FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“IMPROVED PROCESS FOR THE PREPARATION OF AZILSARTAN”

Glenmark Pharmaceutical Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

PRIORITY
The application claims the benefit to Indian provisional Application No. 201621004655, filed on 10 February, 2016, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of azilsartan.

BACKGROUND OF THE INVENTION
Azilsartan chemically known as 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl) methyl)-lH-benzimidazole-7-carboxylic acid represented by Formula I.

Formula I
Azilsartan medoxomil 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-oxodiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate represented by Formula VI.

Formula VI
Edarbi (azilsartan medoxomil), a prodrug, is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is a selective AT1 subtype angiotensin II receptor antagonist.

United States patent No. US 5,243,054 discloses azilsartan and its process for preparation.
There are evolving and more rigorous requirements demanded of drug manufacturers and with the prevailing disadvantages present with the prior art, there is a need for an improved process for the preparation of azilsartan, which circumvents the formation of process related impurities, while ensuring a target azilsartan or azilsartan medoxomil and its salt with optimum yield and high purity.
The present invention provides an improved and cost effective industrial process for the preparation of azilsartan of formula I in high yield and substantially free of desethyl impurity of Formula A.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of azilsartan of formula I, comprising:

Formula I
(a) hydrolyzing a compound of formula II by a base to form a reaction mixture;

Formula II
(b) adding oxalic acid to the reaction mixture of step a); and
(c) isolating azilsartan of formula I from step b);
wherein the resultant azilsartan contains desethyl impurity of formula A in less than 0.05% w/w, as determined by HPLC,

Desethyl impurity (Formula A).
In one aspect, present invention provides a pharmaceutical composition comprising azilsartan of formula I together with one or more pharmaceutically acceptable carriers.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a XRPD of azilsartan of Formula I.
Figure 2 is a XRPD of azilsartan medoxomil potassium.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of azilsartan of formula I.
In one embodiment, the present invention provides a process for the preparation of azilsartan of formula I, comprising:

Formula I
(a) hydrolyzing compound of formula II by a base to form a reaction mixture;

Formula II
(b) adding oxalic acid to the reaction mixture of step a); and
(c) isolating azilsartan of formula I from step b);
wherein the resultant azilsartan contains desethyl impurity of formula A in less than 0.05% w/w, as determined by HPLC,

Desethyl impurity (Formula A).
Base used in (a) includes, but is not limited to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, lithium tert. butoxide and the like or aqueous mixtures thereof.
Suitable solvent may be used in step a) includes, but is not limited to alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate and the like; ether solvents such as dimethyl ether, diethyl ether, methyl tert-butyl ether and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbon solvents such as heptane, hexane, xylene, toluene and the like; dimethylformamide, dimethylacetamide, dimethylsulfoxamide, N-methylpyrrolidone, acetic acid, water or mixtures thereof.
In step a) compound of formula II is added to base and heated at about 30-700C for a period of about 0 – 10 hours.
The oxalic acid in step b) is added to the reaction mixture at room temperature.
The oxalic acid in step b) is added to the reaction mixture so that pH is in the range of 5 to 5.5.
In one embodiment, azilsartan of formula I obtained in (c) is filtered and dried.
In one embodiment, azilsartran of formula I is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, drying may be performed in air oven at a temperature of about 30-100°C, preferably at a temperature of about 50-60°C.
In one embodiment, the present invention provides azilsartan of Formula I, obtained by the processes herein described, having a D90 particle size of less than about 50 microns, preferably less than 10 microns, D50 particle size of less than about 25 microns and D10 particle size of less than about 6 microns.
In one embodiment, the present invention provides azilsartan of formula I with purity of more than 99.9% w/w as determined by HPLC, with less than 0.05% w/w of desethyl impurity of formula A, that is obtained directly from the reaction mixture without any further purification techniques like crystallization, column chromatography.
In one embodiment, the present invention provides azilsartan of formula I, wherein desethyl impurity of formula A is less than 0.05% w/w as determined by HPLC.
In one embodiment, the present invention provides azilsartan of formula I, wherein desethyl impurity of formula A is less than 0.03% w/w as determined by HPLC.
In one embodiment, the present invention provides azilsartan of formula I, wherein desethyl impurity of formula A is preferably absent.
In one embodiment, the present invention provides azilsartran of formula I having lithium content less than 55 ppm, preferably less than 10 ppm.
In one embodiment, the present invention provides a process for the preparation of azilsartan of formula I, comprising:

Formula I
(a) hydrolyzing a compound of formula II by a base to form a reaction mixture;

Formula II
(b) adding acid to the reaction mixture of step a); and
(c) isolating azilsartan of formula I from step b).
Acid used in (b) includes, but is not limited to ascorbic acid benzoic acid, boric acid, citric acid, fumaric acid, hydrofluoric acid, lactic acid, malic acid, propoionic acid, phosphoric acid, tartaric acid, sulphuric acid and the like; or aqueous mixtures thereof
Base used in step a) is as described supra. Solvent used in step a) as described supra.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
In one embodiment, the present invention provides a process for the preparation of azilsartan of formula I, comprising:

Formula I
(a) hydrolyzing a compound of formula II by a base to form a reaction mixture;

Formula II
(b) adding acetic acid to the reaction mixture of step a);
(c) isolating azilsartan of formula I from step b); and
(d) crystallizing azilsartan of formula I from acetic acid.
Base used in step a) is as described supra. Solvent used in step a) as described supra.
In one embodiment, the present invention provides a process for the preparation of compound of formula II,

Formula II
comprising: (a) reacting a compound of formula IV,

Formula IV
with hydroxylamine or its salt to form a compound of formula III; and

Formula III
(b) cyclizing the compound of formula III with 1,1’-carbonyldiimidazole (CDI) to compound of formula II; or
(b) cyclizing the compound of formula III with ethyl chloroformate to compound of formula II.
In one embodiment, in step a) compound of formula IV is reacted with hydroxylamine or its salt in anhydrous condition.
In one embodiment, in step a) compound of formula IV is reacted with hydroxylamine hydrochloride in anhydrous condition.
In one embodiment, in step b) compound of formula III reacted with CDI without any base.
In one embodiment, in step b) compound of formula III reacted with ethyl chloroformate with base.
Suitable solvent includes, but is not limited to dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), tetrahydrofuran (THF) and the like.
In one embodiment, the present invention provides a compound of formula II, in a purity of at least 99% by washing the reaction mixture containing compound of formula II with an organic solvent, followed by treatment with acetic acid and isolating the compound of formula II.
In one embodiment, the present invention provides purification of compound formula II obtained by method described herein is by crystallizing from alcoholic solvents such as methanol, ethanol, isopropanol and the like, preferably by methanol.
In one embodiment, the present invention provides azilsartan of formula I, where is one or more of formula B, formula C, formula D, formula E, formula F, formula G, formula H, or formula I are present less than 0.15% w/w relative to the amount of azilsartan as determined by HPLC.

Formula B Formula C Formula D

Formula E Formula F Formula G

Formula H Formula I
In one embodiment, the present invention provides azilsartan of Formula I, where is one or more of formula J, formula K, formula L, formula M, or formula N are present less than 0.15% w/w relative to the amount of azilsartan as determined by HPLC.

Formula J Formula K Formula L

Formula M Formula N
In one embodiment, the present invention provides azilsartan of Formula I, where is one or more of formula O, formula P, formula Q, or formula R are present less than 0.15% w/w relative to the amount of azilsartan as determined by HPLC.

Formula O: R = COOH & R1 = OC2H5; Formula Q: R=COOH & R1 = CN;
Formula P: R = COOCH3 & R1 = OC2H5 Formula R: R= COOH & R1 = -CH (NH2)=N-OH
In one embodiment, the present invention provides azilsartan of Formula I, where is one or more of formula S, formula T, formula U, or formula V are present less than 0.15% w/w relative to the amount of azilsartan as determined by HPLC.

Formula S: R=H & R1 = OC2H5; Formula T: R=COOH & R1 = OC2H5
Formula U: R=COOCH3 & R1 = OC2H5; Formula V’: R=COOC2H5 & R1 = OC2H5
In one embodiment, the present invention provides azilsartan of Formula I, where is one or more of formula W, formula X, formula Y, or formula Z are present less than 0.15% w/w relative to the amount of azilsartan as determined by HPLC.

Formula W: R=COOCH3, R1 = OC2H5 & R” = - CH(NH2)=NOCOOC2H5
Formula X: R=COOH, R1 = OC2H5 & R” = - CH(NH2)=NOCOOC2H5
Formula Y: R=COOH, R1 = OC2H5 & R” = - CH(NH2)=N-OH
Formula Z: R=COOH, R1 = OC2H5 & R” = - CH(NH)-NH2
In one embodiment, the present invention provides azilsartan of Formula I, where is one or more of formula AA, formula AB, formula AC, formula AD, formula AE or formula AF are present less than 0.15% w/w relative to the amount of azilsartan as determined by HPLC.

Formula AA: R=COOH & R1 = NO2; Formula AB: R=COOH & R1 = NH2

Formula AC: R=COOC2H5, R1 = NH2 & R2 = CONH2
Formula AD: R=COOC2H5, R1 = NH2 & R2 = CN
Formula AE: R=COOC2H5, R1 = NH2 & R2 = -CH-CH2-(NH2)=N-OH
Formula AF: R=COOC2H5, R1 = NH2 & R2 = -CH(NH2)=N-OH
In one embodiment, the present invention provides azilsartan of formula I, wherein level of impurities of desethyl impurity of formula A and impurity of formula V’ is less than 0.15% by crystallization from methanol.
In one embodiment, the present invention provides a process for the preparation of azilsartan medoxomil of formula VI, comprising:

Formula VI
(a) reacting a compound of formula I, with a compound of formula V

Formula I Formula V
In one embodiment, the compound of formula I is reacted with compound of formula V at lower temperature, preferably below 15°C.
In one embodiment, azilsartan medoxomil of formula VI obtained in the present invention is filtered and dried.
In one embodiment, the compound of formula VI is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, drying may be performed under vacuum at a temperature of about 30-90°C, preferably at a temperature of 60-65°C.
In one embodiment, azilsartan of formula I obtained in the present invention is converted into azilsartan medoxomil and its salt thereof.
In one embodiment, azilsartan of formula I obtained in the present invention is converted into azilsartan medoxomil and its potassium salt thereof.
In one embodiment, azilsartan medoxomil obtained in the present invention is converted into azilsartan medoxomil potassium.
In one embodiment, present invention provides stable azilsartran medoxomil potassium by the process comprising:
(i) slurrying azilsartan medoxomil potassium in acetone; and
(ii) isolating stable azilsartran medoxomil potassium from step i).
In one embodiment, present invention provides stable azilsartran medoxomil potassium by the process comprising:
(i) slurrying azilsartan medoxomil potassium in isopropyl alcohol; and
(ii) isolating stable azilsartran medoxomil potassium from step i).
In one embodiment, present invention provides stable azilsartran medoxomil potassium by the process comprising:
(i) slurrying azilsartan medoxomil potassium in acetone;
(ii) isolating the azilsartran medoxomil potassium from step i);
(iii) subjecting azilsartran medoxomil potassium of step ii) in isopropyl alcohol to slurrying; and
(iv) isolating stable azilsartran medoxomil potassium from step iii).
In one embodiment, azilsartan medoxomil potassium obtained in present invention is slurried with isopropyl alcohol (IPA) for a period of about 1–5 hours at room temperature.
In one embodiment, azilsartan medoxomil potassium obtained in present invention is slurried with isopropyl alcohol (IPA) for a period of about 1–10 hours at about 30-560C.
In one embodiment, azilsartan medoxomil potassium obtained in the present invention is filtered and dried.
In one embodiment, azilsartan medoxomil potassium obtained in the present invention is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, drying may be performed under vacuum at a temperature of about 20-35°C.
In one embodiment, azilsartan medoxomil potassium obtained in the present invention is stored at about 2-8°C.
In one embodiment, the present invention provides azilsartran medoxomil potassium having compound of formula I less than 0.15% w/w relative to the amount of azilsartran medoxomil potassium as determined by HPLC.
In one embodiment, the present invention provides azilsartran medoxomil potassium having compound of formula II less than 0.15% w/w relative to the amount of azilsartran medoxomil potassium as determined by HPLC.
In one embodiment, the present invention provides azilsartran medoxomil potassium having compound of formula III less than 0.15% w/w relative to the amount of azilsartran medoxomil potassium as determined by HPLC.
In one embodiment, the present invention provides azilsartran medoxomil potassium having compound of formula IV less than 0.15% w/w relative to the amount of azilsartran medoxomil potassium as determined by HPLC.
In one embodiment, the present invention provides azilsartran medoxomil potassium having compound of formula V less than 0.15% w/w relative to the amount of azilsartran medoxomil potassium as determined by HPLC.
In one embodiment, the present invention provides azilsartran medoxomil potassium having (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-oxo-3-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)-methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (Formula VII) less than 0.15% w/w relative to the amount of azilsartran medoxomil potassium as determined by HPLC.

Formula VII
In one embodiment, the present invention provides azilsartran medoxomil potassium having (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-[(2'-carbamoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (Formula VIII) less than 0.15% w/w relative to the amount of azilsartran medoxomil potassium as determined by HPLC.

Formula VIII
In one embodiment, the present invention provides azilsartran medoxomil potassium having (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-[(2'-carbamoyl biphenyl-4-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (Formula IX) less than 0.15% w/w relative to the amount of azilsartran medoxomil potassium as determined by HPLC.

Formula IX
In one embodiment, the present invention provides azilsartran medoxomil potassium obtained by the processes herein described, with purity more than about 99% as measured by High Performance Liquid Chromatography (HPLC).
In one embodiment, the present invention provides azilsartan medoxomil potassium, obtained by the processes herein described, having a D90 particle size of less than about 40 microns, D50 particle size of less than about 15 microns and D10 particle size of less than about 5 microns.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
EX-1: Preparation of methyl 2-ethoxy-1-[[2'-(hydroxyamidino) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate (Formula III)
A mixture of dimethylsulfoxide (50 ml), hydroxyl amine hydrochloride (6.33 gm) and triethylamine (9.83 gm) was stirred for about 30 minutes. Methyl 1-((2'-cyano-[1,1'-biphenyl]-4-yl) methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (100 gm) of formula IV was added to reaction mixture and heated to about 50-90°C for about 10-20 hours and then cooled to about 20-35°C. The obtained reaction mass was quenched in a mixture of precooled water and acetone. Precipitated solid was filtered, washed with water and dried in air oven at about 55-80°C to yield tilted compound.
EX-2: Preparation of methyl 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (Formula II)
A mixture of formula III (100 gm), dimethylsulfoxide (500 ml) and anhydrous 1,1’- carbonyldiimidazole (55 gm) was heated to about 50-90°C and stirred for about 2-6 hours. The reaction mass was cooled to about 20-35°C and quenched into a mixture of acetic acid (150 ml) and water and further stirred for about 1-6 hours. The reaction mas was filtered, washed with water and dried at about 40-70°C to obtain crude formula II. Methanol was added to formula II and refluxed and then cooled to about 20-30°C, filtered and dried under vacuum at about 55-80°C to yield tilted compound.
EX-3: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then formula II (100 gm) was added. The reaction mixture was heated to about 45-80°C and maintained for about 1-6 hours and then activated charcoal (5 gm) was added stirred for about 60 minutes, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and acetic acid (150 ml) was added slowly till pH 2.5 - 5. The reaction mass was stirred, filtered, washed with water and dried in air oven at about 55-80°C to yield titled compound. Yield: 96%; HPLC Purity: 99.46%; Desethyl Impurity of formula A: 0.105%.
EX-4: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then formula II (100 gm) was added. The reaction mixture was heated to about 45-80°C and maintained for about 1-6 hours and then activated charcoal (5 gm) was added stirred for about 60 minutes, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and boric acid solution (1600 ml) was added slowly till pH 5-5.5. The reaction mass was stirred, filtered, washed with water and dried in air oven at about 55-80°C to yield titled compound.
Yield: 67.4%; HPLC Purity: 98.96%; Desethyl Impurity of formula A: Not detected.
EX-5: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then formula II (100 gm) was added. The reaction mixture was heated to about 50-55°C and maintained for about 2 hours and then activated charcoal was added stirred for about 60 minutes, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and succinic acid solution (1000 ml) was added slowly till pH 5-5.5. The reaction mass was stirred, filtered, washed with water and dried in air oven at about 55-80°C to yield titled compound.
Yield: 89%; HPLC Purity: 98.88%; Desethyl Impurity of formula A: 0.094%.

EX-6: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then compound of formula II (100 gm) was added. The reaction mixture was heated to about 50-55°C and maintained for about 2-6 hours, cooled the reaction mass to 15-30oC followed by pH adjusted 6.5 to 8.0. The reaction mass was washed with MDC. Activated charcoal (5 gm) was added into aqueous layer and stirred for about 30- 120 minutes, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and 10% oxalic acid solution (480 ml) was added slowly till pH 4 – 6.0. The reaction mass was stirred for about 30 -120 minutes, filtered, washed with water and dried in air oven at about 45-80°C to yield titled compound.
Yield: 88.6%; HPLC Purity: 99.97%; Desethyl Impurity of formula A: 0.02%.
PSD: D90 = 38.47 µm; D50 = 17.20 µm; D10 = 4.40 µm

XRPD peaks of azilsartan (XRPD pattern as per figure 1)
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
8.22 10.74 0.57 21.48 4.13 27.27 31.07 2.87 3.07
9.13 9.68 100.00 21.82 4.07 11.10 32.48 2.75 3.61
11.83 7.48 0.73 22.50 3.95 3.28 33.08 2.70 3.02
12.00 7.37 1.38 23.53 3.78 31.28 33.58 2.66 1.10
12.72 6.95 17.63 23.97 3.71 8.89 36.38 2.46 1.82
14.89 5.94 7.61 24.55 3.62 3.53 37.19 2.41 1.51
15.37 5.76 10.55 25.26 3.52 12.95 37.60 2.39 2.15
15.62 5.67 2.30 25.54 3.48 10.80 39.07 2.30 1.57
16.22 5.46 6.23 25.68 3.46 7.04 40.02 2.25 0.77
17.95 4.93 6.33 26.68 3.34 11.55 40.53 2.22 0.77
18.33 4.83 11.87 27.10 3.29 2.66 41.51 2.17 0.87
18.66 4.75 18.62 27.70 3.22 5.66 41.96 2.15 0.78
19.36 4.58 20.05 28.76 3.10 7.36 44.39 2.04 0.95
19.95 4.44 11.22 29.07 3.07 4.65 45.97 1.97 0.70
20.16 4.40 12.14 29.32 3.04 5.04 47.88 1.88 0.73
20.41 4.34 13.58 30.05 2.97 2.10

EX-7: Preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-1-[[2’-(5-oxo-4,5-dihydro-1,2,4-oxodiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate -Azilsartan medoxomil (Formula VI)
A mixture of azilsartan of formula I (100 gm) and N, N-dimethyl acetamide (1000 ml) was cooled to about 5-20°C and powdered potassium carbonate (68 gm) was added. Reaction mass was stirred for about 30 -120 minutes and then 4-(fydroxymethyl)-5-methyl-1,3-dioxol-2-one (51.26 gm) of formula V and 4-dimethyl amino pyridine (10 gm) was added and stirred for about 10-60 minutes followed by addition of p-toluenesulfonyl chloride (73.1 gm) and further stirred for about 2 hours. Reaction mass was quenched by addition of methylene chloride followed by water. Layers separated, aqueous layer was extracted by methylene chloride. Methylene chloride layer was distilled under vacuum and then methanol was added and cooled to about 0-15°C. Reaction mass stirred for about 2 hours and filtered to yield titled compound.
EX-8: Preparation of azilsartan medoxomil potassium.
A mixture of azilsartan medoxomil of formula VI (100 gm) and acetone (2000 ml) was heated to about 50-55°C and then charcoal was added. The reaction mixture was stirred for about 30 minutes, filtered, washed with acetone and filtrate cooled to about 15-25°C. To the reaction mass potassium-2-ethyl hexanoate solution (42 gm of Potassium-2-ethyl hexanoate in 300 ml) was added and stirred for 20-30° for about 3 hours, filtered, washed with acetone to obtain azilsartan medoxomil potassium. Acetone (1000 ml) was added to obtained azilsartan medoxomil potassium and heated to about 30-35°C and stirred for about 60 minutes and the cooled to 25-30°C. The reaction mass further stirred, filtered and washed with acetone to obtain solid. Isopropyl alcohol was added to obtained solid and heated to about 30-35°C and stirred then cooled to about 20-30°C and further stirred, filtered washed with isopropyl, dried in vacuum drier at about 20-35°C to yield titled compound.
PSD: D90 = 25.92 µm; D50 = 7.85 µm; D10 = 1.68 µm

XRPD peaks of azilsartan (XRPD pattern as per figure 2)
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
5.58 15.81 0.59 18.48 4.80 3.33 26.60 3.35 1.89
6.22 14.20 100.00 18.74 4.73 17.26 26.99 3.30 6.16
6.69 13.20 4.73 19.06 4.65 2.22 27.54 3.23 9.26
12.67 6.98 5.95 19.63 4.52 2.31 28.18 3.16 4.96
13.39 6.61 17.91 20.33 4.36 9.84 28.89 3.09 2.25
14.07 6.29 11.57 21.38 4.15 7.88 29.19 3.05 2.90
14.51 6.10 18.37 22.80 3.89 20.69 30.04 2.97 1.45
14.75 6.00 16.76 23.26 3.82 4.36 30.85 2.89 2.45
15.49 5.71 2.02 23.80 3.73 14.50 31.31 2.85 3.78
16.02 5.53 12.79 24.12 3.68 6.12 31.88 2.80 3.31
16.45 5.38 4.73 24.35 3.65 4.00 32.43 2.76 1.66
16.70 5.30 2.49 24.58 3.62 4.59 33.02 2.71 2.49
17.53 5.11 4.71 24.90 3.57 4.89 33.30 2.69 1.16
17.80 4.98 7.53 25.19 3.53 3.39 33.81 2.65 2.86
18.01 4.92 6.98 25.62 3.47 5.00 34.50 2.59 0.52
18.16 4.88 6.51 26.11 3.41 1.70 36.05 2.49 2.47

EX-9: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then formula II (100 gm) was added. The reaction mixture was heated to about 50-55°C and maintained for about 2 hours, cooled to room temperature and methylene chloride (MDC) was added and further oxalic acid (150 ml) was added slowly till pH 6.5 – 8.0 under stirring and layer was separated. Aqueous layer washed with MDC and activated charcoal was added into aqueous layer, stirred, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and oxalic acid (150 ml) was added slowly till pH 3.5 – 5.0. The reaction mass was stirred, filtered, washed with water and again wet material was charged into water and reaction mass was stirred, filtered, washed with water, dried in air oven at about 55-80°C to yield titled compound.
Yield: 96%; HPLC Purity: 99.46%; Desethyl Impurity of formula A: 0.11%.
EX-10: Preparation of methyl 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (Formula II)
A mixture of formula III (100 gm), dimethylsulfoxide (500 ml) and anhydrous 1,1’- carbonyldiimidazole (55 gm) was heated to about 65-85°C and stirred for about 2-6 hours. The reaction mass was cooled to about 15-30°C and quenched into water, stirred and then ethyl acetate was added. pH of aqueous layer was adjusted with acetic acid pH 4 – 5.5. The solid obtained mas was filtered, washed with water and dried to obtain crude formula II. Methanol was added to formula II, refluxed, cooled to about 20-30°C, filtered and dried under vacuum at about 55-80°C to yield tilted compound. Yield: 80 gm; HPLC Purity>99%.
EX-11: Preparation of methyl 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (Formula II)
To a mixture of formula III (100 gm), dimethylsulfoxide (500 ml) and sodium carbonate (120 gm), ethyl chloroformate was slowly added and stirred for about 2-6 hours at 15-40°C. The reaction mass was maintained for 2-6 hours at 65-90°C and then cooled to about 15-30°C and quenched into water. The reaction mass stirred and ethyl acetate was added and further stirred. pH of aqueous layer was adjusted with acetic acid pH 4 - 5.5. The solid obtained mas was filtered, washed with water and dried to obtain crude formula II. Methanol was added to formula II, refluxed, cooled to about 15-30°C, filtered and dried under vacuum at about 55-80°C to yield tilted compound. Yield: 80 gm; HPLC Purity>99%.
EX-12: Preparation of methyl 2-ethoxy-1-[[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (Formula II)
A mixture of formula III (100 gm), dimethylsulfoxide (500 ml) and anhydrous 1,1’- carbonyldiimidazole (55 gm) was heated to about 65-90°C and stirred for about 2-6 hours. The reaction mass was cooled to about 15-30°C and quenched into water, stirred and ethyl acetate was added, further stirred and layer was separated. pH of aqueous layer was adjusted with 10% aqueous oxalic acid solution pH 3.5 – 5.5. The solid obtained mas was filtered, washed with water and dried to obtain crude formula II. Methanol was added to formula II, refluxed, cooled to about 20-30°C, filtered and dried under vacuum at about 55-80°C to yield tilted compound. Yield: 80 gm; HPLC Purity>99%.
EX-13: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then formula II (100 gm) was added. The reaction mixture was heated to about 45-65°C and maintained for about 2 hours and then activated charcoal (5 gm) was added stirred, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and 10% oxalic acid solution was added slowly till pH 4.5 – 6.0. The reaction mass was stirred filtered, washed with water and dried in air oven at about 55-80°C to yield titled compound and then obtained compound was recrystallized with methanol.
EX-14: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then formula II (100 gm) was added. The reaction mixture was heated to about 45 - 65°C and maintained for about 2-6 hours and then activated charcoal was added stirred, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and 10% oxalic acid solution was added slowly till pH 4.5 - 5.5. The reaction mass was stirred filtered, washed with water and dried in air oven at about 55-80°C to yield titled compound and then obtained compound was recrystallized with ethanol. Yield: 80 gm; HPLC Purity>99%

EX-15: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then formula II (100 gm) was added. The reaction mixture was heated to about 45-65°C and maintained for about 2-6 hours, cooled the reaction mass to 15-30oC followed by pH adjusted 6.5 to 8.0. The reaction mass washed with MDC. Activated charcoal (5 gm) was added into aqueous layer and stirred for about 30- 120 minutes, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and 10% oxalic acid solution was added slowly till pH 4.5 – 6.0. The reaction mass was stirred filtered, washed with water and dried in air oven at about 55-80°C to yield titled compound and then obtained compound was recrystallized with methanol. Yield: 75 gm; HPLC Purity>99.5%
EX-16: Preparation of 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid-Azilsartan (Formula I)
In a lithium hydroxide monohydrate (27 gm), water (1500 ml) was added to get clear solution and then formula II (100 gm) was added. The reaction mixture was heated to about 45 - 65°C and maintained for about 2-6 hours, cooled the reaction mass to 15-30oC followed by pH adjusted 6.5 to 8.0. The reaction mass was washed with MDC. Activated charcoal (5 gm) was added into aqueous layer and stirred for about 30- 120 minutes, filtered, and washed with water. The obtained filtrate was charged in a clean 4 neck round bottom flask and 10% oxalic acid solution was added slowly till pH 4.5 - 5.5. The reaction mass was stirred filtered, washed with water and dried in air oven at about 55-80°C to yield titled compound and then obtained compound was recrystallized with ethanol. Yield: 75 gm; HPLC Purity>99.5%
,CLAIMS:We Claim:
1. A process for the preparation of azilsartan of formula I, comprising:

Formula I
(a) hydrolyzing a compound of formula II by a base to form a reaction mixture;

Formula II
(b) adding oxalic acid to the reaction mixture of step a); and
(c) isolating azilsartan of formula I from step b);
wherein the resultant azilsartan contains desethyl impurity of formula A in less than 0.05% w/w, as determined by HPLC,

Desethyl impurity (Formula A).
2. The process as claimed in claim 1, wherein the base is selected from the group consisting of alkali metal hydroxide, alkaline metal hydroxide, alkali metal carbonate and alkali metal bicarbonate.
3. The process as claimed in claim 2, wherein alkali metal hydroxide is sodium hydroxide, potassium hydroxide or lithium hydroxide.
4. The process as claimed in claim 1, wherein azilsartan of formula I, contains the desethyl impurity of formula A in less than 0.03% w/w as determined by HPLC.
5. The process as claimed in claim 1, wherein azilsartan of Formula I is converted into azilsartan medoxomil of formula VI or a salt thereof.

Formula VI

Dated this 2nd day of February, 2017

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED