FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A Process for the Preparation of Azilsartan Acid "
2. APPLICANT (S)
(a) NAME: Wanbury Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Wanbury Ltd.,BSEL Tech park, B-wing, 10th floor, sec -30A, opp. Vashi Railway station, Vashi, Navi- Mumbai-400703, Maharashtra, India.
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention
The present invention relates to an improved process for preparation of Azilsartan acid of Formula (I) from 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyl]-biphenyl-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxylic acid or its derivatives represented by compound of Formula (II);
Wherein R is H, Li, Na, K, Ca, C1C5 alkyl group, p-toluene sulfonate, 4-ethyl-5-methyl-l,3-dioxol-2-one (medoxomil ester), methane sulphonate or ethane sulfonate
Background of the invention
Azilsartan, chemically known as l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazoI-3-yl)[lJ'-biphenyl]-4-yl]methyl]-2-ethoxy-lH-Benzimidazole-7-carboxylic acid, is an angiotensin II receptor antagonist used for treatment of hypertension. Azilsartan medoxomil having structural Formula (la) is a "prodrug" that is easily transformed to Azilsartan.

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field-
Azilsartan was first disclosed in US 5,583,141. This patent provides a process for preparation of Azilsartan, depicted in scheme 1, wherein methyl-1-[(2'-cyanobiphenyl-4-yl]methyI]-2-ethoxybenzimidazole-7-carboxylate of Formula (A) is converted to an oxime of Formula (B) by reaction with hydroxylamine hydrochloride and sodium methoxide. The oxime of Formula (B) is then subjected to reaction with ethylchlorocarbonate followed by cyclization in xylene at reflux temperature to yield methyl ester of Azilsartan of Formula (C) which on hydrolysis provides Azilsartan of Formula (I).

WO2013114305, discloses a process for preparation of Azilsartan medoxomil through formation of 2-ethoxy-l-[[2'-[(hydroxyamino)iminomethyI]-biphenyI-4-yl)]methyl-lH-benzo[d]imidazole-7-carboxylic acid of Formula (II), wherein later is formed by reaction of a cyano ester of Formula (A) with hydroxylamine salt in presence of methanolic sodium hydroxide and dimethyl acetate as solvent, followed by hydrolysis using sodium hydroxide. The intermediate of Formula (II) thus formed

was isolated and further subjected to reaction with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one and ethyl chloroformate followed by cyclization to obtain Azilsartan medoxomil of Formula (la). Said process depicted in scheme 11

WO2013186792, discloses a process for preparation of Azilsartan medoxomil wherein 2-ethoxy-l-((2'-(N,-hydroxycarbamimidoxyl) biphenyl-4-yI) methyl)-1H-benzo [d] imidazole-7-carboxylic acid compound of Formula (II) is treated with ethyl chloroformate in presence of sodium carbonate and tetrahydrofuran at 0-5°C. After completion of reaction, the reaction mixture was diluted with water, acidified and extracted with dichloromethane. The dichloromethatfe layer was distilled off to yield compound of Formula (III). The compound of Formula (III) is reacted with 4-(chloromethyl)-5-methyI-l,3-dioxol-2-one in presence of sodium carbonate and tetrabutylammonium bromide in tetrahydrofuran to obtain compound of Formula (E) which was the reflux with xylene for two hours to obtain Azilsartan medoxomil of Formula (la) which was subjected to column chromatography purification. Said process depicted in scheme \\\.

All the processes known in prior art utilizes multiple organic solvents like xylene, dimethyl acetate, tetrahydrofuran etc., further in some of the prior art processes the intermediate or the final product formed requires purification by column chromatography which in turn leads to the use of a large amount of organic solvents.
Hence, one of the major drawbacks of the processes known in prior art is usage of multiple organic solvents in the process. It is we'l known that, most of organic solvents are hazardous to human health and/or environment in some or the other way. After the usage, these solvents are disposed through a waste disposal process often contributing to global warming, ground water contamination etc., or are recycled u^ing tedious, cumbersome and expensive recycling procedures. Use of multiple organic solvents in a process not only has detrimental effect on environment, but also makes the process uneconomical.
Further, careful inspection of all said prior arts with intrinsic and extrinsic evidences, it was observed that all the prior arts are silent over the amide impurity of Formula (V) formed during the reaction. This is the second major drawback in all said prior arts.
In process for preparation of Azilsartan or its ester, if these impurities are not reduced/ removed in early stages and are carried forward along with compound of Formula (I), the purity of final compound is adversely effected. It is always desirable to prepare a pharmaceutical product of high purity and having minimal amount of impurities in order to reduce adverse side effects and to improve shelf life of active ingredients. Hence, multiple purifications of Azilsartan or its esters are required which leads to reduction of yield
Inventors of present invention skillfully designed the process for preparation of Azilsartan acid in such a way that, formation of impurities like desethyl impurity of Formula (IV) & (IVa), amide impurity of Formula (V) and carbamate impurity of

Formula (VI) is avoided to great extent. Also, these impurities are reduced by using an eco-friendly process thereby making process economic and industrially viable.
Wherein R is same as defined above Object of the invention
1. The main object of the present invention is to provide a process for preparation of Azilsartan acid of Formula (I) from compound of Formula (II).
2. Another object of the present invention is to provide Azilsartan acid of Formula (I) in high yield and purity.

3. Another object of the present invention is to provide Azilsartan acid of Formula (I) substantially free of desethyl impurity of Formula (IV) & (lVa), amide impurity of Formula (V) and carbamate impurity of Formula (VI).
4. Yet another object of the present invention is to provide simple, economic, environment friendly and industrially scalable process for the preparation of Azilsartan acid of Formula (]).
Summary of the invention
According to an aspect of the present invention there is provided a process for preparation of Azilsartan acid of Formula (I),
comprising steps of
a) reacting compound of Formula (11)

wherein R is H, Li, Na, K, Ca, C1-C5 alkyl group, p-toluene sulfonate, 4-ethyl-5-methyl-l,3-dioxol-2-one (medoxomil ester), methane sulphonate or ethane sulfonate.
with ethyl chloroformate in presence of a base in a polar solvent at temperature ranging from 20 to 60°C to form compound of Formula (III);
b) cyclizing compound of Formula (III) in presence of a base in polar solvent at temperature ranging from 50 to 100°C;
c) isolating crude Azilsartan acid of Formula (I);
d) purifying the crude Azilsartan acid by treatment with suitable solvent.
Detailed Description of the Invention
The present invention relates to an eco-friendly process for preparation of Azilsartan acid of Formula (I),

comprising steps of
a) reacting compound of Formula (II)
wherein R is H, Li, Na, K, Ca, C1-C5 alkyl group, p-toluene sulfonate, 4-ethyl-5-methy1-l,3-dioxol-2-one (medoxomri ester), methane su\phonate or ethane sulfonate.
with ethyl chloroformate in presence of a base in a polar solvent at temperature ranging from 20 to 60°C to form compound of Formula (III);
b) cyclizing compound of Formula (111) in presence of a base in polar solvent at temperature ranging from 50 to 100°C;
c) isolating crude Azilsartan acid of Formula (I);
d) purifying the crude Azilsartan acid by treatment with suitable solvent.

The process for preparation of Azilsartan acid of Formula (!) can be depicted in scheme IV:
Wherein R is H, Li, Na, K, Ca, C1-C5 alkyl group, p-to)uene sulfonate, 4-ethyl-5-methyl-l,3-dioxol-2-one (medoxomil ester), methane sulphonate or ethane sulfonate.
According to an embodiment of the present invention, the polar solvent used in step a) and b) is selected from dimethyl sulfoxide, water or mixture thereof.
Preferably, the polar solvent used in step a) is water.
According to an embodiment of the present invention, the base used in step a) and step b) of the process are selected from alkali metal carbonate like sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or mixture thereof, preferably sodium carbonate or potassium carbonate is used.

According to an embodiment of present invention, the molar ratio of ethyl chloroformate used in step a) with respect to compound of Formula (11) is in the range of 1 to 3 w/w.
According to an embodiment of the present invention, isolation of the compound of Formula (III) formed in step a) involves adjustment of pH in the range of 4 to 6, extraction of the reaction mixture with water immiscible organic solvent like ethyl acetate or dichloromethane, and concentrating the organic solvent extract to obtain residue of compound of Formula (III) which is directly used in step b) of the process.
The water immiscible organic solvent used for isolation of the compound of Formula (III) formed in step a) is selected from ethyl acetate or dichloromethane, preferably ethyl acetate is used.
According to another embodiment of the present invention, step a) and b) are carried out insitu, without isolation of compound of Formula (III).
According to yet another embodiment of the present invention, the step c) of process wherein the crude Azilsartan acid is isolated, comprises of, adding water to reaction mixture of step b), acidifying the thus formed aqueous solution and separating the solid crude Azilsartan acid by filtration
According to an embodiment of the present invention, the solvent used in step d) is selected from ethyl acetate, dichloromethane, butyl acetate, methyl acetate but preferably ethyl acetate is used.
It was observed that selection of solvent in step a) has huge impact on formation of impurities like desethyl impurity of Formula (IV) & (IVa), amide impurity of Formula (V) and carbamate impurity of Formula (VI). The inventors of present invention contemplated the use of number of solvents in step a) to facilitate high purity Azilsartan acid of Formula (I). A skillfully selection of solvent(s) for step a) and b) according to the present invention is the one that efficiently yields highly pure

Azilsartan acid of Formula (I) and thereby decreases formation of aforementioned impurities. The observations using different solvents in step a) of the present invention are summarized in Table I
Table I

Sr. Solvent Desethyl Desethyl Amide Carbamate Purity of Yield of
No. impurity impurity impurity impurity of Azilsarta Azilsartan
of of of Formula n acid of acid of
Formula Formula Formula (VI) Formula Formula (I)
(IV) (IVa) (V) formed (I) formed
formed formed formed formed
1 Water Less than 1% 1 to 1.5% Less than
1% Nil 95 to 97% 70 to 75%
2 Dimethyl sulfoxide 4 to 5% 3 to 3.5% 5 to 8% 8 to 10% 75 to 80% 55 to 60%
3 Tetrahydr ofuran 6 to 8 % 4 to 6% 5 to 8% 10 to 15% 70 to 75% 50 to 55%
From above observations, it can be concluded that as compared to dimethyl sulfoxide and tetrahydrofuran, use of water as solvent in step a) reduces the formation of said impurities to great extent and thereby resulting in Azilsartan acid of Formula (I) in high yield and purity.
The detail of the invention provided in the following example is given by the way of illustration only and should not be construed to limit the scope of the present invention

Examples
The starting material i.e. compound of Formula (II), used in process is prepared as the methods known in prior arts, one of such method for preparing compound is provided in our Indian patent application No. 1707/MUM/2014
Example 1: Preparation of compound of Formula (III) from compound of Formula (II); wherein R is H
lOOg of compound of Formula (II) and 30g of sodium carbonate were added to 1500ml of water. The mixture was stirred at 45-50°C for 15 minutes to obtain a clear solution. 35g of ethyl chloroformate was added to the clear solution at 10-20°C and the reaction mixture was maintained at same temperature for 2 hours. After completion of reaction, pH of reaction mixture was adjusted to 5.5 using 2N HC1 followed by addition of 3500ml of ethylacetate and the mixture was stirred for 15-20 minutes. The organic layer was separated, concentrated under vacuum to obtain a residue which was further treated with mixture of ethylacetate and hexane to obtain 105g of compound of Formula (III) having HPLC purity of 97%
Example 2: Preparation of Azilsartan acid of Formula (I) from compound of Formula (III); wherein R is H
a) Preparation of crude Azilsartan acid
lOOg of compound of Formula (III) and 80.25g of potassium carbonate were added to 800ml of dimethyl sulfoxide, the reaction mixture was heated to 80-85°C and maintained till completion of reaction. After completion of reaction, the mixture was cooled to 25-30°C, filtered to remove inorganics followed by addition of 2000ml water to get an aqueous solution. The aqueous solution was acidified to pH 3-3.5 using hydrochloric acid and then the mixture was stirred for 2 hours to get solid. The solid was filtered out, washed with water and dried to obtain 90g of crude Azilsartan acid having HPLC purity of 96%.

b) Purification of crude Azilsartan acid
The crude Azilsartan acid obtained in example 2a) was added to 425ml of ethyl acetate, the mixture was refluxed for 1 hour and then cooled to 25-30°C. The solid obtained was filtered out, washed with ethyl acetate and dried to obtain 80g of Azilsartan acid having HPLC purity of 99%.
The purification of crude Azilsartan acid obtained in example 2a) can also be carried out using different solvents. The results obtained are provided in Table II
Table II

Sr. No. Solvent used HPLC Purity of Yield of
Azilsartan acid Azilsartan acid
obtained obtained
i Dichloromethane 93 to 95% 60 to 65%
ii Butyl acetate 94 to 96% 62 to 66%
iii Methyl acetate 94 to 96% 64 to 67%
Example 3: In-situ preparation of Azilsartan acid of Formula (I) from compound of Formula (II); wherein R is Li
lOOg of compound of Formula (II) and 30 g of sodium carbonate were added to 1500ml water. The mixture was stirred at 45-50°C for 15 minutes to obtain a clear solution. 35g of ethyl chloroformate was added to the clear solution at I0-20°C and the reaction mixture was maintained at same temperature for 2 hours. After completion of reaction, the pH of reaction mixture was adjusted to 5.5 using 2N HC1 followed by addition of 3500ml of ethylacetate and the mixture was stirred for 15-20 minutes. The organic layer was separated and concentrated under vacuum to obtain a

residue. 800ml of dimethyl sulphoxide and 80g of potassium carbonate were then added to said residue and the reaction mixture was heated to 80-85°C. After completion of reaction, the mixture was cooled to 25-30°C, filtered and 2000ml water was added to get an aqueous solution. The aqueous solution was acidified to pH 3-3.5 using hydrochloric acid and then the mixture was stirred for 2 hours to get solid. The solid was filtered out, washed with water and dried to obtain 85g of crude Azilsartan acid. The crude Azilsartan acid obtained was added to 400ml of ethyl acetate, the mixture was refluxed for 1 hour and then cooled to 25-30°C. The solid obtained was filtered out, washed with ethyl acetate and dried to obtain 75g of Azilsartan acid having HPLC purity of 98%.

We claim,
1. A process for preparation of Azilsartan acid of Formula (I),

comprising steps of:
a) reacting compound of Formula (11),

wherein R is H, Li, Na, K, Ca, C1-C5 alky] group, p-toluene sulfonate, 4-ethyI-5-methyl-l,3-dioxol-2-one (medoxomil ester), methane sulphonate or ethane sulfonate.
with ethyl chloroformate in presence of a base in a polar solvent at temperature ranging from 20-60°C to form compound of Formula (III);

b) cyclizing compound of Formula (III) in presence of a base in polar solvent at temperature ranging from 50 to 100°C;
c) isolating crude Azilsartan acid of Formula (I);
d) purifying the crude Azilsartan acid by treatment with suitable solvent.

2. The process as claimed in claim 1, wherein the polar solvent used in step a) and b) is selected from dimethyl sulfoxide, water or mixture thereof
3. The process as claimed in claim 2, wherein the polar solvent used in step a) is water.
4. The process as claimed in claim 1, wherein the base used in step a) and step b) of the process are selected from alkali metal carbonate like sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, preferably sodium carbonate or potassium carbonate is used.
5. The process as claimed in claim 1, wherein the step a) and step b) are carried out in-situ.
6. The process as claimed in claim 1, wherein the isolation of the compound of Formula (III) formed in step a) involves adjustment of pH in the range of 4 to 6, followed by extraction of the reaction mixture with water immiscible

organic solvent like ethyl acetate and concentrating the organic solvent extract to obtain residue of compound of Formula (111)
7. The process as claimed in claim 1, wherein the step c) of the process
comprises:
a) adding water to reaction mixture of step b);
b) acidifying the thus formed aqueous solution and separating the crude solid Azilsartan acid by filtration.
8. The process as claimed in claim 1, wherein the solvent used in step d) is
selected from ethyl acetate, dichloromethane, butyl acetate, methyl acetate but
preferably ethyl acetate is used.