Commercial synthesis of azilsartan kamedoxomil: An angiotensin II receptor blocker

Article abstract of DOI:10.1021/op500357r

A commercially viable process for the preparation of azilsartan kamedoxomil, an angiotensin II receptor blocker, has been developed. The present work describes the novel synthesis of azilsartan medoxomil from amidoxime methyl ester. The present work also describes the improved synthesis of amidoxime methyl ester and azilsartan kamedoxomil. This process features a high overall yield (36%) with 99.52% HPLC purity.

Full text of DOI:10.1021/op500357r

Article
pubs.acs.org/OPRD
Commercial Synthesis of Azilsartan Kamedoxomil: An Angiotensin II
Receptor Blocker
Srinivas Garaga,*,†,‡ Nimesh C. Misra,† Ambati V. Raghava Reddy,† Koilpillai Joseph Prabahar,†
Chandiran Takshinamoorthy,† Paul Douglas Sanasi,‡ and Korupolu Raghu Babu‡
†Chemical Research and Development Department, Aurobindo Pharma Ltd., Survey No: 71&72, Indrakaran Village, Sangareddy
Mandal, Medak District, Hyderabad, 502329 Andhra Pradesh, India
‡Department of Engineering Chemistry, A. U. College of Engineering (A), Andhra University, Visakhapatnam, 530 003 Andhra
Pradesh, India
S
* Supporting Information
ABSTRACT: A commercially viable process for the preparation of azilsartan kamedoxomil, an angiotensin II receptor blocker,
has been developed. The present work describes the novel synthesis of azilsartan medoxomil from amidoxime methyl ester. The
present work also describes the improved synthesis of amidoxime methyl ester and azilsartan kamedoxomil. This process features
a high overall yield (36%) with 99.52% HPLC purity.
xylene at reflux to produce azilsartan methyl ester 7. Hydrolysis
of 7 in aqueous sodium hydroxide produces azilsartan (8).
Finally, azilsartan (8) is treated with medoxomil alcohol (4;
Figure 2) in the presence of tosyl chloride to produce azilsartan
medoxomil (2). Azilsartan medoxomil (2) is treated with
potassium 2-ethylhexanoate in acetone to produce azilsartan
kamedoxomil (1) in 60% yield. The major disadvantage of this
process is the formation of impurities like azilsartan methyl ester
(7) and azilsartan ethyl ester (10) (Figure 3).12 These impurities
are process-related, and azilsartan methyl ester (7) also originates
from methanol contained in the medoxomil alcohol.12,16 These
impurities are very difficult to remove, requiring repeated
crystallizations to achieve the desired purity (below 0.1 level) and
resulting in a low yield of azilsartan kamedoxomil; therefore, this
is not suitable for commercial-scale preparations.
INTRODUCTION
■
Azilsartan medoxomil belongs to the sartan class of drugs.
Sartans inhibit the AT1 receptor of angiotensin II and modulate
the rennin−angiotensin−aldosterone system.1,2 Sartans are used
to treat hypertension, heart failure, cardiovascular disease, stroke,
and nephropathy. There are many sartan drugs available in the
market, such as losartan, candesartan, telmisartan, valsartan, and
others. Azilsartan medoxomil is an AT1-subtype angiotensin II
receptor blocker (ARB). Azilsartan medoxomil (Figure 1), a
Another report4 available for the preparation of azilsartan
medoxomil involves reaction of azilsartan disodium salt with
medoxomil chloride (3). The major disadvantage of this process
is its poor yield due to the formation of byproducts, i.e., N-
alkylation on the oxadiazole ring,12 to produce N-alkylated
impurity 11 and N,O-dialkylated impurity 12 (Figure 4). So, this
process is also not suitable for commercialization of azilsartan
kamedoxomil.
Hence, there is a need to develop an improved alternative
route for the preparation of azilsartan kamedoxomil (1). The
present invention relates to a novel, cost-effective, and
commercially viable process for the preparation of azilsartan
kamedoxomil (1).
Figure 1. Structures of azilsartan kamedoxomil (1) and azilsartan
medoxomil (2).
prodrug form of azilsartan (8), was approved in 2011 and is used
for the treatment of hypertension. It is marketed by Takeda
under the brand name Edarbi. Azilsartan medoxomil (2) is
chemically known as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-
ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-
biphenyl-4yl]methyl}-1H-benzimidazole-7-carboxylate.
There are very few reports for the synthesis of azilsartan
kamedoxomil.3−15 The synthetic route for azilsartan kamedox-
omil (1), as disclosed in previous literature,3 is shown in Scheme
1. The process involves the reaction of methyl 1-((2′-
cyanobiphenyl-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-
carboxylate (BEC methyl ester, 5) with hydroxylamine hydro-
chloride in the presence of sodium methoxide to produce
amidoxime 6. Treatment of 6 with ethyl chloroformate in the
presence of a base produces intermediate 6a, which is cyclized in
RESULTS AND DISCUSSION
■
The present article is covered by our patent17 (Scheme 2) and
involves the reaction of BEC methyl ester 5 with hydroxylamine
hydrochloride in the presence of sodium bicarbonate to produce
Received: November 12, 2014
© XXXX American Chemical Society
A
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Scheme 1. Synthetic Route for Azilsartan Kamedoxomil Reported in the Literature
Figure 2. Structures of medoxomil chloride (3) and medoxomil alcohol
(4).
Figure 4. Structures of azilsartan N-medoxomil 11 and azilsartan
dimedoxomil 12.
condensed with medoxomil chloride (3) to produce trityl
amidoxime medoxomil ester 17. Deprotection of 17 with
trifluoroacetic acid produces amidoxime medoxomil ester 18.
Compound 18 is cyclized with disuccinimidyl carbonate (DSC)
to give azilsartan medoxomil (2). Finally, azilsartan medoxomil is
treated with potassium 2-ethylhexanoate in tetrahydrofuran to
give azilsartan kamedoxomil (1).
We have developed this process for the synthesis of azilsartan
kamedoxomil (1) from amidoxime methyl ester 6. The
preparation of amidoxime methyl ester is known in the
Figure 3. Structures of azilsartan methyl ester (7) and azilsartan ethyl
ester (10).
amidoxime methyl ester 6. Protection of compound 6 with trityl
chloride produces trityl amidoxime methyl ester 15. Hydrolysis
of 15 provides trityl amidoxime sodium salt 16, which is further
B
DOI: 10.1021/op500357r
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Scheme 2. Improved and Alternate Synthetic Route for Azilsartan Kamedoxomil
literature.3−15 The formation of impurities (13 and 14; Figure 5)
was observed during the synthesis of amidoxime methyl ester.
amidoxime acid and amide methyl ester as related substances (13
and 14).
We controlled the formation of these impurities by using fewer
moles of hydroxylamine hydrochloride (5 mol equivalents).
Moreover, the liberated ammonia in the reaction is expelled by
maintaining nitrogen purging. Under these conditions, we
achieved 80−85% yield of amidoxime methyl ester 6 with an
HPLC purity of more than 95%. The experimental details are
tabulated in Table 1.
To protect amidoxime methyl ester 6, we tested different
protecting groups such as benzyl, DIBOC, and trityl (Tr).
Among all of these protecting groups, trityl deprotection is easy
to achieve with trifluoroacetic acid without affecting the 2-ethoxy
group. To optimize the tritylation reaction, we tried different
solvents such as N,N-dimethylformamide and dichloromethane.
In these solvents, we observed the formation of diprotected
amidoxime (ditritylated amidoxime methyl ester, 15a; Figure 6)
of around 10−12%. This ditritylated amidoxime subsequently
reacts with medoxomil chloride in the next step and produces
10−12% ditritylated amidoxime medoxomil ester (17a; Figure
7). Finally, this ditritylated amidoxime medoxomil ester gives the
Figure 5. Structures of amidoxime acid 13 and amide methyl ester 14.
There was a need to control these impurities in the reaction to
obtain a higher yield. Our aim was to investigate the root cause of
the formation of these impurities and to control their formation
in the reaction. Most of the reported methods to prepare
amidoxime methyl ester use excess hydroxylamine hydrochloride
(18 to 25 mol equivalents). Hydroxylamine tends to decompose
at higher temperature, giving ammonia as a byproduct.18 This
liberated ammonia reacts with BEC methyl ester 5, giving
C
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Table 1. Hydroxylamine and Base Screening Studies for Amidoxime Preparation Reaction to Control Formation 13 and 14
reaction monitoring results
entry
NH2OH·HCl moles
NaHCO3 moles
temp (°C)
purity
acid (13)
amide (14)
yield (%)
1
2
3
4
18
18
9
25
25
13
5.5
5.5
80−85
80−85
80−85
95−100
80−85
70.99
72.40
71.80
59.80
81.10
10.99
8.39
14.20
6.39
12.3
4.40
4.10
55
57
55
54
79
5.76
5
16.51
4.21
a
5
5
a
Reaction performed under nitrogen purging.
results were achieved using disuccinimidyl carbonate (DSC) as
the cyclization agent. Under these optimized conditions, an 82%
yield of azilsartan medoxomil 2 with 99.6% HPLC purity was
obtained. The experimental details are tabulated in Table 3.
Finally, the preparation of azilsartan kamedoxomil (1) is
known in the literature.13−15 As per the literature, azilsartan
medoxomil (2) is treated with potassium 2-ethylhexanoate in
acetone to give azilsartan kamedoxomil (1) with 60% yield.
However, the reported yields were very low. To overcome the
low-yield problems associated with the reported process, we
developed an improved process for the preparation of azilsartan
kamedoxomil (1) in tetrahydrofuran. Herein, we report
azilsartan kamedoxomil (1) preparation with 80% yield in
tetrahydrofuran.
Figure 6. Structures of trityl amidoxime methyl ester 15 and ditrityl
amidoxime methyl ester 15a.
desired product, amidoxime medoxomil ester 18, on depro-
tection.
CONCLUSIONS
■
A novel, efficient and commercially viable process for the
preparation of azilsartan kamedoxomil (1) has been developed,
resulting in 99.52% purity. The present process overcomes the
previous problems of low yields of intermediate amidoxime
methyl ester and azilsartan kamedoxomil (1). This improved
process for the preparation of azilsartan kamedoxomil (1)
involves the use of much cheaper medoxomil chloride instead of
medoxomil alcohol. This modification makes the process cost
effective.
Figure 7. Structures of trityl amidoxime medoxomil ester 17 and ditrityl
amidoxime medoxomil ester 17a.
When we used N,N-dimethylformamide as solvent in the
tritylation reaction, we observed the elimination of ditritylated
product into the mother liquor during ethanol purification, and
we achieved 65% yield with 97% HPLC purity, whereas with
dichloromethane as a solvent, we achieved 91% yield with
85.95% (monotritylated) and 11.73% (ditritylated) HPLC
purity. Therefore, dichloromethane was preferred for use as
the solvent for the tritylation reaction because the ditritylated
medoxomil ester also gives the desired amidoxime medoxomil
ester 18 after deprotection. The experimental details are
tabulated in Table 2.
To optimize the cyclization of amidoxime medoxomil ester 18
into azilsartan medoxomil (2), we explored different cyclization
reagents such as carbonyldiimidazole (CDI), triphosgene,
dimethyl carbonate (DMC), diethyl carbonate (DEC), diphenyl
carbonate (DPC), and ethyl chloroformate (ECF). We identified
the formation of azilsartan 8 with all of these reagents. The best
EXPERIMENTAL SECTION
■
Solvents and reagents were obtained from commercial sources
and used without purification. The IR spectra (ϑmax, cm−1) were
recorded in a solid-state KBr dispersion using a PerkinElmer FT-
1
IR spectrometer. The H and 13C NMR spectra were recorded
on Bruker Avance 300 and 500 MHz spectrometers. The
chemical shifts were reported in δ/ppm relative to TMS. The
mass spectra were recorded on an API 2000 PerkinElmer PE-
Sciex mass spectrometer. The reactions were monitored by
HPLC. HPLC analysis was performed on a Waters instrument
with a UV detector (250 nm) using a Sunfire C18 (250 mm × 4.6
mm, 5 μm) column. The column oven temperature was 25 °C.
Mobile phase A was composed of 1 g of potassium dihydrogen
phosphate dissolved in 1 L of water and adjusted to pH 3 with
diluted orthophosphoric acid; mobile phase B, acetonitrile. The
flow rate was 1.2 mL/min. A gradient (A/B) of 65:35 (0−30
min), 15:85 (30−50 min), and 65:35 (50−60 min) was used for
stages 1 and 6. A gradient (A/B) of 65:35 (0−20 min), 15:85
(30−90 min), and 65:35 (91−100 min) was used for stages 2−5.
Melting points were determined on a Polman melting point
apparatus (model no. MP96) by open capillary method and are
uncorrected.
Table 2. Solvent Screening Studies for the Tritylation
Reaction
reaction monitoring
results
purity by HPLC
ditritylated
ditritylated
yield
(%)
entry solvent purity
(15a)
purity
(15a)
Methyl 2-Ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-
biphenyl-4-yl)methyl)-1H benzo[d]imidazole-7-carboxy-
late (Amidoxime Methyl Ester, 6). To a suspension of
1
2
DMF
DCM
84.23
85.13
11.50
11.24
97.05
85.95
65
91
11.73
D
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Table 3. Reagent Screening Studies for the Cyclization Reaction
reaction monitoring results
entry
1
cyclizing agent
solvent
temp (°C)
purity
azilsartan
yield (%)
carbonyldiimidazole
carbonyldiimidazole
dimethyl carbonate
diphenyl carbonate
triphosgene
ACN
ACN
DMSO
DMF
DCM
EA
55−60
25−30
55−60
75−80
25−30
40−45
39.20
7.08
33.25
6.48
8.32
3.52
a
2
3
4
45.25
95.27
75
82
b
5
6
disuccinimidyl carbonate
98.51
0.5
a
b
No reaction. No product formation.
hydroxylamine hydrochloride (5.07 kg, 72.99 mol) and sodium
bicarbonate (6.74 kg, 80.29 mol) in dimethyl sulfoxide (30 L)
was added compound BEC methyl ester 5 (6 kg, 14.59 mol) at
45−50 °C. The reaction mixture was stirred at 80−85 °C for 4 h
under nitrogen purging. Then, water (60 L) was added to the
reaction mixture at 25−30 °C, and the mixture was stirred for 1 h.
The resulting product was filtered and purified with ethanol,
yielding 5.1 kg (79%) of white crystals. mp 204−207 °C. HPLC
purity: 97.74%. HRMS for C25H25N4O4: (M + H)+ calcd
6.5 kg of 16 as a foamy solid. HPLC purity: 86.46 + 11.55%
(ditrityl). HRMS for C43H35N4NaO4: (M + H)+ calcd, 695.2556;
found, 695.2579. 1H NMR (300 MHz, DMSO): δ 7.31−7.10 (m,
31H, Ar), 7.087 (m, 1H, Ar), 5.917 (s, 2H, N-CH2-Ar), 4.506 (q,
J = 6.9 Hz, 2H, OCH2CH3), 1.337 (t, J = 6.9 Hz, 3H,
OCH2CH3). IR (KBr pellet): 3392, 3023, 2978, 1751, 1616,
1545, 1276, 1251, 1154 cm−1.
(5-Methyl-2-oxo-2H-1,3-dioxol-4yl)methyl 2-ethoxy-
1-[(4-(2-[N′-(triphenylmehoxy)cabamimidoyl]phenyl)-
phenyl)methyl]-1H-1,3-benzodiazole-7-carboxylate (Tri-
tyl Amidoxime Medoxomil Ester, 17). To a solution of trityl
amidoxime sodium salt 16 in dimethylacetamide (32.5 L) were
added sodium iodide (195 g, 3%) and medoxomil chloride 3
(1.55 kg, 10.42 mol) at 0−5 °C. The reaction mixture was stirred
for 2 h at 0−5 °C to complete the reaction. Then, the reaction
mixture was poured into a solvent mixture of water (260 L) and
ethyl acetate (65 L), and the pH was adjusted to 7.0 with
hydrochloric acid. The organic layer was separated and
concentrated under reduced pressure at 50−55 °C. The resulting
residue was crystallized with ethyl acetate (32.5 L), yielding 6.5
kg (88%) of 17 as a white compound. mp 90−93 °C. HPLC
purity: 84.96 + 11.38% (ditrityl, 17a). HRMS for C48H40N4O7:
1
445.1876; found, 445.1879. H NMR (500 MHz, DMSO): δ
9.176 (s, 1H, OH), 7.704 (dd, J = 7, 1 Hz 1H, Ar), 7.466 (dd, J =
7.5, 1 Hz, 1H, Ar), 7.449−7.368 (m, 3H, Ar), 7.358 (d, J = 8 Hz,
2H, Ar), 7.297 (d, J = 8 Hz, 1H, Ar), 7.195 (t, J = 8.5 Hz, 1H, Ar),
6.942 (d, J = 8 Hz, 2H, Ar), 5.539 (br s, 2H, NH2), 5.507 (s, 2H,
N-CH2-Ar), 4.644 (q, J = 7 Hz, 2H, OCH2CH3), 3.721 (s, 3H,
OCH3), 1.433 (t, J = 7 Hz, 3H, OCH2CH3). IR (KBr pellet):
3516, 3409, 3274, 2985, 1718, 1634, 1612, 1547, 1285, 1257,
1134 cm−1.
Methyl 2-Ethoxy-1-[(4-(2-(N′-(triphenylmethoxy)-
carbamimidoyl)phenyl) phenyl)methyl]-1H-1,3-benzo-
diazole-7-carboxylate (Trityl Amidoxime Methyl Ester,
15). To a solution of amidoxime methyl ester 6 (5 kg, 11.26 mol)
in dichloromethane (25 L) were added triethylamine (1.99 kg,
19.7 mol) and trityl chloride (4.7 kg, 16.89 mol) at 25−30 °C.
The reaction mixture was stirred for 16 h at 25−30 °C. DM water
(30 L) was added to the above reaction mass and stirred for 30
min. The organic layer was separated and concentrated at 40 °C
under reduced pressure. The resulting residue was purified with
ethanol, yielding 7 kg (91%) of pure compound 15. mp 190−193
°C. HPLC purity: 85.95 + 11.73% (ditrityl, 15a). HRMS for
1
(M + H)+ calcd, 785.2897; found, 785.2896. H NMR (300
MHz, DMSO): δ 7.769 (d, J = 7.8 Hz, 1H, Ar), 7.518 (d, J = 7.8
Hz, 1H, Ar), 7.383 (d, J = 7.2 Hz, 1H, Ar), 7.303−7.101 (m, 24H,
Ar), 6.81 (d, J = 7.8 Hz, 2H, Ar), 5.829 (s, 2H, NH2), 5.541 (s,
2H, N-CH2-Ar), 5.074 (s, 2H, CH2), 4.608 (q, J = 7.2 Hz, 2H,
OCH2CH3), 2.111 (s, 3H, CH3), 1.387 (t, J = 6.9 Hz, 3H,
OCH2CH3). IR (KBr pellet): 3495, 3391, 2979, 1717, 1631,
1617, 1550, 1279, 1247, 1149, 1118 cm−1.
1
C44H38N4O4: (M + H)+ calcd, 687.2893; found, 687.2918. H
(5-Methyl-2-oxo-2H-1,3-dioxol-4yl)methyl 2-ethoxy-
1-[(4-(2-[N-hydroxy carbamimidoyl]phenyl)phenyl)-
methyl]-1H-1,3-benzodiazole-7-carboxylate (Amidox-
ime Medoxomil Ester, 18). To a solution of trityl amidoxime
medoxomil ester 17 (6.4 kg, 8.16 mol) in dichloromethane (64
L) was added trifluoroacetic acid (1.12 kg, 9.8 mol) at 0−5 °C.
The reaction mixture was stirred for 6 h at 20−25 °C to complete
the reaction. Thereafter, the reaction mixture was washed with
saturated sodium bicarbonate solution (32 L). The organic layer
was concentrated under reduced pressure at 35−40 °C. The
resulting residue was crystallized with ethyl acetate (64 L),
yielding 3.84 kg (87%) of 18 as a white compound. mp 179−181
°C. HPLC purity: 98.76%. HRMS for C29H26N4O7: (M + H)+
calcd, 543.1859; found, 543.1871. 1H NMR (300 MHz, DMSO):
δ 9.187 (s, 1H, OH), 7.742 (d, J = 7.8 Hz, 1H, Ar), 7.53 (d, J = 7.8
Hz, 1H, Ar), 7.398−7.213 (m, 7H, Ar), 6.944 (d, J = 8.1 Hz, 2H,
Ar), 5.554 (br s, 2H, NH2), 5.532 (br s, 2H, N-CH2-Ar), 5.147 (s,
2H, CH2), 4.659 (q, J = 6.9 Hz, 2H, OCH2CH3), 2.179 (s, 3H,
CH3), 1.443 (t, J = 6.9 Hz, 3H, OCH2CH3). IR (KBr pellet):
3515, 3406, 3255, 2985, 1716, 1630, 1612, 1547, 1282, 1255,
1127 cm−1.
NMR (500 MHz, DMSO): δ 7.727 (d, J = 7.5 Hz, 1H, Ar), 7.453
(d, J = 8 Hz, 1H, Ar), 7.378 (d, J = 7.5 Hz, 1H, Ar), 7.312−7.217
(m, 6H, Ar), 7.201−7.117 (m, 15H, Ar), 6.843 (d, J = 7.5 Hz, 2H,
Ar), 5.825 (s, 2H, NH2), 5.53 (s, 2H, N-CH2-Ar), 4.631 (q, J =
7.5 Hz, 2H, OCH2CH3), 3.668 (s, 3H, OCH3), 1.398 (t, J = 7 Hz,
3H, OCH2CH3). 13C NMR (125 MHz, DMSO): δ 145.119,
129.989, 129.692, 129.13, 128.634, 128.545, 127.76, 127.501,
127.153, 126.828, 126.62, 126.495, 125.762, 122.927, 121.587,
120.839, 66.63, 52.232, 46.347, 39.833, 39.67, 39.5, 39.337,
39.167, 14.368. IR (KBr pellet):3478, 3371, 3000, 2951, 1720,
1630, 1616, 1549, 1280, 1248, 1149 cm−1.
Sodium 2-Ethoxy-1-[(4-(2-(N′-(triphenylmethoxy)-
carbamimidoyl)phenyl) phenyl)methyl]-1H-1,3-benzo-
diazole-7-carboxylate (Trityl Amidoxime Sodium Salt,
16). To a solution of trityl amidoxime methyl ester 15 (6.5 kg,
9.47 mol) in a mixture of tetrahydrofuran (39 L) and methanol
(6.5 L) was added 20% aqueous sodium hydroxide (473 g, 11.84
mol) at 25−30 °C. The reaction mixture was stirred for 8 h at
40−45 °C to complete the reaction. Then, the reaction mixture
was concentrated under reduced pressure at 50−55 °C, yielding
E
DOI: 10.1021/op500357r
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(5-Methyl-2-oxo-1,3-dioxo-4yl)methyl 1-[2′-(4,5-dihy-
dro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]-
methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate
(Azilsartan Medoxomil, 2). To a solution of amidoxime
medoxomil ester 18 (3.7 kg, 6.82 mol) in ethyl acetate (18.5 L)
was added disuccinimidyl carbonate (1.92 kg, 7.5 mol) at 25−30
°C. The reaction mixture was stirred for 16 h at 40−45 °C to
complete the reaction. Thereafter, DM water (7.4 L) was added
to the reaction mixture at 25−30 °C, and the product was cooled
to 5−10 °C. The product was filtered and purified with ethanol,
yielding 3.14 kg (82%) of azilsartan medoxomil (2) as a white
compound. mp 174−177 °C. HPLC purity: 99.60%. HRMS for
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the management of
Aurobindo Pharma Limited for allowing us to carry out this
research work.
ABBREVIATIONS
■
TsCl, para-toluenesulfonyl chloride; DMSO, dimethyl sulfoxide;
DMAP, dimethylaminopyridine; DMAc, N,N-dimethylaceta-
mide; DMF, N,N-dimethylformamide; TrCl, trityl chloride;
DSC, disuccinimidyl carbonate; TFA, trifluoroacetic acid;
DIBOC, di-tert-butyl dicarbonate; DMC, dimethyl carbonate;
DEC, diethyl carbonate; DPC, diphenyl carbonate; CDI,
carbonyldiimidazole; ECF, ethyl chloroformate
1
C30H25N4O8: (M + H)+ calcd, 569.1594; found, 569.1667. H
NMR (500 MHz, DMSO): δ 12.374 (br s, 1H, NH), 7.737 (d, J =
8 Hz, 1H, Ar), 7.68−7.562 (m, 2H, Ar), 7.549 (dd, J = 7, 1 Hz,
1H, Ar), 7.531 (dd, J = 7.5, 1 Hz, 1H, Ar), 7.514−7.467 (m, 1H,
Ar), 7.231−7.20 (m, 3H, Ar), 7.007 (d, J = 8.5 Hz, 2H, Ar), 5.554
(s, 2H, N-CH2-Ar), 5.116 (s, 2H, COOCH2), 4.606 (q, J = 7 Hz,
2H, OCH2CH3), 2.16 (s, 3H, CH3), 1.401 (t, J = 7 Hz, 3H,
OCH2CH3). IR (KBr pellet): 3537, 3436, 2988, 1781, 1727,
1609, 1546, 1280, 1249, 1128 cm−1.
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(5-Methyl-2-oxo-1,3-dioxo-4yl)methyl 1-[2′-(4,5-dihy-
dro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]-
methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate, Mo-
nopotassium Salt (Azilsartan Kamedoxomil, 1). To a
solution of azilsartan medoxomil 2 (3 kg, 5.28 mol) in
tetrahydrofuran (300 L) was added activated carbon (150 g,
5%) at 25−30 °C. The slurry mass was stirred for 30 min at 40−
45 °C. The reaction mass was filtered under hot conditions and
then cooled to 20−25 °C. A tetrahydrofuran solution of
potassium 2-ethylhexanoate (0.94 kg, 5.17 mol) was added to
the above reaction mass at 20−25 °C. The slurry mass was stirred
for 2 h at 20−25 °C. The product was filtered and washed with
acetone (6 L), yielding 2.55 kg (80%) of 1 as a white compound.
HPLC purity: 99.52%. HRMS for C30H24KN4O8: (M + H)+
calcd, 607.1153; found, 607.1227. 1H NMR (500 MHz, DMSO):
δ 7.732 (d, J = 8 Hz, 1H, Ar), 7.501 (d, J = 5.5, 1 Hz, 2H, Ar),
7.396−7.332 (m, 2H, Ar), 7.258 (d, J = 7 Hz, 1H, Ar), 7.221−
7.191 (m, 3H, Ar), 6.871 (d, J = 8 Hz, 2H,Ar), 5.52 (s, 2H, N-
CH2-Ar), 5.11 (s, 2H, COOCH2), 4.61 (q, 2H, OCH2CH3), 2.16
(s, 3H, CH3), 1.42 (t,3H, OCH2CH3). 13C NMR (125 MHz
DMSO-d6): δ 173.064, 168.793, 165.062, 158.414, 151.856,
141.685, 140.360, 140.315, 139.804, 135.096, 133.261, 131.047,
130.936, 129.974, 129.915, 128.893, 128.582, 126.798, 125.562,
123.223, 122.031, 120.832, 114.680, 66.697, 54.683, 46.370,
39.996, 39.922, 39.833, 39.752, 39.663, 39.589, 39.500, 39.419,
39.330, 39.167, 38.997, 14.391, 8.876. IR (KBr pellet): 3537,
3436, 2988, 1781, 1727, 1609, 1546, 1280, 1249, 1128 cm−1.
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ASSOCIATED CONTENT
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* Supporting Information
Characterization spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
*Tel.: +91-8455-223757; Fax: +91-8455-23044873; E-mail:
srinivasgaraga@yahoo.com.
Notes
The authors declare no competing financial interest.
F
DOI: 10.1021/op500357r
Org. Process Res. Dev. XXXX, XXX, XXX−XXX