Convergent Synthesis of Angiotensin II Receptor Blockers through C-H Arylation of 1-Benzyl-5-phenyl-1 H -tetrazole with Functionalized Aryl Bromides

Article abstract of DOI:10.1055/a-1472-0925

Highly convergent synthesis of angiotensin II receptor blockers has been accomplished by means of late-stage C-H arylation using functionalized aryl bromides. C-H arylation of 1-benzyl-5-phenyl-1 H -tetrazole with aryl bromides carrying methyl 2-ethoxyben

Full text of DOI:10.1055/a-1472-0925

SYNTHESIS
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1
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–D
paper
A
en
M. Seki, Y. Takahashi
Paper
Synthesis
Convergent Synthesis of Angiotensin II Receptor Blockers through
C–H Arylation of 1-Benzyl-5-phenyl-1H-tetrazole with Functional-
ized Aryl Bromides
Masahiko Seki*
N
N
N
N
Yusuke Takahashi
Bn
Ar
H
Ar
MA Group, Tokuyama Corporation, 40, Wadai, Tsukuba,
Ibaraki 300-4247, Japan
3 steps
candesartan cilexetil
olmesartan medoxomil
RCO2H
[RuCl2(p-cymene)]2
ma-seki@tokuyama.co.jp
N
Br
N
N
N
K2CO3, 1, 4-dioxane
Bn
HO
N
N
N
nPr
OEt
Ar:
N
EtO2C
MeO2C
Corresponding Author
Received: 12.03.2021
HO
Accepted after revision: 31.03.2021
Published online: 31.03.2021
DOI: 10.1055/a-1472-0925; Art ID: ss-2021-f0128-op
N
N
O
OEt
nPr
N
N
N
N
N
O
NH
Abstract Highly convergent synthesis of angiotensin II receptor
blockers has been accomplished by means of late-stage C–H arylation
using functionalized aryl bromides. C–H arylation of 1-benzyl-5-phenyl-
1H-tetrazole with aryl bromides carrying methyl 2-ethoxybenzimidaz-
ole-7-carboxylate unexpectedly provided coupling products where eth-
yl group was migrated from oxygen to nitrogen atom. The O-to-N ethyl
migration was completely suppressed by the use of N-pivaloyl-L-valine
rather than the combined use of triphenylphosphine and sodium mesi-
tylenesulfonate to result in the preferential formation of a key interme-
diate of candesartan cilexetil. In contrast, when an aryl bromide having
O
O
O
O
O
O
O
O
N
N
NH
N
1a (CAN)
1b (OLM)
Figure 1 Candesartan cilexetil (1a) and olmesartan medoxomil (1b)
ethyl
4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate
was employed, the C–H arylation proceeded smoothly to provide a late-
stage intermediate, which rapidly led to olmesartan medoxomil in 3
steps.
Previously reported synthetic method of 1a involves a
synthetic route where C–H arylation of 1-benzyl-5-phenyl-
1H-tetrazole (2) with 4-benzoyloxymethylphenyl bromide
gave biphenyltetrazole 3. This was elaborated to chloride 5
in two steps and by alkylation of 5 with benzimidazole de-
rivative 6 to afford an intermediate 7 having candesartan
framework.3f Even though it is efficient in view of employ-
ing preformed benzimidazole 6 and coupling it with 5 in a
later stage of the synthesis, it took 5 steps to obtain 7
(Scheme 1, route A).
To further reduce the number of steps and to enhance
convergency, an alternative route of synthesis was consid-
ered in that alkylation of 6 with commercially available 4-
bromobenzyl bromide to provide aryl bromide 8, which
was subjected to C–H arylation with 2 to give 7 just in 2
steps (Scheme 1, route B).4 Therefore, use of route B would
enable a reduction of 3 steps in comparison with route A.
The process development was initiated by the synthesis
of aryl bromide 8, which was accomplished in high yield
(72%) by regioselective alkylation of 6 with 4-bromobenzyl
Key words tetrazole, ruthenium, hypertensive drugs
Angiotensin II receptor blockers (ARBs) 1 have gained
keen interest as hypertensive drugs due to the high efficacy
and safety. Among them, candesartan cilexetil (CAN, 1a)1
and olmesartan medoxomil (OLM, 1b)2 (Figure 1), have
been recognized as the leading contributors to this kind of
drugs and extensive process research has been devoted to
accomplish a really efficient synthetic method. We have al-
ready established a conceptually practical synthesis of 1 by
means of C–H arylation.3 As one of our continuing research
projects to establish an efficient synthesis of pharmaceuti-
cals, described herein is an alternative synthetic method
employing functionalized aryl bromides as a substrate for
C–H arylation to enhance convergency of the methodology.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Seki, Y. Takahashi
Paper
Synthesis
Route A (Previous Work)
OH
Br
Br
OBz
Bn
N
OEt
N
N
N
H
N
N
N
N
N
N
Cl
OBz
OH
OEt
N
N
6
N
N
CO2Me
N
N
N
N
N
N
N
N
Bn
Bn
Bn
N
N
Bn
MeO
O
5
2
3
4
7
Route B (This Work)
N
N
N
N
Bn
Br
N
N
2
N
OEt
OEt
Br
N
H
7
MeO2C
MeO2C
Br
6
8
Scheme 1 Strategy for synthesis of CAN key intermediate 7
bromide in the presence of K2CO3 and TBAI in butan-2-ol
(Scheme 2). A similar regioselectivity on the alkylation of 6
was observed as well in the reaction employing biphenyl-
methyl chloride 5.3f
The C–H arylation of 8 with phenyltetrazole 2 was then
tested using our previously developed procedure employing
MesSO3Na, [RuCl2(p-cymene)2]2, PPh3, and K2CO3 in NMP.3f
The reaction proceeded completely by heating the mixture
N
N
N
N
Bn
Br
H
N
N
Br
N
N
N
OEt
2
K2CO3
OEt
OEt
N
N
TBAI
2-BuOH
45 °C, 15 h
72%
N-Piv-L-ValOH
N
H
N
N
MeO2C
Bn
MeO2C
(30 mol%)
[RuCl2(p-cymene)]2
(10 mol%)
MeO2C
Br
8
6
7
K2CO3, 1,4-dioxane
120 °C, 16 h
42%
N
N
N
N
Bn
H
O-to-N
ethyl migration
Et
N
2
O
N
N
N
MesSO3Na
(10 mol%)
N
N
Bn
MeO2C
[RuCl2(p-cymene)]2
(2.5 mol%)
PPh3 (10 mol%), K2CO3, NMP
138 °C, 10 h
9
83%
Scheme 2 Synthesis of CAN key intermediate 7 through C–H arylation
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–D

C
M. Seki, Y. Takahashi
Paper
Synthesis
HO
N
N
N
N
Bn
N
Br
H
HO
nPr
EtO2C
N
HO
N
Br
K2CO3
2
nPr
EtO2C
N
N
MesCO2H
(30 mol%)
DMA
25 °C, 48 h
80%
nPr
EtO2C
N
N
H
N
[RuCl2(p-cymene)]2
(10 mol%)
N
N
Br
Bn
10
11
12
59%
K2CO3, 1,4-dioxane
120 °C, 18 h
Scheme 3 Synthesis of OLM key intermediate 12 through C–H arylation
at 138 °C for 10 hours though undesirable O-to-N ethyl mi-
grated compound 9 was formed exclusively. This type of mi-
gration was reported by Dong5 and the presence of PPh3
was shown to accelerate the transformation.
ter hydrolysis, prodrug ester formation, and final deben-
zylation.3e
In conclusion, novel and practical syntheses of cande-
sartan cilexetil (1a) and olmesartan medoxomil (1b) have
been worked out by means of C–H arylation of elaborated
aryl bromides bearing functional groups. Use of C–H aryl-
ation procedure without PPh3 has avoided the unfavorable
side reaction of ethyl group migration in the synthesis of
1a. Higher convergency combined with the use of readily
available reagents, mild reaction conditions of the current
process would permit much easier access to ARB drugs.
To avoid the undesirable O-to-N ethyl migration, we ini-
tially tested the reaction in the absence of PPh3. However, it
failed to provide 7 under otherwise identical conditions
and only 9 was obtained in 60% yield. Finally, to our delight,
by treating 8 with 2 at 120 °C for 16 hours in 1,4-dioxane
using N-Piv-L-ValOH4 as an additive, the desired coupling
product 7 was obtained without any O-to-N ethyl migration
even though the reaction rate was very slow and higher Ru
catalyst loading (10 mol%) was required to obtain a moder-
ate yield of 7 (42%). Biphenyltetrazole 7 thus obtained was
converted to CAN (1a) in 3 steps by simple hydrolysis, prod-
rug ester formation, and final debenzylation.3e,f
Although the overall yield of route B (30%) developed is
slightly lower than that of route A (34%),3f a significant re-
duction in the number of reaction steps and need of num-
ber of solvents for reaction and work up (i.e., NMP, MTBE,
THF, IPE, n-heptane, IPA, MeOH, acetone) compensates for
this reduction in overall yield. In addition, though much
amount of Ru catalyst was required to effect the reaction to
reasonable level, the price of Ru ($12/g) is currently very
low and affordable when compared with well-employed Pd
catalysts (Pd: $92/g).
We then moved to the synthesis of olmesartan medox-
omil (OLM, 1b). The same strategy as that used for the syn-
thesis of 1a was conducted for the synthesis of 1b (Scheme
3). To begin with, alkylation of ethyl 4-(1-hydroxy-1-meth-
ylethyl)-2-propylimidazole-5-carboxylate (10) with 4-bro-
mobenzyl bromide led to the 1-alkylated product 11 in high
yield (80%). Aryl bromide 11 obtained was subjected to Ru-
catalyzed C–H arylation using MesCO2H6 as an additive to
furnish the desired OLM key intermediate 12. It is worth
noting that the transformation successfully proceeded well
with the substrate 11 carrying a free hydroxyl group. From
12, OLM (1b) was obtained just in three steps including es-
1H and 13C NMR spectra (400 and 100 MHz, respectively) were record-
ed with TMS as an internal standard. Silica gel column chromatogra-
phy was performed using Kieselgel 60 (E. Merck). TLC was carried out
on E. Merck 0.25 mm pre-coated glass-backed plates (60 F254). Devel-
opment was accomplished using 5% phosphomolybdic acid in
EtOH/heat or visualized by UV light where feasible. All solvents and
reagents were used as received.
Methyl 1-(4-Bromobenzyl)-2-ethoxy-1H-benzimidazole-7-carbox-
ylate (8)
To a suspension of methyl 2-ethoxy-1H-benzimidazol-7-carboxylate
(6; 10 g, 45.4 mmol) and K2CO3 (12.5 g, 90.8 mmol) in butan-2-ol (100
mL) were added 4-bromobenzyl bromide (12 g, 47.9 mmol) and TBAI
(0.839 g, 2.27 mmol) at 25 °C. The mixture was stirred at 45 °C for 15
h. After completion of the reaction, the mixture was evaporated. To
the residue was added EtOAc (100 mL) and the EtOAc layer was
washed with H2O (3 × 100 mL). The organic phase was separated,
dried (MgSO4), and evaporated. The residue was recrystallized from
EtOAc to give 8 as a white fine solid; yield: 12.8 g (72%); mp 121 °C
(EtOAc).
1H NMR (CDCl3):  = 7.72 (1 H, dd, J = 8.0, 0.8 Hz), 7.57 (1 H, dd, J = 8.0,
1.2 Hz), 7.35 (2 H, m), 7.17 (1 H, t, J = 8.0 Hz), 6.85 (2 H, d, J = 8.4 Hz),
5.57 (2 H, s), 4.64 (2 H, q, J = 7.2 Hz), 3.75 (3 H, s), 1.46 (3 H, t, J = 7.2
Hz)
13C NMR (CDCl3):  = 166.8, 158.7, 142.0, 136.6, 131.6, 128.3, 123.9,
122.2, 121.1, 121.0, 115.6, 66.8, 52.3, 46.9, 14.7.
HRMS: m/z [M + H]+ calcd for C18H18BrN2O3: 389.0402; found:
389.0499.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–D

D
M. Seki, Y. Takahashi
Paper
Synthesis
Methyl 1-Ethyl-2-oxo-3-({2′-[1-(phenylmethyl)-1H-tetrazol-5-
yl][1,1′-biphenyl]-4-yl}methyl)-2,3-dihydrobenzimidazole-4-car-
boxylate (9)
13C NMR (100 MHz, CDCl3):  = 161.5, 159.0, 151.4, 136.3, 132.0,
127.2, 121.3, 116.9, 70.4, 61.3, 48.6, 29.4, 29.3, 21.4, 14.0, 13.9.
HRMS: m/z [M + 1]+ calcd for C19H26BrN2O3: 411.1062; found:
To a mixture of 2 (1.0 g, 4.23 mmol), [RuCl2(p-cymene)]2 (65 mg,
0.106 mmol, 2.5 mol%), 8 (1.81 g, 4.65 mmol, 1.1 equiv), MesSO3Na
(94 mg, 0.423 mmol, 10 mol%), PPh3 (111 mg, 0.423 mmol, 10 mol%),
and K2CO3 (585 mg, 4.23 mmol, 1.0 equiv) was added NMP (5 mL) un-
der N2 atmosphere. The mixture was stirred under N2 atmosphere at
138 °C for 10 h. After completion of the reaction, the mixture was di-
luted with EtOAc and filtered through Celite. The solids were washed
with EtOAc. The filtrate and washings were combined and evaporat-
ed. The residue was purified by silica gel column chromatography
(n-hexane/EtOAc 2:1) to provide 9 as a colorless oil; yield: 1.9 g (83%).
1H NMR (CDCl3):  = 7.60 (1 H, ddd, J = 7.6, 1.6 Hz), 7.50 (1 H, dd, J =
7.6, 0.8 Hz), 7.42–7.33 (3 H, m), 7.19–7.09 (5 H, m), 7.02–6.95 (4 H,
m), 6.72 (2 H, d, J = 7.2 Hz), 5.46 (2 H, s), 4.62 (2 H, s), 4.06 (2 H, q, J =
7.2 Hz), 3.70 (3 H, s), 1.40 (3 H, s).
411.1110.
Ethyl 4-(1-Hydroxy-1-methylethyl)-1-({2′-[1-(phenylmethyl)-1H-
tetrazol-5-yl][1,1′-biphenyl]-4-yl}methyl)-2-propyl-1H-imidaz-
ole-5-carboxylate (12)3d
A mixture of 1-benzyl-5-phenyl-1H-tetrazole (2; 0.945 g, 4 mmol), 11
(1.80 g, 4.4 mmol, 1.1 equiv), [RuCl2(p-cymene)]2 (0.245 g, 0.4 mmol,
10 mol%), mesitylenecarboxylic acid (0.197 g, 1.2 mmol, 0.3 equiv),
and K2CO3 (1.7 g, 12 mmol, 3 equiv) in 1,4-dioxane (4 mL) was stirred
at 120 °C for 18 h under N2 atmosphere. To the mixture was added
activated carbon (0.25 g) and EtOAc (3 mL) and filtered through Celite.
The solid materials were washed thoroughly with EtOAc. The filtrate
and washings were combined and evaporated. The residue was puri-
fied by silica gel column chromatography (n-hexane/EtOAc 1:1) to
give 12 as a white fine solid; yield: 1.33 g (59%); mp 88–91 °C (EtOAc/
n-hexane).
1H NMR (400 MHz, CDCl3):  = 7.63 (1 H, ddd, J = 8.0, 7.8, 1.2 Hz), 7.53
(1 H, dd, J = 7.8, 1.2 Hz), 7.43 (1 H, ddd, J = 7.8, 7.4, 1.6 Hz), 7.31 (1 H,
dd, J = 7.6, 0.8 Hz), 7.23–7.13 (3 H, m), 7.07 (2 H, d, J = 8.8 Hz), 6.84 (2
H, d, J = 8.0 Hz), 6.78 (2 H, d, J = 6.8 Hz), 5.76 (1 H, br s), 5.42 (2 H, s),
4.82 (2 H, s), 4.21 (2 H, q, J = 7.2 Hz), 2.63 (2 H, t, J = 8.0 Hz), 1.72 (2 H,
m), 1.64 (6 H, s), 1.16 (3 H, t, J = 7.6 Hz), 0.97 (3 H, t, J = 7.6 Hz).
13C NMR (CDCl3):  = 166.5, 154.8, 154.5, 141.0, 137.8, 137.2, 133.2,
131.6, 131.4, 130.6, 130.2, 128.7, 128.5, 127.9, 127.8, 127.6, 127.4,
122.8, 122.7, 120.7, 115.5, 110.8, 52.6, 50.7, 45.8, 36.4, 13.6.
HRMS: m/z [M + H]+ calcd for C32H29N6O3: 545.2256; found: 545.2301.
Methyl 2-Ethoxy-1-({2′-[1-(phenylmethyl)-1H-tetrazol-5-yl][1,1′-
biphenyl]-4-yl}methyl)-1H-benzimidazole-7-carboxylate (7)3f
A mixture of 1-benzyl-5-phenyl-1H-tetrazole (2; 0.5 g, 2.12 mmol), 8
(0.907 g, 2.33 mmol, 1.1 equiv), [RuCl2(p-cymene)]2 (0.13 g, 0.212
mmol, 10 mol%), N-Piv-L-ValOH (0.128 g, 0.636 mmol, 0.3 equiv), and
K2CO3 (0.879 g, 6.36 mmol, 3.0 equiv) in 1,4-dioxane (3 mL) was
stirred at 120 °C for 16 h under N2 atmosphere. To the mixture was
added activated carbon (0.13 g) and EtOAc (2 mL) and filtered through
Celite. The solid materials were washed thoroughly with EtOAc. The
filtrate and washings were combined and evaporated. The residue
was purified by silica gel column chromatography (n-hexane/EtOAc
2:1) to give 7 as white prisms; yield: 0.485 g (42%); mp 146 °C (EtOAc/
n-hexane).
MS: m/z = 565 [M + H]+.
Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1472-0925. Su
1H NMR (CDCl3):  = 7.73 (1 H, d, J = 7.6 Hz), 7.57–6.89 (13 H, m), 6.71
(2 H, d, J = 7.2 Hz), 5.59 (2 H, s), 4.68 (4 H, m), 3.76 (3 H, s), 1.50 (3 H, t,
J = 7.2 Hz).
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References
13C NMR (CDCl3):  = 166.8, 158.8, 154.6, 142.1, 141.2, 137.9, 137.4,
133.2, 131.6, 131.5, 131.4, 130.2, 128.8, 128.7, 128.6, 128.0, 127.8,
127.4, 123.8, 122.8, 122.1, 121.1, 115.8, 66.9, 52.5, 50.8, 46.9, 14.8.
(1) (a) Kubo, K.; Inada, Y.; Kohara, Y.; Sugiura, Y.; Ojima, M.; Itoh,
K.; Furukawa, Y.; Nishikawa, K.; Naka, T. J. Med. Chem. 1993, 36,
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Y.; Furukawa, Y.; Nishikawa, K.; Naka, T. J. Med. Chem. 1993, 36,
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J. Org. Chem. 2011, 76, 10198. (c) Seki, M. Synthesis 2012, 44,
3231. (d) Seki, M. RSC Adv. 2014, 4, 29131. (e) Seki, M. Synthesis
2014, 46, 3249. (f) Seki, M. ACS Catal. 2014, 4, 4047. (g) Seki, M.
Arylation Using a Ruthenium(II) Catalyst, In Science of Synthesis,
Catalytic Transformation via C–H Activation, Vol. 1, Chap. 1.1.4;
Yu, J.-Q., Ed.; Thieme Verlag: Stuttgart, 2015, 119–154. (h) Seki,
M. Synthesis 2015, 47, 1423. (i) Seki, M. Synthesis 2015, 47, 2985.
(j) Seki, M. Org. Process Res. Dev. 2016, 20, 867.
MS: m/z = 545.40 [M + H]+.
Ethyl 1-(4-Bromobenzyl)-4-(1-hydroxy-1-methylethyl)-2-propyl-
1H-imidazole-5-carboxylate (11)
A mixture of ethyl 5-(1-hydroxy-1-methylethyl)-2-propyl-3H-imid-
azol-4-carboxylate (10; 10 g, 41.7 mmol), K2CO3 (7.1 g, 51.6 mmol),
and 4-bromobenzyl bromide (10.8 g, 43 mmol) in DMA (40 mL) was
stirred at 25 °C for 48 h. After completion of the reaction, H2O (120
mL) was added to the reaction mixture. The solids formed were col-
lected and recrystallized from EtOAc/n-hexane to give 11 as a white
fine solid; 13.6 g (80%); mp 86 °C (EtOAc/n-hexane).
1H NMR (400 MHz, CDCl3):  = 7.44 (2 H, d, J = 8.4 Hz), 6.81 (2 H, d, J =
8.0 Hz), 5.75 (1 H, br s), 5.41 (2 H, s), 4.22 (2 H, q, J = 7.2 Hz), 2.61 (2 H,
t, J = 7.6 Hz), 1.70 (2 H, m), 1.64 (6 H, s), 1.16 (3 H, t, J = 7.2 Hz), 0.94 (3
H, t, J = 7.2 Hz).
(4) Hubrich, J.; Ackermann, L. Eur. J. Org. Chem. 2016, 3700.
(5) Yeung, C. S.; Hsieh, T. H. H.; Dong, V. M. Chem. Sci. 2011, 2, 544.
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–D