a, 12c, and 14 were subsequently conduct-
ed in DMSO under the similar conditions (Scheme 4). The iso-
Conflicts of interest
lated yield of 5 obtained from the iodo precursor 12c (93%) was There are no conicts of interest to declare.
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