Synthesis of angiotensin II receptor blockers by means of a catalytic system for C-H Activation

Article abstract of DOI:10.1021/jo202041e

A highly efficient catalytic system for C-H activation has been worked out that involves inexpensive RuCl₃·xH₂O and a specific amount of PPh₃. This procedure has been successfully applied to a practical synthesis of angiotensin II receptor blockers (ARBs). The residual ruthenium that existed in the reaction mixture was thoroughly removed by treatment with properly selected metal scavengers. The new process permits ready access to the important class of drugs in a highly atom-economical and sustainable manner (Figure presented).

Full text of DOI:10.1021/jo202041e

Article
pubs.acs.org/joc
Synthesis of Angiotensin II Receptor Blockers by Means of a Catalytic
System for C−H Activation
Masahiko Seki* and Masaki Nagahama
Process Research & Development Laboratory, API Corporation 1-1, Shiroishi, Kurosaki, Yahatanishi-ku, Kitakyushu, Fukuoka
806-0004, Japan
S
* Supporting Information
ABSTRACT: A highly efficient catalytic system for C−H activation has been
worked out that involves inexpensive RuCl3·xH2O and a specific amount of PPh3.
This procedure has been successfully applied to a practical synthesis of
angiotensin II receptor blockers (ARBs). The residual ruthenium that existed in
the reaction mixture was thoroughly removed by treatment with properly selected
metal scavengers. The new process permits ready access to the important class of
drugs in a highly atom-economical and sustainable manner.
methods have critical drawbacks of need of stoichiometric
amounts of expensive and/or hazardous organometallics
such as Grignard reagents and boronic acids to install the
fundamental biphenyltetrazole framework.6
To address the challenge, the authors have considered
synthesizing them through C−H activation. New insights into
C−H activation have merged on a daily basis. However, the
commercial application is still rare and challenging. There are
significant drawbacks such as need of unaffordable amount of
precious metals and toxic chemicals like silver salts.4a,c,k,x,y
Described herein is our course of the investigation on an
efficient catalytic system for the C−H activation and application
of the technology to a practical synthesis of ARBs 1.7
INTRODUCTION
■
To comply with the recently enhanced need to produce organic
substances with minimum amount of reagents and energy,
development of a truly efficient synthetic method has recently
been a subject of much attention and urgent need. To address the
challenge, organic chemists from both academia and industries have
focused on a more atom-economical approach whose E-factor is
conceptually low.1 The carbon−carbon bond formation is one of
the most important classes of the reactions that enable construction
of sophisticated architecture of organic molecules. Especially, the
bond formation through the C−H activation2−4 is one of the most
modern and well-recognized tactics of this category.
In the meantime, to produce active pharmaceutical
ingredients (APIs) of high quality and lower cost is a significant
goal for process chemists in pharmaceutical communities.
Through the efforts, the resulting low price APIs can save many
lives of people who are otherwise unable to access the drugs
that are crucial to maintain their lives. Angiotensin II receptor
blockers (ARBs) 1 have received much attention as one of the
most efficient antihypertensives due to their high efficacy and
safety (Figure 1).5 Annual production of ARBs is more than
1000 t. ARBs contain a biphenyltetrazole unit as the key and
common structural motif. However, the previous synthetic
RESULTS AND DISCUSSION
■
Our strategy for the synthesis of ARBs 1 is shown in Scheme 1.
The synthesis utilizes C−H activation for the key biphenyl
formation. This type of C−H activation has been demonstrated for
benzene derivatives substituted with nitrogen-containing hetero-
cycles such as oxazoline, oxazole, imidazoline, imidazole and
pyrazole as the directing group.2,3a,b,d,g−i,o,q,r Site-selective C−H
activation has been realized through formation of a cyclometalated
intermediate by chelation of a transition metal. The C−H bond α
to the phenyltetrazole derivative 2 is supposed to be activated as
well by means of chelation of Ru with the tetrazole moiety which
permits the coupling of 2 with aryl bromide 3a. The resulting
biphenyl derivative 4 might readily be converted to bromide
5 which, upon coupling with various functionalized fragments
(R−H) followed by deprotection, would provide ARBs 1 in very
short steps and in a highly convergent manner.
Synthesis of 1-N-Protected Phenyltetrazole Deriva-
tives. Synthesis of the protected phenyltetrazole 2a or 7 was
Received: October 6, 2011
Published: October 28, 2011
Figure 1. Structure of compounds 1.
© 2011 American Chemical Society
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Scheme 1. Strategy for the Synthesis of ARBs (1)
Scheme 2. Synthesis of Protected Phenyltetrazoles (2a, 7)
and Biphenylation
a
first investigated using 4-methoxybenzyl (PMB) group as the
protecting group. In our initial study the compounds were
synthesized by alkylation of commercially available 1-phenyl-
5H-tetrazole 6 (Scheme 2).6a However, regioselectivity of the
alkylation was poor to give a mixture of 1-N- and 2-N-protected
phenyltetrazoles 2a and 7 as a mixture of 2a/7 = 73:27. In
addition, in the biphenylation (vide infra), 2-N-protected
phenyltetrazole 7 provided considerable amount of diarylation
byproduct 10 beside the desired monoarylation counterpart 9
even at low conversion of the substrate (Figure 2).8
The disappointing results led us to test an alternative
approach9 employing readily available benzylamine derivatives
11a,b as the starting material and was found to give exclusively
the desired 1-N-protected phenyltetrazoles 2a,b in high yields
(Scheme 3). 2-MeO-Bn derivative 2b was stable solids and easy
to be isolated by simple crystallization.
Biphenylation through C−H Activation. This type of
aryl−aryl coupling in which a nitrogen-containing heterocycle
serves as the directing group for the C−H activation has been
reported.2,3a,b,d,g−i,o,q,r In our initial study, the biphenylation of
1-N-protected phenyltetrazole 2 with aryl bromide 3a was thus
examined by the use of the literature precedent catalyst and
procedure.3a We chose Ru complex as the catalyst. Actually, the
Ru catalysis of the direct C−H arylation performs better than
the Pd counterpart for the 6-phenylpurine derivatives.3y,4gg The
protected phenyltetrazole 2a was treated with aryl bromide 3a
in the presence of [RuCl2(C6H6)]2 (8a) (Ru = 10 mol %) and
K2CO3 in NMP at 140 °C. As expected, the desired biphenyl 4a
was obtained in 48% yield (Table 1, Entry 1). However, the
catalyst 8a is not available on scale and is not applicable to
the commercial production. The use of less expensive
[RuCl2(COD)]n 8b resulted in unsatisfactory improvement
(63%, Table 1, Entry 2). RuCl2(PPh3)3 8c, obtained as stable
catalysts by treatment of inexpensive RuCl3·xH2O with excess
a
Biphenylation conditions: for 2a, 3a (2.5 equiv), 8a (Ru = 10 mol %),
PPh3 (20 mol %), K2CO3 (4 equiv), 140 °C, 12 h; for 7, 3a (1 equiv), 8a
(Ru = 10 mol %), PPh3 (20 mol %), K2CO3 (4 equiv), 140 °C, 12 h.
a dramatical increase of yield (81%) with an extremely low
catalyst loading (1.3 mol %) was accomplished by employing a
specific amount of PPh3 (PPh3/Ru = 1.8/1) (Table 1, Entry 7).
By either lowering or heightening the ratio of PPh3, the
conversion remarkably dropped down (Figures 3 and 4). The
arylation via C−H activation employing inexpensive
RuCl3·xH2O (8d) is known,3c,d but combined use of 8d with
a phosphine ligand has never been demonstrated in this type of
reaction.2 The present reaction did not take place well in the
absence of PPh3 (Table 1, Entry 4). The reaction with aryl
bromides carrying a hydroxyl or an aldehyde group, both of
which can provide the intermediate for further elaboration, gave
no desired product (Table 1, Entries 10, 11). Those unfavorable
results are accounted for by their reducing ability of ruthenium
catalysts to undesirable low valent species such as Ru0 black.12
There is a possibility that the benzyl cation generated by
elimination of the acetoxy group in 3a can participate in the reac-
tion.13 However, any products attributable to such transformations
were not detected in the reaction mixture. The water in
RuCl3·xH2O (8d) has a significant role in the reaction because
10
PPh3 was tested and found to give 4a in a moderate yield
(Table 1, Entry 3). To address this challenge, the authors
focused on a recently published literature. They noted in the
literature that unstable catalyst species are expected to provide
higher rate acceleration since it would decrease the activation
energy by heightening energy level of the ground state.11 With
the concept in mind, the authors came up with an idea in
which experiments employing inexpensive RuCl3·xH2O (8d)
with varying amount of PPh3 might result in a discovery of a
better catalytic system (Table 1, Entries 4−9). As we expected,
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Table 1. Synthesis of Biphenyltetrazoles 4 through C−H
Activation
Figure 2. Reaction profile of the biphenylation using 2-PMB-
phenyltetrazole 7. The biphenylation conditions: 3a (1 equiv), 8a
(Ru = 10 mol %), PPh3 (20 mol %), K2CO3 (4 equiv), 140 °C.
Selectivity: 9/(9 + 10) × 100.
Ru
ligand/ yield
c
a
b
entry
sub.
cat.
ligand
PPh3
Ru (mol %)
Ru
(%)
d
1
2a, 3a
2a, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3b
2b, 3c
2b, 3a
2b, 3a
8a
8b
8c
8d
8d
8d
8d
8d
8d
8d
8d
8e
8e
8d
8a
8a
8d
8d
8d
8d
8d
8d
8d
8d
8d
10
2.0
2.0
3.0
0
48
d
2
PPh3
10
63
Scheme 3. Improved Synthesis of 1-N-Protected Pheny-
ltetrazoles 2
3
10
31
14
65
70
81
64
4
4
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
10
5
PPh3
1.0
1.5
1.8
2.0
3.0
1.8
1.8
1.8
1.8
2.0
2.0
2.0
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
0.9
6
PPh3
7
PPh3
PPh3
8
9
PPh3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
PPh3
0
PPh3
0
e
PPh3
3
f
e
PPh3, H2O
PPh3
3
g
2c, 3a
7
0
neither anhydrous RuCl3 (8e) nor 8e with external addition of
equal amount of water to that in 8d (i.e., 2.5 molar equiv to Ru)
catalyzed the reaction (Table 1, Entries 12 and 13). The role of
water in RuCl3·xH2O (8d) can be dissolving the catalyst into
the reaction mixture. Water itself does not interfere with the
reaction, because the biphenylation can be facilitated by
employing water as the solvent.3q However, in the present
case, addition of water more than 5 wt % resulted in a lower
conversion, possibly due to the removal of the acetoxy group in
bromide 3a and biphenyl 4. The resulting benzyl alcohol
derivatives are supposed to deteriorate the biphenylation (vide
supra).
Another substrate 2c and 2d carrying a protective group such
as sterically more demanding DPM (diphenylmethyl) group
and Tri (trityl) group,6a respectively, were then tested, because
deblocking of the protecting group would be much easier.
However, the use of 2c and 2d gave either very poor yield or
none of the desired product 4c and 4d, respectively (Table 1,
Entries 14 and 15). In case of 2d, the trityl group was cleaved
under the reaction conditions. Finally, the unprotected 5-phenyl-
1H-tetrazole 2e was tested. But no reaction took place possibly
due to the catalytic poison caused by the free NH group in 2e.6a
From the results descrived above, the methoxy-subsituted benzyl
group (PMB, OMB) was chosen as the protecting group for
5-phenyl-1H-tetrazole in the biphenylation reaction.
g
2d, 3a
PPh3
2e, 3d
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
2b, 3a
PPh3
10
0
P(2-MePh)3
P(4-MePh)3
P(4-MeOPh)3
P(4-FPh)3
P(4-CF3Ph)3
PPh2Cy
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
0
68
71
32
29
45
e
PCy3
17
e
XPhos
7
e
dppe
13
a
Biphenylation conditions: 3 (1.1 equiv), K2CO3 (2 equiv), 140 °C.
8a, [RuCl2(C6H6)]2; 8b, [RuCl2(COD)]n; 8c, RuCl2(PPh3)3; 8d,
RuCl3·xH2O; 8e, RuCl3. Assay yield of the biphenylation product
measured by HPLC. Isolated yield purified by silica-gel column
b
c
d
e
f
chromatography. Conversion assayed by HPLC. Relative to 8e, 2.5
equiv was added. Prepared according to a literature.14
g
PPh3 resulted in much inferior yields (Table 1, Entries 20−25).
Fortunately, very simple and inexpensive PPh3 is thus the
optimal phosphine ligand for the biphenylation.
A possible mechanism of the biphenylation is illustrated in
Scheme 4. RuII/RuIV mechanism is the most well recognized
mechanism2,3t and the intermediates such as RuII ruthenacycle
derivative 13 has been isolated and demonstrated to provide
biphenylation product under biphenylation conditions.3t,v From
the results shown in Table 1, Entries 4−9, Figures 3 and 4), the
use of excess PPh3 deteriorated the reaction possibly by
forming a stable complex like RuCl2(PPh3)3 8c to kick out the
carboxylate anion in 1215 which is required for the abstraction
of hydrogen atom of the C−H bond. And the excess addition of
PPh3 might effect reduction of the Ru complexes to inactive
The screening of the phosphine ligands was further
conducted. As shown in Table 1, Entries 17−19, the steric
bulk of the ligand is quite sensitive to the reaction: the use of
2-Me-Ph3P resulted in no conversion at all though 4-Me-Ph3P
or 4-MeO-Ph3P gave slightly inferior yields compared to PPh3.
Other phosphine ligands with an electron-withdrawing group
or an alkyl substituent or bidentate phosphine ligands instead of
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which undergoes oxidative addition of aryl bromide 2a may
furnish complex 14. Complex 14 can be an unstable <16
electron species and thus might rapidly provide the desired
biphenyl 4a and regenerate RuII complex 12 to complete the
catalytic cycle.
Recovery/Removal of the Residual Ru with Metal
Scavengers. Drug substances require extremely high quality
as governed by good manufacturing practice (GMP).1 The
residual metal, for example, Ru, in active pharmaceutical
ingredient (API) must not exceed 10 ppm. To substantiate the
absence of the residual metals in API as well as to minimize loss
of the precious metals into the waste stream are thus to be
indispensable criteria and frequently encountered concern in
the process development. With this in mind, we have initiated
to explore an efficient and reliable method for recovery of the
ruthenium in the biphenylation reaction, a key step of the
present synthesis.
Figure 3. Reaction profile of the biphenylation of 2a to 4a. For the
biphenylation conditions, see Table 1, Entries 4−9.
The use of metal scavengers for recovery of transition metals
has been implemented with some measure of success.17 They
carry functional groups on polymer (e.g., polypropylene,
viscose, silica beads) to absorb selectively the precious metals
from the mixture (Figure 5). Generally, to achieve an efficient
Figure 4. Conversion at 1.4 h in the biphenylation of 2a to 4a. For
entire reaction profile of the biphenylation, see Figure 3.
Scheme 4. Possible Mechanism of the Biphenylation of 2b
to 4b
Figure 5. Structure of metal scavengers. “Smopex” is a series of metal
scavengers in which functional groups are located on the surface of the
fiber. In case of “Quadrasil”, the supported materials are slica-gel.
recovery of the metals, proper choice of scavengers carrying
specific functional group and other parameters such as solvent,
temperature and contact time need to be fully optimized.
The aqueous and organic phases, obtained through the
workup after the biphenylation reaction, were submitted to the
recovery experiments. By screening a wide range of com-
mercially available scavengers,18 Smopex-234 and Quadrasil-
MP carrying thiol group absorbed Ru in 84.6 and 98.3% yield,
respectively (Table 2, Entries 3, 4). In marked contrast, for the
aqueous phase, treatment with a combination of Smopex-101
and 234, which have sulfonic acid and thiol group, respectively,
recovered Ru more effectively (85.8%) than employing the
individual counterpart (64.6 and 35.4%, respectively) (Table 2,
Entry 7 versus Entries 5, 6). The difference of the performance
of the scavengers may attribute to the different distribution of
the metal species among the two phases (oxidized or reduced
form with or without ligand). From the results described above,
the residual Ru in the biphenylation is able to be removed/
recovered effectively by proper use of the metal scavengers.
Conversion to ARBs. The obtained biphenyl 4a,b was
readily converted to ARBs 1 as exemplified by the synthesis of
Losartan (1a) and Valsartan (1b) (Schemes 5−7). The biphenyl
4a was first converted to alcohol 15 followed by bromination
provided bromide 16 which is regarded as a key and common
intermediate for ARB synthesis. This compound 16 was coupled
with imidazole aldehyde 17 to give the alkylated product 18
Ru0 black to terminate the reaction.12 Since the use of 1.8 equiv
of PPh3 relative to Ru is optimal and 0.5 equiv of PPh3 is
required for reduction of RuIII to RuII (Table 1, Entry 7), one
molecule of PPh3 possibly coordinates to Ru as complex 12
in which one L is PPh3.16 The addition mode in the present
biphenylation is important as well. Prior heating of
RuCl3·xH2O (6d) (1.3 mol %) and PPh3 (1.3 × 1.8 mol %)
in NMP at 140 °C for 1 h followed by addition of 2b and 3a
(1.1 equiv) and K2CO3 (2 equiv) at room temperature and
then heating the mixture at 140 °C for 12 h resulted in a poor
yield of 4b (42%). As we expected (vide supra), it may
demonstrate that the transient Ru complex is unstable (active)
and, to achieve a higher conversion, the substrates need to
coexist with the active catalyst species formed in situ during the
reaction. Complex 12 reversibly3t provides the ruthenacycle 13
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Table 2. Recovery/Removal of the Residual Ru with Metal
Scavengers
Scheme 6. Synthesis of Losartan (1a) from 18
Ru concentration
a
b
entry
Aqueous phase
− (Initial)
scavengers
(mg/L)
recovery (%)
117
104
87
1
2
3
4
Smopex-101
Smopex-105
Smopex-234
Quadrasil-MP
11.1
25.6
84.6
98.3
18
2
Organic phase
− (Initial)
117
40
5
6
7
Smopex-101
64.6
35.4
85.8
Scheme 7. Synthesis of Valsartan (1b)
Smopex-234
73
Smopex-101 +
234
16
a
Screen was conducted by employing 5 w/v% of the scavenger (0.5 g
b
in 10 mL solution) at 60 °C for 18 h. Assayed by ICP analysis.
Scheme 5. Synthesis of Losartan Intermediate 18
converted to alcohol 21 and subjected to coupling with L-valine
benzyl ester without isolation of potentially hazardous bromide.
The in situ bromination and subsequent coupling was accomplished
by treatment of 21 with TMSBr followed by L-valine benzyl ester in
the presence of iPr2EtN in CH3CN. The product was acylated and
deprotected by transfer hydrogenation to furnish Valsartan (1b) in
excellent yield. It should be noticed that proper selection of Pd−C is
crucial for the clean deprotection. The oxidized egg shell type Pd−C
performed better than thick shell oxidized or egg shell reduced
counterparts.20
regioselectively6a and in high yield (Scheme 4). The removal of
the protecting group of the tetrazole unit was conducted before
reduction of aldehyde 18 to corresponding alcohol 19 because
facile formation of carbocation from benzylic alcohol in 19 would
lead to many side products. Treatment of 18 with TFA in the
presence of carbocation scavenger (anisole) smoothly removed
the p-methoxybenzyl (PMB) group to provide the desired
deprotected aldehyde 20 quantitatively.19 The compound 20 was
finally converted to Losartan (1a) by reduction with NaBH4 in
aq. NaOH.
CONCLUSIONS
■
In summary, a highly efficient catalytic system for C−H
activation has been developed which was applied to a practical
synthesis of ARBs 1. The efficient catalytic system has been
developed by changing the amount of phosphine ligand to Ru.
The present work demonstrates importance of this approach to
develop an efficient catalytic system. Applying the C−H
activation significantly reduces E-value compared to previous
methods making the synthesis significantly green. The short
steps, easy operation and low cost of the present process would
enable a much facile access to ARBs than previous methods.
The synthesis of Valsartan (1b) started from 2-methoxy-
benzyl protected biphenyl 4b, which is derived from readily
available 2-methoxybenzyl protected phenyltetrazole 2b. It was
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AcOEt and combined extracts were washed with sat. aq. NaCl, dried
over anhydrous MgSO4 and evaporated. The solids formed were
collected by adding AcOEt and dried to give N-benzoyl-
p-methoxybenzylamine (273 g, 85.6%). To a mixture of N-benzoyl-
p-methoxybenzylamine (20 g, 82.9 mmol) in CH2Cl2 (161 mL) was
added PCl5 (19.1 g, 91.5 mmol) at −16 to −12 °C over 11 min and
the mixture was warmed up to 17 °C for 1 h. The mixture was
evaporated to ca. 50 mL under 17 °C. The mixture dissolved in
CH2Cl2 (112 mL) was added TMSN3 (14.0 g, 122 mmol) at −10 to
−8 °C over 12 min. The mixture was stirred at 20 °C for 8 h. Into the
mixture was added dropwise sat. aq. NaHCO3 (350 mL). The phase
was separated and the aqueous layer was extracted with CH2Cl2. The
organic phases were combined and washed with sat. aq. NaCl2, dried
over anhydrous MgSO4 and evaporated. The crude prodcut was
purified by silica gel column chromatography (hexane/AcOEt = 3:1)
to give 2a (22.3 g, 95.8% based on N-benzoyl-p-methoxybenzylamine)
in colorless crystals (content: 94.7% measured by HPLC (Cadenza
CD-C18, 4.6 × 150 mm, 3 μm, MeCN/30 mmol/L KH2PO4 = 11:9,
225 nm, 40 °C, 1.0 mL/min). The reference sample of 2a was
obtained by recrystallization from AcOEt and hexane), The character-
ization data of the product 2a were in good accordance with those
obtained by the product from 6 (vide supra).
EXPERIMENTAL SECTION
■
General. Melting points are uncorrected. 1H and 13C NMR
spectra (400 and 100 MHz, respectively) were recorded with
tetramethylsilane used as an internal standard. Silica gel column
chromatography was performed using Kieselgel 60 (E. Merck). Thin-
layer chromatography (TLC) was carried out on E. Merck 0.25 mm
precoated glass-backed plates (60 F254). Development was accom-
plished using 5% phosphomolybdic acid in ethanol-heat or visualized
by UV light where feasible. Ruthenium catalysts 8a-8e were purchased
from Johnson Matthey and Sigma Aldrich. Metal scavengers are
available at Johnson Matthey. All solvents and reagents were used as
received.
1-(p-Methoxybenzyl)-5-phenyl-1H-tetrazole 2a and 2-(p-Me-
thoxybenzyl)-5-phenyl-1H-tetrazole 7. To a mixture of 6 (14.6 g,
0.1 mol), K2CO3 (15.9 g, 0.15 mol), tetra-n-butylanmmonium
bromide (0.71 g, 2.2 mmol) in water (120 mL) was added dropwise
a solution of 4-methoxybenzyl chloride (15.4 g, 98 mmol) in CHCl3
(160 mL) over 1 h at 10 °C and the mixture was stirred at 55 °C for
1 h. The aqueous phase was extracted with CHCl3 and combined
organic solution was dried over anhydrous MgSO4 and evaporated.
Into the residue in THF (100 mL) were added Ac2O (6 g, 59 mmol),
Et3N (1.8 g, 18 mmol) and 4-N,N-dimethylaminopyridine (0.66 g, 5.4
mmol). The mixture was stirred at 20 °C for 1 h. Methanol (20 mL)
was added and the mixture was evaporated. The residue was dissolved
in AcOEt and washed with water, dried over anhydrous MgSO4 and
evaporated. The residue was purified by silica gel column
chromatogaraphy (hexane/AcOEt = 3:1) to give 2a21 (13.7 g,
52.6%) and 7 (5.1 g, 19.4%). 2a: mp 37.7−38.3 °C; IR (KBr): ν
{2′-[1-(p-Methoxybenzyl)-1H-tetrazol-5-yl}biphenyl-4-yl}methyl
Acetate 4a. A mixture of 2a (160 mg, 0.60 mmol), 3a (345 mg, 1.5
mmol), [RuCl2(COD)]n, 8c (16.9 mg, 0.06 mmol), PPh3 (31.8 mg,
0.12 mmol) and K2CO3 (333 mg, 2.4 mmol) in NMP (1.2 mL) was
stirred at 140 °C for 2 h. Into the mixture was added AcOEt (9 mL)
and the mixture was filtered. The filtrate was evaporated to give crude
product (504 mg). A portion of the material (419 mg) was purified by
silica gel column chromatography (hexane/AcOEt = 4:1) to provide
1
1611 cm−1; H NMR (400 MHz, CDCl3): δ 7.48−7.62 (m, 5H),
7.08−7.13 (m, 2H), 6.84−6.88 (m, 2H), 5.55 (s, 2H), 3.79 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 159.0, 154.3, 131.1, 129.0, 128.8,
128.6, 125.7, 123.8, 114.4, 55.4, 51.0; MS m/z: 266 [M]+. 7: mp 56.5−
1
4a (131 mg, 63%) in colorless oil. IR (KBr): ν 1612 cm−1; H NMR
(400 MHz, CDCl3) δ 7.62−7.68 (m, 1H), 7.57 (dd, J = 8.0, 0.8 Hz,
1H), 7.43−7.48 (m, 1H), 7.35 (dd, J = 7.6, 1.2 Hz, 2H), 7.24−7.29
(m, 2H), 7.10−7.15 (m, 2H), 6.64−6.72 (m, 4H), 5.08 (s, 2H), 4.75
(s, 2H), 3.73 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.3, 159.3, 153.9, 140.9, 138.4, 135.6, 131.3, 130.9, 130.0, 129.1,
128.5, 128.2, 127.7, 124.8, 122.5, 113.8, 65.4, 55.1, 50.4, 20.9; EIMS
m/z: 414 [M]+; Anal. Calcd for C24H22N4O3: C, 69.55; H, 5.35; N,
13.52; Found: C, 69.36; H, 5.15; N, 13.45.
1
57.0 °C; IR (KBr): ν 1610 cm−1; H NMR (400 MHz, CDCl3): δ
8.10−8.15 (m, 2H), 7.42−7.51 (m, 3H), 7.39 (d, J = 8.4 Hz, 2H), 6.90
(d, J = 8.4 Hz, 2H), 5.74 (s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 165.1, 159.8, 130.1, 129.9, 128.7, 127.3, 126.7, 125.3, 114.2,
56.5, 55.7; EIMS m/z: 266 [M]+; Anal. Calcd for C15H14N4O: C,
67.65; H, 5.30; N, 21.04; Found: C, 67.44; H, 5.13; N, 21.03.
{2′-[2-(p-Methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl
acetate 9 and {2′-[2-(p-Methoxybenzyl)-2H-tetrazol-5-yl]-1,1′:3′,1″-
terphenyl-4,4″-diyl}dimethyl Diacetate 10. A mixture of 7 (228 mg,
0.86 mmol), 3a (490 mg, 2.1 mmol), [RuCl2(benzene)]2, 8a (21.4 mg,
0.086 mmol), PPh3 (44.9 mg, 0.17 mmol) and K2CO3 (474 mg,
3.4 mmol) in NMP (1.7 mL) was stirred at 140 °C. The reaction was
monitored by HPLC (Cadenza-CD-C18, 3 μm, 4.6 × 150 mm,
CH3CN/30 mM KH2PO4 = 3:2, 225 nm, 40 °C, 1 mL/min) and
described in Figure 2. To the mixture was added AcOEt and the
mixture was wshed with sat. aq. NaCl dried over anhydrous MgSO4
and evaporated. The authentic samples of 9 and 10 were obtained by
purifying the residue by thin layer chromatography (hexane/AcOEt =
1.5:1). 9 (72.9 mg, 21%): oil; IR (KBr): ν 1613, 1733 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.86−7.84 (m, 1H), 7.52−7.42 (m, 3H), 7.26−
7.11 (m, 6H), 6.66−6.80 (m, 2H), 5.56 (s, 1H), 5.10 (s, 1H), 3.81
(s, 3H), 2.12 (s, 3H); 13C-NMR (DMSO-d6) δ 170.9, 165.4, 159.9,
141.5, 140.9, 134.5, 130.7, 130.4, 130.0, 129.9, 129.4, 127.8, 127.6,
126.2, 125.4, 114.1, 66.1, 56.1, 55.3, 21.1. HRMS: Calcd for
C24H22N4O3, 414.1692; Found 414.1690 [M]+. 10 (106 mg, 22%):
{2′-[1-(p-Methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}-
methanol 15. To a mixture of 4a (268 mg, 0.65 mmol) in MeOH
(15 mL) was added NaOMe in MeOH (125 mg, 0.65 mmol) and the
mixture was stirred at 20 °C for 1.5 h. The mixture was evaporated and
the residue was purified by silica gel column chromatography (hexane/
AcOEt = 2:1) to provide 15 in cloreless oil (216 mg, 90%). IR (KBr):
ν 1612 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.61−7.67 (m, 1H), 7.57
(dd, J = 8.0, 1.2 Hz, 1H), 7.41−7.46 (m, 1H), 7.33 (dd, J = 7.6, 1.2
Hz, 1H), 7.24−7.29 (m, 2H), 7.08−7.12 (m, 2H), 6.63−6.72 (m, 2H),
4.74 (s, 2H), 4.68 (s, 2H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 159.4, 154.2, 141.2, 140.8, 137.7, 131.4, 131.0, 130.1, 129.2, 128.5,
127.6, 127.1, 124.9, 122.5, 113.9, 64.4, 55.2, 50.2; EIMS m/z: 372
[M]+; HRMS: Calcd for C22H20N4O2, 373.1655 [M + H]+. Found
373.1654 [M + H]+.
5-[4′-(Bromomethyl)biphenyl-2-yl]-1-(p-methoxybenzyl)-1H-tet-
razole 16. To a solution of 15 (891 mg, 2.39 mmol) in THF (80 mL)
was added PBr3 (1.3 g, 4.8 mmol) at 0 °C over 1.5 h. The mixture was
stirred at 20 °C for 4 h. Into the mixture was added water and the
mixture was extracted with AcOEt. The organic phase was washed
with water, dried over anhydrous MgSO4 and evaporated. The residue
was purified by silica gel column chromatography (hexane/AcOEt =
2:1) to afford 16 in yellow oil (1.09 g, quant.). IR (KBr): ν 1611 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.62−7.68 (m, 1H), 7.55−7.59 (m,
1
mp 103.2−106.4 °C; IR (KBr): ν 1734, 1613 cm−1; H NMR (400
MHz, CDCl3) δ 7.61−7.57 (m, 1H), 7.44−7.40 (m, 2H), 7.10 (s, 8H),
6.98−6.96 (m, 2H), 6.81−6.79 (m, 2H), 5.50 (s, 2H), 5.02 (s, 4H), 3.82
(s, 3H), 2.11 (s, 6H); 13C-NMR (DMSO-d6) δ 170.9, 163.9, 159.8,
143.2, 140.3, 134.5, 129.9, 129.4, 129.3, 129.2, 127.6, 125.59, 125.55,
114.03, 65.9, 56.0, 55.3, 21.0. HRMS: Calcd for C33H30N4O5, 562.2216
[M]+; Found 562.2266 [M]+.
1-(p-Methoxybenzyl)-5-phenyl-1H-tetrazole 2a. To a mixture of
p-methoxy benzylamine (181 g, 1.32 mol) and Et3N (134 g, 1.32 mol)
in THF (800 mL) was added dropwise benzoyl chloride (185 g,
1.32 mol) at <16 °C. The mixture was stirred at 20 °C for 3 h and
evaporated. To the mixture was added water (400 mL) and the
mixture was extracted with AcOEt. The water phase was extracted with
1H), 7.44−7.49 (m, 1H), 7.34−7.38 (m, 1H), 7.28−7.33 (m, 2H),
7.07−7.13 (m, 2H), 6.64−6.73 (m, 4H), 4.75 (s, 2H), 4.46 (s, 2H),
3.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5, 154.0, 140.8,
138.7, 137.5, 131.5, 131.1, 130.1, 129.4, 129.3, 128.9, 127.9, 124,9,
122.7, 114.0, 55.3, 50.6, 32.7; EIMS m/z: 434 [M]+; HRMS: Calcd for
C22H20N4OBr, 435.0820 [M + H]+. Found 435.0821 [M + H]+.
1-(o-Methoxybenzyl)-5-phenyl-1H-tetrazole 2b. To a mixture of
o-methoxy benzylamine (300 g, 2.19 mol) and Na2CO3 (232 g, 2.19
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1H NMR (CDCl3): δ 7.57−7.38 (m, 5H), 7.367−7.365 (m, 6H),
mol) in a mixture of water (1500 mL) and toluene (1500 mL) was
added dropwise benzoyl chloride (307 g, 2.19 mol) at 3−8 °C. The
mixture was stirred at 20 °C for 20 min and evaporated. The solids
formed was dissolved by adding CH2Cl2 and water. The organic phase
was separated and washed with water, dried over anhydrous MgSO4
and evaporated. The solids formed were collected by adding isopropyl
ether and dried to give N-benzoyl-o-methoxybenzylamine (530 g,
quant.). To a mixture of N-benzoyl-o-methoxybenzylamine (16 g, 66.3
mmol) in CH2Cl2 (139 mL) was added PCl5 (15.2 g, 73.1 mmol) at
−15 to −11 °C over 11 min and the mixture was warmed up to 21 °C
for 2 h. The mixture was evaporated under 20 °C. To the residue
dissolved in CH2Cl2 (111 mL) was added TMSN3 (11.2 g, 97.5
mmol). The mixture was stirred at 20 °C for 4 h. Into the mixture was
added dropwise sat. aq. NaHCO3 (280 mL). The phase was separated
and the aqueous layer was extracted with CH2Cl2. The organic phases
were combined and washed with sat. aq. NaCl2, dried over anhydrous
MgSO4 and evaporated. The solids formed were collected by adding
AcOEt to provide 2b (16.7 g, 94%) in colorless crystals. mp 100−102
°C; IR (KBr): ν 1603 cm−1; 1H NMR (DMSO-d6): δ 7.76 (dd, J = 7.9,
2.2 Hz, 2H), 7.65−7.60 (m, 3H), 7.32 (td, J = 8.0, 1.5 Hz, 1H), 7.09
(dd, J = 8.0, 1.5 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz,
1H), 5.64 (s, 2H), 3.58 (s, 3H); 13C NMR (DMSO-d6): δ 156.6,
154.3, 131.0, 130.1, 129.5, 129.0, 128.7, 124.0, 122.2, 120.4, 111.0,
55.2, 46.9. SIMS m/z: 267 [M + H]+; Anal. Calcd for C15H14N4O: C,
67.65; H, 5.30; N, 21.04; Found: C, 67.47; H, 5.12; N, 20.92.
7.26−7.21 (m, 4H), 6.78 (s, 1H); 13C-NMR (DMSO-d6) δ 155.0, 137.5,
131.4, 129.3, 129.1, 129.0, 128.8, 128.2, 123.9, 65.9. Anal. Calcd for C20H16N4:
C, 76.90; H, 5.16; N, 17.94; Found: C, 76.70; H, 4.97; N, 17.92.
{2′-[1-(Diphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl
Acetate 4c. A mixture of RuCl3·xH2O (8d) (Ru 40.01%, 6.7 mg, 27
μmol), PPh3 (12.2 mg, 46.5 μmol), 2c (552 mg, 1.77 mmol), K2CO3
(488 mg, 3.53 mmol), 3a (445 mg, 1.94 mmol) and NMP (2.2 mL)
was stirred under N2 atmosphere at 140 °C for 12 h. The mixture was
cooled to 20 °C and it was diluted with AcOEt (10 mL) and washed
twice with water, dried over MgSO4 and evaporated. The residue wqas
purified by preparative TLC (hexane/AcOEt = 4:1) to afford 4c (9.5
mg, 7%) in colorless crystals. mp 140.9−141.2 °C; IR (KBr): ν 1735,
1
1600 cm−1; H NMR (DMSO-d6): δ 7.66−7.64 (m, 1H), 7.58−7.56
(m, 1H), 7.46−7.43 (m, 1H), 7.29−7.27 (m, 1H), 7.24−7.21 (m, 2H),
7.19−7.16 (m, 8H), 6.69 (brs, 1H), 6.10 (s, 1H), 5.04 (s, 1H), 2.14
(s, 3H); 13C-NMR (DMSO-d6) δ 170.8, 155.1, 141.4, 138.5, 136.7,
135.9, 131.6, 131.3, 130.4, 129.2, 128.6, 128.5, 128.3, 128.0, 127.9,
122.8, 65.9, 65.4, 21.0. HRMS: Calcd for C29H24N4O2, 460.1899 [M]+;
Found 460.1897 [M]+.
Recovery of Ru from the Mixure Obtained through the
Bipnenylation of 2b to 4b. A mixture of RuCl3·xH2O (8d) (Ru
40.01%, 501 mg, 1.98 mol), PPh3 (1.04 mg, 3.96 mmol), 2b (42.2 g,
159 mmol), K2CO3 (43.8 g, 317 mmol), 3a (39.9 g, 174 mmol) and
NMP (169 mL) was stirred under N2 atmosphere at 140 °C for 12 h.
The conversion of this reaction was 74%. The mixture was cooled to
20 °C, and toluene (900 mL) and water (480 mL) were added. The
obtained organic and water phases (combined volume was 1.6 L) were
separated and allowed to test removal of Ru with metal scavengers.
The content of Ru in both phases was assayed by ICP analysis and
deduced to be 130 mg/L. A part of the sample solution was mixed
with 5 mol % of the metal scavengers tested at inidicated temperature
and for appropiate period (Table 2). Then, after filtration of the
mixture, the concentartion of Ru in the filtrate was assayed by ICP
analysis, which is shown in Table 2.
2-Butyl-4-chloro-1-({2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]-
biphenyl-4-yl}-methyl)imidazole-5-carbaldehyde 18. A mixture of
16 (93 mg, 0.213 mmol), 17 (40.5 mg, 0.217 mmol) and K2CO3 (30.3
mg, 0.219 mmol) in N,N-dimethyl acetamide (1 mL) was stirred at
−10 °C for 4 h followed by at rt for 4 h. The mixture was filtered and
solids were washed with AcOEt. The combined AcOEt solution was
evaporated. The residue was purified by slica-gel column chromatog-
raphy (AcOEt/hexanes = 1:2) to afford 18 (0.106 g, 92%) in colorless
crystals. mp 47.1−48.6 °C; IR (KBr): ν 1664 cm−1; 1H NMR (CDCl3)
δ 9.75 (s, 1H), 7.65 (t, J = 7.6, 1H), 7.53 (d, J = 7.6, 1H), 7.46 (t, J =
7.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.97
(d, J = 8.0 Hz, 2H), 6.70 (q, J = 8.8 Hz, 4H), 5.52 (s, 2H), 4.74 (s,
2H), 3.72 (s, 3H), 2.61 (t, J = 7.6 Hz, 2H), 1.61−1.73 (m, 2H), 1.30−
1.42 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3) δ 177.6,
159.5, 154.3, 153.9, 143.0, 140.7, 138.5, 135.4, 131.4, 131.1, 130.1,
129.3, 129.1, 127.9, 126.7, 124.9, 124.1, 122.6, 114.0, 55.3, 50.5, 47.9,
29.3, 26.6, 22.5, 13.8; EIMS (m/z): 540 [M]+; HRMS: Calcd for
C30H30N6O2Cl, 541.2119 [M + H]+. Found 541.2111 [M + H]+.
2-Butyl-4-chloro-1-({2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]-
biphenyl-4-yl}-methyl)imidazole-5-methanol 19. To a solution of 18
(438 mg, 0.8 mmol) in MeOH (0.5 mL) was added NaBH4 (90.8 mg,
2.4 mmol) at −10 °C and the mixture was stirred at 20 °C for
1.5 h. Then, NaBH4 (30.3 mg, 0.8 mmol) was added and the mixture
was stirred at 30 °C for 1 h. 50% aq. AcOH (0.029 mL) was added and
the mixture was stirred at 20 °C for 30 min. Water (1.6 mL) was
added and the mixture was stirred at 20 °C for 2 h and at 5−10 °C for
30 min. The solids formed were collected to afford 19 (373 mg, 86%)
in colorless crystals. mp 119.5−120.8 °C; IR (KBr): ν 1612, 1583
cm−1; 1H NMR (CDCl3) δ = 7.62−7.68 (m, 1H), 7.51−7.55 (m, 1H),
7.42−7.50 (m, 1H), 7.30−7.35 (m, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.91
(d, J = 8.0 Hz, 2H), 6.64−6.75 (m, 4H), 5.18 (s, 2H), 4.78 (s, 2H)
4.49 (d, J = 6.4 Hz, 2H), 3.73 (s, 3H), 2.54 (dd, J = 7.6 Hz, 2H), 1.60−
1.70 (m, 2H), 1.28−1.41 (m, 2H), 0.88 (t, J = 7.6 Hz, 3H); 13C NMR
(CDCl3) δ 159.5, 153.9, 148.4, 140.9, 138.4, 135.9, 131.4, 131.0, 130.1,
129.3, 129.1, 127.9, 127.5, 126.3, 124.9, 124.6, 122.6, 114.0, 55.3, 53.2,
{2′-[1-(o-Methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl
Acetate 4b. A mixture of RuCl3·xH2O (8d) (Ru 40.01%, 5.7 mg, 23
μmol), PPh3 (10.4 mg, 40.3 μmol), 2b (481 mg, 1.81 mmol), K2CO3
(499 mg, 3.61 mmol), 3a (455 mg, 1.99 mmol) and NMP (1.9 mL)
was stirred under N2 atmosphere at 140 °C for 12 h. The mixture was
cooled to 20 °C and it was diluted with AcOEt (10 mL) and washed
twice with water, dried over anhydrous MgSO4 and evaporated. The
residue contained 4b (607 mg, 81%) as assayed by HPLC (Cadenza
CD-C18, 3 μm, 4.6 × 150 mm, CH3CN/30 mM KH2PO4 (3:2), 225
nm, 40 °C). The authentic sample of 4b was obtained by purification
with silica-gel column chromatography using a mixture of hexane/
1
AcOEt = 4:1). mp 117−118 °C; IR (KBr): ν 1735, 1603 cm−1; H
NMR (CDCl3): δ 7.65−7.62 (m, 1H), 7.57−7.56 (m, 1H), 7.45−7.43
(m, 2H), 7.27−7.14 (m, 5H), 6.80−6.70 (m, 3H), 5.09 (s, 2H), 4.76
(s, 2H), 3.51 (s, 3H), 2.13 (s, 3H); 13C NMR (DMSO-d6): δ 170.2,
156.6, 154.1, 141.1, 138.4, 135.7, 131.5, 130.9, 130.3, 130.2, 130.1,
128.5, 128.0, 127.8, 122.5, 121.3, 120.2, 110.9, 64.9 55.1, 45.9, 20.6;
MS: m/z = 415 [M + H]+; Anal. Calcd for C24H22N4O3: C, 69.55; H,
5.35; N, 13.52; Found: C, 69.55; H, 5.11; N, 13.45.
{2′-[1-(o-Methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}-
methanol 21. To a solution of 4b (1.01 g, 2.44 mmol) in MeOH
(5.0 mL), was added MeONa in MeOH (28 wt %) (24 μL, 23 mg,
0.12 mmol) and the mixture was stirred for 9 h. The mixture was
evaporated and the residue was dissolved in CHCl3 and washed, dried
over MgSO4 and evaporated. The solids formed were collected by
adding hexane to provide 21 (820 mg, 90%) in colorless crystals. mp
139−141 °C; IR (KBr): ν 3398, 1605 cm−1; 1H NMR (DMSO-d6): δ
7.73 (td, J = 7.8, 2.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.59−7.55 (m,
2H), 7.26 (td, J = 7.9, 1.6 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 6.96 (d,
J = 8.2 Hz, 2H), 6.91 (dd, J = 7.9, 1.6 Hz, 1H), 6.89 (d, J = 7.9 Hz,
1H), 6.81 (t, J = 7.9 Hz, 1H), 5.22 (t, J = 5.9 Hz, 1H), 4.93 (s, 2H),
4.49 (d, J = 5.9 Hz, 2H), 3.50 (s, 3H); 13C NMR (DMSO-d6): δ
156.6, 154.2, 142.1, 141.4, 137.1, 131.4, 131.1, 130.8, 130.2, 128.1,
127.8, 127.5, 126.5, 122.5, 121.3, 120.2, 110.9, 62.4, 55.1, 45.8; MS:
m/z = 373 [M + H]+; Anal. Calcd for C22H20N4O2: C, 70.95; H, 5.41;
N, 15.04; Found: C, 70.76; H, 5.27; N, 15.01.
1-Diphenylmethyl-5-phenyl-1H-tetrazole 2c. A mixture of 5-
phenyl-1H- tetrazole (14.6 g, 0.1 mol), Na2CO3, nBu4NBr (710 mg,
2.2 mmol) and benzhydryl chloride (19.9 g, 98 mmol) in a mixture of
CHCl3 (160 mL) and water (120 mL) was stirred at 2 °C for 3 h and
at 20 °C for 3 h and finally at 55 °C for 3 h. The organic phase was
separated and washed with water, dried over anhydrous MgSO4 and
evaporated. The residue was purified by silica gel column
chromatography (hexane/ACOEt = 4:1) to provide 2c in colorless
crystals (13.5 g, 43%). mp 170.4−171.6 °C; IR (KBr): ν 1601 cm−1;
10204
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50.6, 47.2, 29.8, 26.9, 22.5, 13.9; HRMS: Calcd for C30H32N6O2Cl,
543.2275 [M + H]+; Found 543.2271 [M + H]+.
(7 mL) and TBME (5 mL). The aqueous phase was washed with
TBME and treated with 1N HCl (1.7 mL) and AcOEt (40 mL). The
aqueous phase was extracted twice with AcOEt and the combined
extracts were washed with sat. aq. NaCl, dried over MgSO4 and
evaporated. The solids formed were collected by adding a mixture of
cyclohexane and AcOEt to afford 1b (99.5 mg, 76%) in colorless
crystals. mp 70−95 °C (Valsartan 1b is known to exist in several
2-Butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl)-
imidazole-5-carbaldehyde 20.5a A mixture of 18 (93 mg, 0.172
mmol), anisol (63 mg, 0.59 mmol) and TFA (1.3 mL) was stirred at
20 °C for 3 h, at 45 °C for 1 h, 65 °C for 4 h and finally at 80 °C for
5 h. The mixture was evaporated and the residue was treated with 1 N
aq. KOH (5 mL), water (20 mL) and toluene (20 mL). The aqueous
phase was washed with toluene and acidified (pH 1.8) by adding 1 N
HCl. The product was extracted by AcOEt and the organic solution
was washed with sat. aq. NaCl, dried over anhydrous MgSO4 and
evaporated to afford 20 (89.4 mg, quant.) in amorphous solid. IR
crystalline forms (P. Buhimayer, F. Ostermayer, T. Schmidlin (Ciba-
̈
Geigy), EP0443983A1 (priority date: February 19, 1990)). Control of
the polymorph was not examined in this study. IR (KBr): ν 1730, 1619
cm−1; 1H NMR (DMSO-d6): (CM: major rotamer; Cm: minor rotamer):
δ 16.3 (brs, 1H), 12.6 (brs, 1H), 7.70−7.63 (m, 2H, CM, Cm), 7.58−
7.53 (m, 2H, CM, Cm), 7.20 (d, J = 8.2 Hz, 1H, CM), 7.08 (d, J = 8.2 Hz,
1H, Cm), 7.07 (d, J = 8.2 Hz, 1H, CM), 6.97 (d, J = 8.2 Hz, 1H, Cm),
4.62 (s, 2H, CM), 4.48 (d, J = 15.2 Hz, 1H, Cm), 4.46 (d, J = 10.3 Hz,
1H, CM), 4.43 (d, J = 15.2 Hz, 1H, Cm), 4.08 (d, J = 10.5 Hz, 1H, Cm),
2.53−2.45 (m, 2H, Cm), 2.22−2.12 (m, 1H, CM, Cm), 2.21 (dt, J = 15.8,
7.9 Hz, 1H, CM), 2.03 (dt, J = 15.8, 7.9 Hz, 1H, CM), 1.54 (quint, J = 6.9
Hz, 2H, Cm), 1.41 (dquint, J = 14.1, 7.9 Hz, 1H, CM), 1.37 (dquint, J =
14.1, 7.9 Hz, 1H, CM), 1.31 (sext, J = 6.9 Hz, 2H, Cm), 1.15 (sext, J = 7.9
Hz, 2H, CM), 0.93 (d, J = 6.9 Hz, 3H, Cm), 0.93 (d, J = 7.9 Hz, 3H, CM),
0.88 (t, J = 6.9 Hz, 3H, Cm), 0.76 (t, J = 7.9 Hz, 3H, CM), 0.75 (d, J =
7.9 Hz, 3H, CM), 0.70 (d, J = 6.9 Hz, 3H, Cm); HRMS: Calcd for
C24H29N5O3, 435.2270 [M]+; Found 435.2267 [M]+.
1
(KBr): ν 1667, 1604 cm−1; H NMR (400 MHz, CDCl3): δ 9.69 (s,
1H), 8.04 (dd, J = 7.7, 1.5 Hz, 1H), 7.60 (td, J = 7.7, 1.5 Hz, 1H), 7.54
(td, J = 7.7, 1.5 Hz, 1H), 7.42 (dd, J = 7.7, 1.5 Hz, 1H), 7.18 (d, J = 8.2
Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 5.54 (s, 2H), 2.64 (t, J = 7.7 Hz,
2H), 1.68 (quint, J = 7.7 Hz, 2H), 1.36 (sext, J = 7.7 Hz, 2H), 0.89 (t,
J = 7.7 Hz, 3H); 13C NMR (DMSO-d6) δ 177.4, 173.3, 153.9, 140.6,
140.4, 138.1, 135.0, 130.6, 130.1, 128.7, 127.4, 125.4, 123.5, 46.6, 28.0,
24.9, 21.1, 13.0; SIMS m/z: 421 [M + H]+; HRMS: Calcd for
C22H21N6OCl, 421.1544 [M + H]+; Found 421.1541 [M + H]+.
2-Butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl)-
imidazole-5-methanol (Losartan) 1a.6a To a mixture of 20 (101 mg,
0.24 mmol), 1N aq. NaOH (0.24 mL) and water (0.24 mL), NaBH4
(18.4 mg, 0.486 mmol) was added at 5 °C. The mixture was stirred at
5 °C for 25 min and at 20 °C for 3 h. Into the mixture was added
NaBH4 (8.6 mg, 0.23 mmol) at 20 °C and the mixture was stirred at
the same temperature for 1 h. Into the mixture was added water (0.5
mL) and the mixture was washed with diisopropyl ether. The mixture
was acidified (pH 2) by adding 1% HCl and extracted with AcOEt.
The organic phase was separated and washed with sat. aq. NaCl, dried
over anhydrous MgSO4 and evaporated to provide 1a
(66.1 mg, 65%). The pure sample of 1a was obtained by recrystallization
from a mixture of CH3CN and water (3:4). mp 161−164 °C; IR (KBr):
ν 3374, 1604, 1579, 1469 cm−1; 1H NMR (DMSO-d6): δ 7.68 (t, J = 7.4
Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.55 (d, J =
7.4 Hz, 1H,), 7.08 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 5.23,
(s, 1H), 4.32 (s, 1H), 2.45 (t, J = 7.5 Hz, 2H), 1.44 (quint, J = 7.5 Hz,
2H), 1.23 (sext, J = 7.5 Hz, 2H), 0.80 (t, J = 7.7 Hz, 3H); SIMS:m/z
423 [M + H]+; HRMS: Calcd for C22H24N6OCl, 423.1700 [M + H]+;
Found 423.1696 [M + H]+.
N-Pentanoyl-N-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-va-
line (Valsartan) 1b. A mixture of 21 (1.00 g, 2.69 mmol) and TMSBr
(0.711 mL, 822 mg, 5.37 mmol) in CH3CN (5.0 mL) was stirred at
50 °C for 4.5 h. The mixture was cooled to 20 °C and to the mixture
were added iPr2EtN (1.57 g, 12.1 mmol) and L-valine benzyl ester
p-toluenesulfonate (1.53 g, 4.03 mmol) and CH3CN (4.0 mL). The
mixture was stirred at 50 °C for 2 h. After cooling the mixture to
20 °C, it was diluted with AcOEt (20 mL) and water (1.7 mL). The
aqueous phase was extracted with AcOEt and combined organic phases
were washed with sat. aq. NaCl, dried over MgSO4 and evaporated. The
residue was dissolved in CHCl3 and 84.1% portion of this material was
evaporated. Into the residue were added toluene (6.4 mL), pyridine
(0.275 mL, 0.269 g, 3.40 mmol) and n-pentanoyl chloride (0.376 mL,
0.382 g, 3.17 mmol) and the mixture was stirred at 20 °C for 4 h and at
40 °C for 2 h. Pyridine (92.8 mg, 1.17 mmol) and nBuCOCl (141 mg,
1.17 mol) were added and it was stirred at 40 °C for 3 h. The mixture
was cooled down to 20 °C and 1 M HCl (5 mL) and AcOEt (20 mL)
were added. The aqueous phase was extracted with AcOEt and the
combined extracts were washed successively with sat. aq. NaHCO3 and
sat. aq. NaCl, dried over MgSO4 and evaporated. The residue was
purified by silica-gel column chromatography using a mixture of
toluene/AcOEt = 50:1 to 5:1 to afford n-pentanoyl derivative (1.47 g).
It was dissolved in 2-propanol (4.53 g). To a portion (800 mg) of the
solution were added Pd/C (5%Pd, water: 58.8 wt %, 128 mg),
ammonium formate (96.2 mg, 1.53 mmol) and water (0.51 mL) and the
mixture was stirred at 20 °C for 14 min and at 45 °C for 6 h. The
mixture was filtered by adding 2-propanol (10 mL). The filtered solids
were washed with 2-propanol (5 mL) and the combined solution was
evaporated. Into the residue were added 0.5 M NaOH (2.0 mL), water
ASSOCIATED CONTENT
■
S
* Supporting Information
1H- and 13C NMR spectra for unknown compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*seki.masahiko@mm.api-corp.co.jp
■
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