An Improved Preparation of Azilsartan

Full text of DOI:10.1080/00304948.2020.1809271

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
An Improved Preparation of Azilsartan
Vijaya Lakshmi Chapala , Naresh Kumar Katari , Giri Prasad Malavattu ,
Vishnu Murthy Marisetti & Sreekantha B. Jonnalagadda
To cite this article: Vijaya Lakshmi Chapala , Naresh Kumar Katari , Giri Prasad
Malavattu , Vishnu Murthy Marisetti & Sreekantha B. Jonnalagadda (2020): An Improved
Preparation of Azilsartan, Organic Preparations and Procedures International, DOI:
10.1080/00304948.2020.1809271
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Published online: 24 Oct 2020.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1809271
OPPI BRIEF
An Improved Preparation of Azilsartan
a
a,c
a
Vijaya Lakshmi Chapala , Naresh Kumar Katari
, Giri Prasad Malavattu ,
b
c
Vishnu Murthy Marisetti , and Sreekantha B. Jonnalagadda
a
Department of Chemistry, School of Science, GITAM (Deemed to Be University) Hyderabad, Rudraram,
b
Sangareddy, Telangana, India; Analytical Research and Development, ScieGen Pharmaceuticals Inc.,
Hauppauge, New York, USA; School of Chemistry and Physics, College of Agriculture, Engineering and
c
Science, Westville Campus, University of KwaZulu-Natal, Durban, South Africa
ARTICLE HISTORY Received 10 August 2019; Accepted 4 May 2020
1
,4
Azilsartan (I) is an orally administered drug to control high blood pressure in adults.
Azilsartan medoxomil (II), a US FDA approved prodrug of Azilsartan (Figure 1), is an
angiotensin II receptor type 1 blocker in the treatment of hypertension. Due to its eco-
nomic importance, the synthesis of Azilsartan has received considerable attention in the
pharmaceutical industry.
A literature survey on synthetic methods for Azilsartan reveals very few prepara-
5
–16
tions
using 1-[(2 cyanobiphenyl-4-yl) methyl]-2-ethoxy benzimidazole-7-carboxylate
(BEC methyl ester, 5) as a starting material. Scheme 1 illustrates the sequence of steps
for the synthesis of Azilsartan. The reaction of 5 with hydroxylamine hydrochloride in
the presence of alkoxide (sodium methoxide in methanol or sodium ethoxide in etha-
nol) gave product 4. Then, the reaction of 4 with ethyl chloroformate in the presence of
base gave product 3a, which was subsequently cyclized in xylene under reflux to pro-
duce compound 2. Compound 2 upon hydrolysis with alkali produced Azilsartan 1
(Scheme 1).
Although it is a straightforward procedure, this approach suffers from some draw-
backs, such as low yields and the formation of impurities, including the congener amide
methyl ester 5a and desethyl amidoxime methyl ester 5c (Scheme 2). According to the
International Conference on Harmonization (ICH) guidelines, any impurity present to
the extent of 0.15% or higher is to be identified and characterized. Some of the previ-
ously reported processes do not meet this requirement. Another method reported a
17
modified synthesis of Azilsartan with an overall yield of 58% with 98.9% HPLC purity.
While the method has the appeal of being direct, the potential for impurity formation is
a concern.
We now report on our own work in this area, in which we have systematically
focused on each of the four steps for the synthesis of Azilsartan, to improve the overall
yield and reduce the level of impurities (Scheme 3). In the first step, BEC methyl ester
(
1
5) was reacted with hydroxylamine hydrochloride and sodium bicarbonate in DMSO at
00 C under continuous stirring for 18 h. The resultant yield of 4 was 96%. The reac-
ꢀ
tion of Boc anhydride in t-butanol with compound 4 yielded compound 3 (98%).
CONTACT Naresh Kumar Katari
nareshkumar.katari@gitam.edu
Department of Chemistry, School of Science,
GITAM (Deemed to Be University) Hyderabad, Rudraram, Sangareddy, Telangana, 502 329 India.
ß 2020 Taylor & Francis Group, LLC

2
V. L. CHAPALA ET AL.
Figure 1. Structure of Azilsartan (I) and Azilsartan medoxomil (II).
1
6
Scheme 1. Synthesis of Azilsartan from BEC methyl ester 5.
1
7
Scheme 2. Observed by-products in Azilsartan synthetic route.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Scheme 3. Azilsartan optimized synthetic route.
Unlike ethyl or methyl chloroformates, which offer N and O formate products, Boc
anhydride reacts only with the NH function and has no reaction with OH, thus reduc-
2
ꢀ
ing the level of impurities. The compound 3 undergoes cyclization in DMF at 100 C to
produce 2 (92%), again lessening the impurities formed. With ethyl or methyl chloro-
formates, the N and O formate compounds are produced, generating two possible cyc-
1
6,18
lization compounds.
From compound 2 to 1, the final step, the ester hydrolysis was
carried out in methanolic NaOH at room temperature for 2 hr and gave the sodium salt
of Azilsartan (96%). At 200 g scale, the overall yield of the four-step reaction path was
enhanced to 95%, with HPLC 99.95% purity (Scheme 3).
In summary, we have developed an efficient and scalable new method for the synthe-
sis of Azilsartan by a simplified approach. The salient features of this method include
high yields and reduction of impurities.
Experimental section
Analytical reagent grade chemicals and solvents were used without further purification.
All the reactions were performed in oven-dried flasks. Analytical thin layer chromatog-
raphy (TLC) was done on silica gel (GF254) pre-coated plates, eluted with ethyl acetate/
n-hexane or methanol/methylene chloride. Solvents were distilled off under vacuum.
Silica gel (100-200 mesh) was employed for column chromatography. The elution was
supported by slight pressure with an air pump. Proper names were formed for all the
new compounds using ChemBioOffice 2008. IR spectra were determined (as neat liquids
or KBr pellets) on a Perkin-Elmer 1000 instrument and absorptions were stated in
ꢁ1
cm . A Varian (400 MHz) instrument was used to record the 1H NMR spectra with a
suitable solvent using TMS as internal standard or the solvent signals as secondary
13
standards, and the chemical shifts are shown in ppm d. C NMR spectra were recorded
on Varian 75 and 125 MHz spectrometers. Mass spectra were recorded with a PE Scitex
model API 3000 instrument. HPLC analysis was performed on a reverse phase column;
Waters, symmetry shield RP18 (250 x 4.6 mm, 5 microns). The mobile phase consisted
of 10 mM ammonium acetate buffer:acetonitrile 55:45, v/v. The flow rate of the mobile
phase was adjusted to 1.0 mL/min, and the injection volume was 20 lL. The sample
concentration was 1.0 mg/mL. Copies of original H-NMR, C-NMR and mass spectra

4
V. L. CHAPALA ET AL.
were submitted for review, as was the HPLC of the Azilsartan derived from
our procedures.
Methyl (Z)- 2-ethoxy-1-((2’-(N’-hydroxycarbamimidoyl)-[1,1’-biphenyl]-4-yl)methyl)-
1
H-benzo[d]imidazole-7-carboxylate (4)
Sodium bicarbonate (4.5 mole, 378.0 g) was added to a solution of hydroxylamine
ꢀ
hydrochloride (3.3 mole, 232.0 g) in dimethyl sulfoxide (1250.0 ml) at 25-30 C.
ꢀ
Thereafter, the temperature was increased to 45-50 C. At this temperature, l-[(2’-cyano-
19
biphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.60 mole, 250.0 g) (5)
was added to the resulting solution and the mixture was heated up to 100 C followed
by stirring at the same temperature for 18 h. After completion (TLC), the reaction mass
was cooled to 15-20 C, then poured into water. The solution was stirred for 15-20 min
at 15-20 C and filtered. The formed product was washed with water and dried to
ꢀ
ꢀ
ꢀ
obtain methyl 2-ethoxy[[2’-(hydroxyamidino) biphenyl-4-yl] methyl]-lH-benzimidazole-
ꢀ
1
7
1
-carboxylate (4). Yield: 260.0 g; 96%; mp 203-206 C; H NMR (DMSO) d ¼ 9.17 (s,
H, OH), 7.70 (d, 1H, Ar), 7.46 (d, 1H,Ar), 7.46 (d, 1H, Ar), 7.29 (d, 1H, Ar), 7.19
(
t,1H, Ar), 6.94 (d, 2H, Ar), 5.55 (bs, 2H, NH ), 5.50 (s, 2H, N-CH -Ar), 4.62 (q, 2H,
2 2
OCH CH ), 3.71 (s, 3H, OCH ), 1.42 (t, 3H, OCH CH ). IR (KBr pellet): 3514, 3407,
2
3
3
2
3
ꢁ
1
3
268, 2985, 1718, 1634, 1612, 1547, 1284, 1257, 1133 cm . Mass: C H N O LCMS:
m/z 446.17 (M þ H) .
25 25 4 4
þ
Methyl 2-ethoxy [[2’-(hydroxy-tertiary-butoxycarbonyl amidino) biphenyl-4-yl]
16
methyl]-lH-benzimidazole-7-carboxylate (3)
Compound 4 (0.55 mole, 260.0 g) in tertiary-butanol (910.0 ml) was taken in a round
bottom flask, then Boc anhydride (0.69 mole, 152.0 g) was added slowly through an add-
ꢀ
ition funnel at 25-30 C. After completion of addition, the temperature was increased to
ꢀ
5
0-55 C and stirring was continued at the same temperature for 12 h. The progress of
the reaction was monitored by TLC. After completion of reaction, the reaction mixture
ꢀ
ꢀ
was cooled to 15-20 C and stirred for 60 min at 15-20 C to obtain the solid. The prod-
uct was filtered, washed with tertiary-butanol (260.0 ml) and dried under vacuum at 55-
ꢀ
6
0 C. This afforded methyl 2-ethoxy [[2’-(hydroxy tertiary-butoxycarbonyl amidino)
1
biphenyl-4-yl] methyl]-lH-benzimidazole-7-carboxylate (3). Yield: 312.0 g; 98%.
H
NMR (DMSO) d ¼ 9.17 (s, 1H, OH), 7.70 (d, 1H, Ar), 7.46 (d, 1H, Ar), 7.46 (d, 1H,
Ar), 7.29 (d, 1H, Ar), 7.19 (t,1H, Ar), 6.94 (d, 2H, Ar), 5.55 (bs, 1H, NH), 5.50 (s, 2H,
N-CH -Ar), 4.62 (q, 2H, OCH CH ), 3.71 (s, 3H, OCH ), 1.42 (t, 3H, OCH CH ) 1.27
2
2
3
3
2
3
(
1
s, 9H, Boc). IR (KBr pellet): 3514, 3407, 3268, 2985, 1718, 1634, 1612, 1547, 1284,
ꢁ
1
þ
257, 1133 cm . Mass: C H N O (M þ H) LCMS: m/z 546.17.
3
0
34 4 6
Methyl l-[[2’-(4,5-dihydro-5-oxo-4H-l,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl]-2-
16
ethoxy-lH-benzimidazole-7-carboxylate (2)
Compound 3 (312.0 g) was placed in DMF (1248.0 ml) and then the reaction was heated
ꢀ
up to 110-115 C. The resulting solution was stirred at the same temperature for 12 h.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
ꢀ
After completion of reaction (TLC), the mixture was cooled to 20-25 C, diluted with
water (3744.0 ml), and stirred for 4 hours. The reaction mixture was filtered, washed
ꢀ
with water (624.0 ml) and dried under vacuum at 80 C. After that, compound 2 was
dissolved in a mixture of methanol and water under reflux and allowed to cool to room
ꢀ
temperature, then to cool to 0-5 C for recrystallization. After recrystallization, the prod-
uct was filtered and washed with methanol to get pure methyl l-[[2’-(4, 5-dihydro-5-
oxo-4H-l,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl]-2-ethoxy-lH-benzimidazole-7-carb-
1
oxylate (2). Yield: 248.5 g; 92%. H NMR (DMSO) d ¼ 13.15 (bs, 1H, NH), 12.4, 7.68-
7
2
.63 (m, 3H, Ar), 7.56-7.55 (m, 2H, Ar), 7.52-7.46 (m, 1H, Ar), 7.245 (d, J ¼ 8.3 Hz,
H, Ar), 7.197 (t, 1H, Ar), 7.05 (d, J ¼ 8.3 Hz, 2H, Ar) 5.67 (s, 2H, N-CH -Ar), 4.578
2
(
q, 2H, OCH CH ), 3.71 (s, 3H, OCH ), 1.38 (t, J ¼ 7.1 Hz, 3H, OCH CH ). IR (KBr
2
3
3
2
3
ꢁ1 þ
pellet): 2989, 1774, 1733, 1613, 1552, 1286, 1145 cm . Mass: C H N O (M þ H)
26
24 4 5
LCMS: m/z 473.17.
1
6
Azilsartan (I)
Compound 2 (0.52 mole, 248.5 g) was placed in a mixture of 10% water and methanol
ꢀ
(
1242.0 ml). Then, sodium hydroxide (1.17 mole, 47.0 g) was added at 25-30 C and
stirred at the same temperature for 4 h. After completion of reaction (TLC), the reaction
mixture was diluted with water (750.0 ml) and methanol was distilled from the reaction
ꢀ
mixture under vacuum below 50 C. After completion of the distillation process, the
ꢀ
reaction mixture was allowed to cool to 20-25 C and the pH was adjusted with 1M
ꢀ
HCl to pH 1-2. The formed solid was obtained and stirred again for 60 min at 20-25 C.
Then the reaction mass was filtered, washed with water (500.0 ml) and dried under vac-
ꢀ
uum at 65-70 C to obtain l-[[2’-(4, 5-dihydro-5-oxo-4H-l, 2,4-oxadiazol-3-yl)biphenyl-
4
9
7
8
4
1
4
-yl]methyl]-2-ethoxy-lH-benzimidazoIe-7-carboxylic acid (Azilsartan, I). Yield: 231.4 g;
ꢀ
1
6%; mp: 210-213 C; H NMR (DMSO) d ¼ 13.15 (bs, 1H, NH), 12.4 (bs, 1H, OH),
.68-7.63 (m, 3H, Ar), 7.56-7.55 (m, 2H, Ar), 7.52-7.46 (m, 1H, Ar), 7.245 (d, J ¼
.3 Hz, 2H, Ar), 7.197 (t, 1H, Ar), 7.05 (d, J ¼ 8.3 Hz, 2H, Ar) 5.67 (s, 2H, N-CH -Ar),
2
.578 (q, 2H, OCH CH ), 1.38 (t, J ¼ 7.1 Hz, 3H, OCH CH ). IR (KBr pellet): 2989,
2
3
2
3
ꢁ
1
þ
774, 1733, 1613, 1552, 1286, 1145 cm . Mass: C H N O (M þ H) LCMS: m/z
25
21 4 5
56.14. HPLC purity 99.95%.
ORCID
Naresh Kumar Katari
http://orcid.org/0000-0002-5737-8528
Sreekantha B. Jonnalagadda
http://orcid.org/0000-0001-6501-8875
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