FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of Azilsartan medoxomil of Formula I.

BACKGROUND OF THE INVENTION

Azilsartan medoxomil is chemically known as (5-methyl-2-oxo-l,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.
Azilsartan medoxomil is an ATi-subtype angiotensin II receptor blocker (ARB). Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan medoxomil blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATi receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. Azilsartan medoxomil is approved for the treatment of hypertension and is marketed under the brand name Edarbi®.

US patent No. 5,583,141 disclosed Azilsartan and pharmaceutically acceptable esters and salts thereof.

The process disclosed in US '141 for the preparation of Azilsartan involves, the reaction of 1 -[(2'-cyano[ 1,1 '-biphenyl]-4-yl)methyl]-2-ethoxy-1 H-benziimidazole-7-carboxylic acid methyl ester (BEC methyl ester) (II) with hydroxylamine hydrochloride in the presence of sodium methoxide to produce methyl 2-ethoxy-l-[[2'-hydroxycarbamimidoyl)biphenyl)-4-yl]methyl]-lH-benzimidazole-7-carboxylate (III), which is further reacted with ethyl chlorocarbonate to produce Azilsartan methyl ester (IV), followed by hydrolysis in the presence of aqueous LiOH to produce Azilsartan (V). The process is as shown in Scheme-I below:

SCHEME I
US 7,157,584 discloses Azilsartan medoxomil and pharmaceutically acceptable salts thereof.

US '584 disclose two different synthetic processes for the preparation of Azilsartan medoxomil. One of the synthetic process involves reacting Azilsartan disodium salt (Va) with (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl chloride (Medoxomil chloride) (VI) in the presence of DMF and CHC13 to produce Azilsartan medoxomil (I).

The process is as shown in Scheme-II below:

SCHEME II
The major disadvantage with the above prior-art process is the formation of N-alkylated impurity (Azilsartan N-medoxomil) and N,0-dialkylated impurity (Azilsartan dimedoxomil). Removal of these impurities in the final stage is very difficult and requires repeated crystallizations, which results in the low yield of Azilsartan medoxomil (I) and hence is not suitable for industrial scale operations.

Another variant process in US '584 for the preparation of Azilsartan medoxomil involves, reacting Azilsartan (V) with 2,4,6-trichlorobenzoyl chloride (VII) in presence of TEA to produce Azilsartan mixed acid anhydride (VIII), followed by reacting with 4-hydroxymethyl-5-methyl-l,3-dioxol-2-one (medoxomil alcohol) (Via) in the presence of N,N-dimethylaminopyridine to produce Azilsartan medoxomil (I). The process is as shown in scheme -III as below:

SCHEME III
The major disadvantage with the above prior-art process is the use of reactive derivative of Azilsartan, which involves the use of expensive 2,4,6-trichlorobenzoyl chloride and this process is not suitable for commercial scale production of Azilsartan medoxomil.

However, there is always a need for alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and / or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.

The present invention is specifically directed towards a novel, improved and cost effective process for the preparation of Azilsartan medoxomil (I), comprising the steps of, hydrolysis of amidoxime alkyl ester (Ilia) to provide amidoxime acid (XIII) or its pharmaceutically acceptable salt thereof, or its reactive derivative, which is further condensed with medoxomil chloride or medoxomil alcohol, followed by deprotection to provide Azilsartan amidoxime (XII). The compound (XII) is cyclized to produce

Azilsartan medoxomil (I), which involves short periods of time, easy work-up and high purity.

The present invention is also directed towards a simple and cost effective process for the preparation of Azilsartan medoxomil (I) by utilizing protected Azilsartan (IX) in the condensation with medoxomil chloride (VI) to produce protected Azilsartan medoxomil (X), followed by deprotection to produce Azilsartan medoxomil (I), which involves short periods of time, easy work-up and high purity.

The present invention is also directed towards a novel synthesis of Azilsartan medoxomil (I), wherein BEC acid (Ha) or a salt is condensed with medoxomil chloride (VI) to produce Azilsartan cyano medoxomil (XI), which is further converted to Azilsartan medoxomil (I) with high yield and purity.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Azilsartan medoxomil (I) with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of Azilsartan medoxomil (I), which comprises, cyclising Azilsartan amidoxime (XII)
to produce Azilsartan medoxomil (I).

In another embodiment, the present invention also provides a process for the preparation of Azilsartan amidoxime (XII), which comprises:

(i) coupling amidoxime acid (XIII) or its pharmaceutically acceptable salt thereof,

wherein, R represents hydrogen or OH-protecting group, with medoxomil chloride (VI),
to produce amidoxime medoxomil ester (XIV),

wherein, R is as defined above, (ii) if appropriate, deprotecting the compound (XIV) to produce compound (XII).

In another embodiment, the present invention also provides a process for the preparation of Azilsartan medoxomil (I), which comprises:

(i) coupling amidoxime acid (XIII) or its reactive derivative,

wherein, R represents hydrogen or OH-protecting group, with medoxomil alcohol (Via),
to produce the amidoxime medoxomil ester (XIV), (ii) converting the compound (XIV) to Azilsartan medoxomil (I).

In another embodiment, the present invention also provides a process for the preparation of amidoxime acid (XIII) or its pharmaceutically acceptable salt thereof, which comprises: hydrolyzing amidoxime alkyl ester (Ilia),

wherein, R is as defined above; Ri is C 1.5 alkyl; to produce amidoxime acid (XIII) or its pharmaceutical^ acceptable salt thereof.

In another embodiment, the present invention provides a process for the preparation of Azilsartan medoxomil (I) using Azilsartan amidoxime (XII), amidoxime acid (XIII) or it's pharmaceutical ly acceptable salt, amidoxime medoxomil ester (XIV) and amidoxime alkyl ester (Ilia).

In another embodiment, the present invention provides a process for the preparation of Azilsartan medoxomil (I),

which comprises: (i) reacting protected Azilsartan (IX),
wherein, R2 represents N-protecting group,

with medoxomil chloride (VI) to produce protected Azilsartan medoxomil (X);

(ii) de-protecting the compound of formula (X) to produce Azilsartan medoxomil (I).

In another embodiment, the present invention provides a process for the preparation of Azilsartan medoxomil (I), which comprises: (i) reacting BEC acid (Ha) or its salt,

with medoxomil chloride (VII) to produce Azilsartan cyano medoxomil (XI),
(ii) reacting the Azilsartan cyano medoxomil (XI) with hydroxyl amine to produce Azilsartan amidoxime (XII);

(iii) cyclising the Azilsartan amidoxime (XII) to produce Azilsartan medoxomil (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Azilsartan medoxomil of formula (I).

The process comprises cyclizing Azilsartan amidoxime (XII) to produce Azilsartan medoxomil (I).

The cyclisation is carried out using a carbonyl source, which is selected from N,N-carbonyldiimidazole, dialkyl carbonate, phosgene equivalents, alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide, N,N-dicyclohexylcarbodiimide, diphenyl carbodiimide, ditolyl carbodiimide and the like; or an alkyl haloformate such as methyl chloroformate and ethyl chloroformate and the like in presence of an organic solvent selected from chloroform, methylene chloride, dioxane, tetrahydrofuran, acetonitrile, pyridine, N,N-dimethylformamide (DMF), N,N-dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide (DMAc) or mixture thereof.

The cyclisation is carried out in the presence or absence of a base and the base is selected from organic such as triethylamine, diisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropyl ethylamine (DIPEA), tetramethyl guanidine (TMG), pyridine and the like; or inorganic base such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate.

After completion of the reaction, the solvent is evaporated and the residue is treated with a solvent such as chloroform, methylene chloride, ethyl acetate, toluene, acetonitrile, acetone or mixtures thereof. The reaction mass is further treated with an acid selected from hydrochloric acid, sulfuric acid, acetic acid, formic acid or mixtures thereof, and the layers are separated. The organic layer is concentrated to produce Azilsartan medoxomil (I), which is crystallized by a solvent selected from ethanol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, 1-butanol or mixtures thereof.

In another embodiment the present invention provides a process for the preparation of Azilsartan amidoxime (XII).

The process comprises, hydrolyzing Amidoxime alkyl ester (Ilia) to produce Amidoxime acid (XIII) or salt.
The protecting group is selected from triphenylmethyl (Trityl), t-butoxycarbonyl (Boc), trichloro-t-butoxycarbonyl (TCBoc), benzyl, allyl, phenacyl, acetoxypropyl, methoxymethyl, benzyloxymethyl, pivaloyloxymethyl, tertrahydropyranyl, 2,4-dinitrophenyl, o-nitrobenzyl, di(p-methoxyphenyl)methyl, (p- methoxyphenyl)diphenylmethyl, diphenyl-4-pyridylmethyl, 2-picolyl N-oxide, N'- isopropylidene, benzylidene, /?-nitrobenzylidene, salicylidene, (5,5-dimethyl-3-oxo-l-cyclohexenyl), diphenylphosphinyl, dimethylthiophosphinyl, benzenesulfenyl, o-nitrobenzenesulfenyl, 2,4,6-trimethylbenzenesulfonyl, toluenesulfonyl, benzylsulfonyl,trifluoromethylsulfonyl, phenacylsulfonyl; carbamates such as methylcarbamate, 1,1-dimethylpropynyl carbamate, 1 -methyl- 1-phenylethylcarbamate, 1-methyl-1(4-biphenylyl)ethyl carbamate, l,l-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2-cyanoethyl carbamate, cyclobutylcarbamate, 1-methylcyclobutylcarbamate, vinyl
carbamate, 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, 4,5-diphenyl-3-oxolin-2-one, carbobenzoxy (Cbz), 9-fluorenylmethyloxycarbonyl (9-Fmoc), 3,4-dimethoxy-6-nitrobenzyl carbomate, 2,4-dichlorobenzyl carbomate, 5-benzisoxazolylmethyl carbomate,9-anthrylmethyl carbamate, isonicotinyl carbamate, S-benzyl carbamate, N-(N'-phenylaminothiocarbonyl)derivative, p-nitrobenzyloxycarbonyl,p-
methoxybenzyloxycarbonyl,trityloxycarbonyl(triphenylmethyloxycarbonyl),diphenylmethyloxycarbonyl, 1-adamantyloxycarbonyl, cinnamyloxycarbonyl, N-hydroxy piperidinyloxycarbonyl, 2-rimethylsilylethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl (Troc), allyloxycarbonyl (Alloc); amides such as formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, acetoacetyl, 3-phenylpropionyl, 3-(p-hydroxyphenyl)propionyl, 2-methyl-2-(o-nitrophenoxy)propionyl, 2-methyl-2~(o-phenylazophenoxy)propionyl, 4-chlorobutyryl, o-nitrocinnamoyl, picolinoyl, (N-acetylmethionyl), benzoyl, phthaloyl, dithiasuccinoyl.

The hydrolysis is carried out in presence of a base in a solvent. The base is selected from alkali metal carbonate sodium carbonate, potassium carbonate, lithium carbonate or an alkali metal hydrogencarbonate, such as sodium hydrogencarbonate or potassium hydrogencarbonate; or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium tert.butoxide or mixture thereof.

Solvent used in hydrolysis is selected from water, tetrahydrofuran, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, toluene, acetone, methylene chloride, dimethylformamide or mixtures thereof.

After completion of the reaction, Amidoxime acid (XIII) or pharmaceutically acceptable salt thereof; is isolated by removing the solvent from the reaction mass or by precipitating using the solvent.

The compound (XIII) is isolated as a solid or as such used in next step. Optionally, Compound (XIII) is subjected to purification either by column chromatography or crystallization.

The pharmaceutical ly acceptable salt may include, but are not limited to an inorganic base (e.g., alkali metals such as sodium, potassium and the like; alkaline earth metals such as calcium, magnesium and the like; etc.), an organic base (e.g., organic amines such as tromethamine tris(hydroxymethyl)methylamine], ethanolamine, trimethylamine, triethylamine, t-butylamine, pyridine, picoline, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, DBU, DIPEA, TMG and the like; basic amino acids such as arginine, lysine, ornithine and the like; etc.).
Amidoxime acid (XIII) or pharmaceutically acceptable salt thereof is condensed with medoxomil chloride (VI) to produce amidoxime medoxomil ester (XIV).

The condensation step is carried out in presence of an alkali halide, which is selected from sodium chloride, sodium bromide, sodium iodide, potassium iodide, lithium chloride, cesium chloride or mixtures thereof, and a solvent, which is selected from tetrahydrofuran, N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, ethyl acetate, toluene, acetone, acetonitrile, methanol, ethanol, isopropanol, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof.

This reaction is optionally carried out in the presence of a phase transfer catalyst (PTC), selected from tetraethylammonium-p-toluenesulfonate, tetrapropylammonium trifluoromethane sulfonate, tetraphenylphosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride, benzyltriethylammonium chloride, benzyltrimethylammonium
chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide, phenyltrimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutylammonium
perchlorate, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctylammonium bromide,
tetraphenylphosphoniu bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride, wherein tetrabutylammonium salts and particularly tetrabutylammonium halides, e.g. the bromides are especially preferred.

After completion of the reaction, the reaction mass is treated with a solvent selected from water, ethyl acetate, methylene chloride, toluene, acetonitrile, acetone or mixtures thereof. The reaction mixture is further treated with an acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid and the like. The layer is separated and the product is isolated by adding hexanes, heptane, cyclohexane, ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether (MTBE) and the like to produce amidoxime medoxomil ester (XIV).

The compound (XIV) is isolated as a solid or as such used in next step. Optionally, Compound (XIV) is subjected to purification either by column chromatography or crystallization.

The compound (XIV) is deprotected when R is hydroxy protected group. When the hydroxy protecting group is trityl or BOC, the de-protection is carried out in the presence of an acid selected from organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid in presence of a solvent selected from ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol, a halogenated hydrocarbon, such as methylene chloride, chloroform; ethyl acetate, methyl acetate or mixtures of to produce Azilsartan amodoxime (XII).

The compound (XII) is isolated as a solid or as such used in next step. Optionally, Compound (XII) is subjected to purification either by column chromatography or crystallization.

In another embodiment, the present invention relates to a process for the preparation of Azilsartan medoxomil (I).

The process comprises, reacting Amidoxime acid (XIII) or its reactive derivative with medoxomil alcohol (Via) or a salt thereof to produce amidoxime medoxomil ester (XIV).

The reactive derivative is selected from a mixed acid anhydride, an acid halide and the like. The reaction is carried out in presence of a condensing agent, which is selected from dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide (DIC), l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide (WSQ, Mitsunobu reagents and the like.

The condensation step is carried out in presence of a base, which is selected from triethylamine, diisopropylethylamine, DBU, 4-dimethylaminopyridine, sodium hydride, potassium t-butoxide, potassium carbonate and sodium carbonate and the like; and a solvent, which is selected from dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, toluene, acetonitrile, acetone, ethyl methyl ketone, dioxane, N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, methanol, ethanol, isopropanol, methyl isobutyl ketone or mixtures thereof.

This reaction is optionally carried out in the presence of a phase transfer catalyst (PTC), which is same as described above.

After completion of the reaction, the reaction mass is treated with a solvent selected from water, ethyl acetate, methylene chloride, toluene, acetonitrile, acetone or mixtures thereof. The reaction mixture is further treated with an acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid and the like.

The layer is separated and the product is isolated by adding hexanes, heptane, cyclohexane, ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether (MTBE) and the like to produce amidoxime medoxomil ester (XIV).

The compound (XIV) is converted to Azilsartan medoxomil (I) as the process described above.
In another embodiment, the present invention relates to a process for the preparation of Azilsartan medoxomil of formula (I).

The process comprises, protected Azilsartan (IX) is reacted with medoxomil chloride (VI) in presence of a base selected from inorganic base selected from an alkali metal carbonate sodium carbonate or potassium carbonate; or an alkali metal hydrogencarbonate, such as sodium hydrogencarbonate or potassium hydrogencarbonate; or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or mixture thereof, or an organic base such as triethylamine, pyridine or N-methylmorpholine in a solvent selected from an amide, such as N,N-dimethylformamide or N,N-dimethylacetamide; a halogenated hydrocarbon, such as methylene chloride, chloroform; a ketone, such as acetone or methyl ethyl ketone; or an ether, such as tetrahydrofuran or dioxane or mixtures thereof to produce protected Azilsartan medoxomil (X).

The compound (X) is isolated as a solid or as such used in next step. Optionally, Compound (X) is subjected to purification either by column chromatography or crystallization.

N-protecting group of the protected Azilsartan (IX) is same as defined above.

De-protection of protected Azilsartan medoxomil (X), when O-protecting group is trityl or BOC, the de-protection is carried out in the presence of an acid selected from organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid in presence of a solvent selected from ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol, a halogenated hydrocarbon, such as methylene chloride, chloroform; ethyl acetate, methyl acetate or mixtures of to produce Azilsartan medoxomil (I).

Protected Azilsartan (IX) used in the present invention is prepared by reacting Azilsartan (V) with a protecting reagent under suitable reaction conditions.

In another embodiment the present invention also relates to an alternate process for the preparation of Azilsartan medoxomil of formula (I).

The process comprises, l-[(2'-cyano[l,l'-biphenyl]-4-yl)methyl]-2-ethoxy-l^-benziimidazole-7-carboxylic acid methyl ester (BEC methyl ester) (II) is hydrolyzed using a base selected from sodium hydroxide, potassium hydroxide or mixture thereof; in a solvent selected from methanol, ethanol, isopropanol or in water or mixtures thereof to produce BEC acid (Ila).

The compound (Ila) is isolated as a solid or as such used in next step. Optionally, Compound (Ila) is subjected to purification either by column chromatography or crystallization.

BEC acid (Ila) or a salt is reacted with medoxomil chloride (VI) in presence of a base selected from inorganic base such as an alkali metal carbonate, such as sodium carbonate or potassium carbonate or mixture thereof; an alkali metal hydrogencarbonate, such as sodium hydrogencarbonate or potassium hydrogencarbonate or organic base such as triethylamine, pyridine or N-methylmorpholine, DBU, DIPEA, TMG; in a solvent selected from an amide, such as N,N-dimethylformamide or N,N-dimethylacetamide; a halogenated hydrocarbon, such as methylene chloride; a ketone, such as acetone or methyl ethyl ketone; or an ether, such as tetrahydrofuran or dioxane or mixtures thereof to produce Azilsartan cyano medoxomil (XI).

The compound (XI) is isolated as a solid or as such used in next step. Optionally, Compound (XI) is subjected to purification either by column chromatography or crystallization.

Azilsartan cyano medoxomil (XI) is reacted with hydroxyl amine hydrochloride in presence of base selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, triethylamine, sodium methanolate, sodium ethanolate and sodium hydride, a solvent selected from amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, alcohols such as methanol and ethanol, isopropanol, ethers such as dioxane and tetrahydrofuran and halogenated hydrocarbons such as methylene chloride and chloroform to produce Azilsartan amidoxime (XII).

The compound (XII) is isolated as a solid or as such used in next step. Optionally, Compound (XII) is subjected to purification either by column chromatography or crystallization.

Azilsartan amidoxime (XII) is cyclized using a carbonyl source selected from N,N-carbonyldiimidazole, dialkyl carbonate, phosgene equivalents, alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide, N,N di cyclohexyl carbodiimide, diphenyl carbodiimide, ditolyl carbodiimide and the like; or an alkyl haloformate such as methyl chloroformate and ethyl chloroformate in presence of an organic solvent selected from chloroform, methylene chloride, dioxane, tetrahydrofuran, ethyl acetate, DMF, DMSO, DMAc, acetonitrile and pyridine and in the presence or absence of a base, wherein the base is selected from triethylamine, pyridine, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, DBU to produce Azilsartan medoxomil (I).

Azilsartan medoxomil (I) is converted to its potassium salt by conventional methods, which is then purified by known methods, for example recrystallization by dissolving in a solvent selected from methanol, ethanol, isopropanol, methylene chloride, tetrahydrofuran, acetone, acetonitrile, ethyl acetate or mixtures thereof; preferably in acetone/ethyl acetate mixture, and precipitating pure Azilsartan kamedoxomil by cooling the solution or by adding an anti solvent.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example:
Step-1: Preparation of methyl 2-ethoxy-l-[(4-(2-(N'-(triphenylmethoxy) carbamimidoyl)phenyl)phenyl)methyl]-lH-l,3-benzodiazole-7-carboxylate (Trityl amidoxime methyl ester)
Potassium carbonate (31.08 g, 2.0 m.eq), followed by trityl chloride (47.04 g, 1.5 m.eq) were added to a solution of methyl 2-ethoxy [2'-(hydroxyamidino)biphenyl-4-yl]methyl]-lh-benzimidazole carboxylate (Amidoxime methyl ester, 50 g) in N,N-dimethylformamide (500ml), at room temperature. After stirring ~ 3h at 20-30°C the reaction mass was added to water (2000 ml) at 20-30°C to precipitate the product. The product was collected by filtration and washed with ethanol, then dried at ~50°C under reduced pressure to obtain 55 g of pure compound.

Step-2: Preparation of sodium 2-ethoxy-l-[(4-(2-(N'-(triphenylmethoxy) carbamimidoyl) phenyI)phenyl)methyl]-l//-l,3-benzodiazole-7-carboxylate (trityl amidoxime sodium salt)
20% Aqueous sodium hydroxide solution (30 ml, 2.0 m.eq) was added to a solution of methyl 2-ethoxy-1 -[(4-(2-(N'-(triphenylmethoxy) carbamimidoyl)phenyl)phenyl)methyl]-lH-l,3-benzodiazole-7-carboxylate (Trityl amidoxime methyl ester, 50 g) in a mixture of tetrahydrofuran (300 ml) and methanol (25 ml) at 20-30°C. The reaction mixture was stirred at 20-30°C to complete the hydrolysis reaction. After completion of the reaction the reaction mass was concentrated at <50°C under reduced pressure to obtain sodium 2-ethoxy-1 -[(4-(2-(N'-(triphenylmethoxy) carbamimidoyl) phenyl)phenyl)methyl]- 1H-1,3-benzodiazole-7-carboxylate (trityl amidoxime sodium salt) as a residue. The residue obtained was as such taken for the next step.

Step-3: Preparation of (5-methyI-2-oxo-2#-l,3-dioxol-4-yI)methyI 2-ethoxy-l-[(4-(2-[N'-(triphenylmethoxy)carbamiinidoyl]phenyl)phenyl)methyl]-lH-l^-benzodiazole-7-carboxylate (trityl amidoxime medoxomil ester)

The residue obtained in the Step-2 was dissolved in dimethylacetamide (250 ml) and cooled to 0-5°C. Sodium iodide (1.5 g) was added to the reaction mass, followed by 4- (chloromethyl)-5-methyl-l,3-dioxol-2-one (medoxomil chloride, 13.84 g, 1.1 m.eq) was added at 0-5°C. The reaction mass temperature was slowly raised to 20-30°C and continued stirring at 20-30°C till completion of the reaction. Thereafter, the reaction mass was poured into a solvent mixture of water (2000 ml) and ethyl acetate (1000 ml) and the pH was adjusted to ~ 7.0 with hydrochloric acid. The layers were separated and the aqueous layer was discarded. The organic layer was concentrated at <50°C under reduced pressure and the product was isolated by adding hexanes. The product was dried at 45- 50°C under reduced pressure to give 50 g of pure 5-methyl-2-oxo-2H-l,3-dioxol-4- yl)methyl2-ethoxy-1 -[(4-(2-[N'- riphenylmethoxy)carbamimidoyl]phenyl) phenyl) ethyl]-lH-l,3-benzodiazole-7-carboxylate (trityl amidoxime medoxomil ester).

Step-4: Preparation of (5-methyl-2-oxo-2^M,3-dioxol-4-yl)methyl 2-ethoxy-l-[(4-(2-[N-hydroxycarbamimidoyl]phenyl)phenyl)methyl]-li/-l,3-benzodiazole-7-carboxylate (amidoxime medoxomil ester) Trifluoroacetic acid (8.7 g, 1.2 m.eq) was added to a solution of trityl amidoxime medoxomil ester (50 g) in methylene chloride ( 500 ml) and stirred for ~ 2h at 20 -30°C for completion of the deprotection reaction. There after the reaction mass was washed with 250 ml saturated sodium bicarbonate and the aqueous layer was discarded. Methylene chloride layer was concentrated at <40°C and the product was crystallized by adding ethyl acetate. After filtration, the product was dried at ~ 50°C to get 30 g of (5-methyl-2-oxo-2H-l,3-dioxol-4-yl)methyl2-ethoxy-l-[(4-(2-[N-hydroxycarbamimidoyl] phenyl)phenyl)methyl]-lH-l,3-benzodiazole-7-carboxylate .

Step-S: Preparation of (5-methyI-2-oxo-l,3-dioxo-4-yl)methyl l-[2'-(4,5-dihydro-5-oxo-4/M,2,4-oxadiazolO-yl)biphenyl-4-yl]methyI]-2-ethoxy-l/7-benziimidazole-7-carboxylate (I) (Azilsartan medoxomil)
N,N-Carbonyldiimidazole (22.43 g, 1.5 m.eq) was added to a solution of (5-methyl-2-oxo-2//-l,3-dioxol-4-yl)methyl-2-ethoxy-l-[(4-(2-[N-hydroxycarbamimidoyl]phenyl)phenyl) methyl]-l//-l,3-benzodiazole-7-carboxylate (amidoxime medoxomil ester, 50 g) in acetonitrile (500 ml) at 20-30°C. After stirring for ~1 h at 20-30°C the reaction mass temperature was raised to 55-60°C and the reaction was monitored by HPLC till completion of the cyclization reaction. After completion of the cyclization the solvent was evaporated at < 50°C and the residue was dissolved in methylene chloride (500 ml). The pH was adjusted to ~ 4.5 by adding dilute hydrochloric acid to the methylene chloride solution and after 30 min stirring the layers were separated. The organic layer was concentrated till foamy solid results, which was crystallized from ethanol to get pure Azilsartan medoxomil.

We claim:
1. A process for the preparation of Azilsartan medoxomil (I), which comprises, cyclising
Azilsartan amidoxime (XII),

to produce Azilsartan medoxomil (I).

2. According to claim 1, wherein the cyclization is carried out in presence of carbonyl source selected from N,N-carbonyldiimidazole, dialkyl carbonate, phosgene equivalents, alkyl and aryl carbodimides such as N,N-diisopropylcarbodimide, N,N- dicyclohexylcarbodimide, diphenyl carbodimide, ditolyl carbodiimide and the like; or alkyl haloformate such as methyl chloroformate and ethyl chloroformate and the like.

3. According to claim 1, wherein the cyclization is carried out using an organic solvent, which is selected from chloroform, methylene chloride, dioxane, tetrahydrofuran, acetonitrile, pyridine, N,N-dimethylformamide (DMF), N,N-dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide (DMAc) or mixture thereof.

4. According to claim 1, wherein the cyclisation is carried out in the presence or absence of abase.

5. According to claim 4, wherein the base is selected from organic such as triethylamine, diisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) , N,N- diisopropyl ethylamine (DIPEA), tetramethyl guanidine (TMG), pyridine and the like; or inorganic base such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate.

6. A process for the preparation of Azilsartan amidoxime (XII), which comprises: (i) coupling amidoxime acid (XIII) or its pharmaceutically acceptable salt thereof,

wherein, R represents hydrogen or OH-protecting group, with medoxomil chloride (VI),
wherein, R is as defined above, (ii) if appropriate, deprotecting the compound (XIV) to produce compound (XII).

7. According to claim 6, wherein the condensation in step-(i) is carried out in presence of an alkali halide, which is selected from sodium chloride, sodium bromide, sodium iodide, potassium iodide, lithium chloride, cesium chloride or mixtures thereof, and a solvent, which is selected from tetrahydrofuran, N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, ethyl acetate, toluene, acetone, acetonitrile, methanol, ethanol, isopropanol, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof.

8. According to claim 6, wherein the deprotection in step-(ii), is carried out in the presence of an acid selected from organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

9. A process for the preparation of amidoxime acid (XIII) or its pharmaceutically acceptable salt thereof, which comprises, hydrolyzing amidoxime alkyl ester (Ilia) wherein, R is as defined above; Ri is C].5 alkyl; to produce amidoxime acid (XIII) or its pharmaceutically acceptable salt thereof.

10. According to the proceeding claims, a process for the preparation of Azilsartan medoxomil (I) using Azilsartan amidoxime (XII), amidoxime acid (XIII) or it's pharmaceutically acceptable salt, amidoxime medoxomil ester (XIV) and amidoxime alkyl ester (IIIa).