Priority Claim:
This application claims the priority of an earlier Indian patent application number: 1975/CHE/2009 filed on 19*" August 2009.
Field of the Invention:
The present invention relates to an improved process for the preparation of olmesartan medoxomil. Olmesartan medoxomil is chemically known as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-( 1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2-(tetrazol-5-yl) phenyl] phenyljmethyl imidazole-5-carboxylate having the following structural formula-1,

The present invention also relates to an improved process for the purification of trityl olmesartan, which is chemically known as (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl4-(l -hydroxy-1 -methylethyl)-2-propyl-l -[4-[2-(trityltetrazol-5-yl)phenyl] phenyl] methyl imidazole-5-carboxylate.
Olmesartan medoxomil is a prodrug that is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective ATi subtype angiotensin II receptor antagonist. Angiotensin II is formed fi*om angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kinase II). Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATi receptor in vascular smooth muscle. Olmesartan medoxomil is marketed under the brand name of BENICAR® in film-coated tablets of 5 mg, 20 mg and 40 mg for the treatment of hypertension in human.

Background of the Invention:
Olmesartan medoxomil and process for its preparation was disclosed in US 5616599. The disclosed process involves the condensation of ethyl 4-( 1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with4-[2-trityltetrazole-5-yl)phenylbenzyl bromide in presence of sodium hydride in dimethylformamide to provide ethyl 4-(l-hydroxy-1 -methyl ethyl)-2-propyl-1 - {4-[2-(trityltetrazol-5-yl)phenyl]phenyl} methyl imidazole -5-carboxylate. The obtained ester is treated with lithium hydroxide in dioxane to provide the corresponding lithium carboxylate compound, which is then reacted with 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene in presence of potassium carbonate in dimethylacetamide and the obtained trityl olmesartan was recrystallised from isopropyl ether. Thus obtained trityl olmesartan was treated with an aqueous acetic acid to provide olmesartan medoxomil. The purity of the obtained final compound was not satisfactory and required number of recrystallizations to get the desired purity. This was due to the presence of high level of impurities in the previous stage i.e., in the trityl olmesartan, even after recrystallisation from isopropyl ether. Moreover the usage of ether solvent is not recommended in commercial scale.
There are number of processes reported for the preparation of olmesartan which are in general proceeding through the trityl olmesartan. All the prior art processes for the preparation of trityl olmesartan involves the condensation of 4-(l-hydroxy-1-methyl ethyl)-2-propyl-l-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methyl imidazole-5-carboxylic acid or its salts with 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene in presence of base and a solvent selected from dimethylacetamide, dimethyl formamide, 1,4-dioxane or acetonitrile, followed by recrystallisation of the crude trityl olmesartan from methanol, acetonitrile or by purification with acid-base treatment. However still the purity and yield of trityl olmesartan obtained by the prior art processes are not satisfactory and do not meet the regulatory requirements.
Hence there is a need in the art for the process which provides highly pure trityl olmesartan and avoids the unwanted recrystallisation in final stages and avoids the problems pertaining to prior art. Also provides an improved process for the preparation of pure olmesartan medoxomil.

Brief Description of the Invention:
The first aspect of the present invention is to provide a process for the purification of trityl olmesartan compound of fomiula-8, which comprises of recrystallizing the trityl olmesartan from a mixture of ketone and ester solvents to provide the pure trityl olmesartan compound of formula-8.
The second aspect of the present invention is to provide an improved process for the preparation of highly pure olmesartan medoxomil compound of formula-1, which comprises of the following steps,
a) Treating the trityl olmesartan compound of formula-8 or its solvates with a suitable acid in aqueous solution at a suitable temperature,
b) stirring the reaction mixture,
c) quenching the reaction mixture with water and stirred,
d) filtering off the unwanted solid,
e) adding suitable solvent to the filtrate,
f) adjusting the pH of the reaction mixture with aqueous ammonia,
g) stirring the reaction mixture and filtering off the solid,
h) dissolving the obtained solid in a suitable solvent followed by washing it with water, i) isolating the pure olmesartan medoxomil from a suitable solvent.
The third aspect of the present invention is to provide an improved process for the preparation of olmesartan medoxomil compound of formula-1, which comprises of the following steps;
a) Reacting dimethyl-2-propylimidazole-4,5-dicarboxylate compoimd of formula-2 with 4-[2-(2-trityltetrazole-5-yl)phenyl]benzyl bromide compound of formula-3 in presence of a suitable alkali base and in a suitable solvent to provide the diester compound of formula-4,
b) reacting the diester compound of formula-4 with grignard reagent in a suitable solvent to provide the methyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(2-trityhetrazole-5-yl)phenyl]phenyl] methyl imidazole-5-carboxylate compound of formula-5, followed by its hydrolysis in presence of a suitable base and in a suitable solvent to provide the monoacid compound of formula-6,

c) reacting the monoacid compound of formula-6 with 4-chloromethyl-5-methyl-2-oxo-
1,3-dioxolene compoimd of formula-? in presence of a suitable base and a phase
transfer catalyst in a suitable solvent, followed by purification of the obtained
compound in a suitable solvent to provide the trityl olmesartan medoxomil
compound of formula-8,
d) treating the trityl olmesartan medoxomil compound of formula-8 with suitable acid in
aqueous solutions, followed by removing the unwanted solid and isolating the
olmesartan medoxomil by basifying the filtrate using ammonia in presence of a
suitable solvent,
e) recrystallizing the compound of formula-1 in a suitable solvent to get the pure
olmesartan medoxomil compound of formula-1.
Detailed Description of the Invention:
The present invention relates to an improved process for the preparation of olmesartan medoxomil and a process for the purification of trityl olmesartan medoxomil.
As used herein the term "ammonia" refers to the either ammonia gas or aqueous ammonia solution.
The first aspect of the present invention provides a process for the purification of trityl olmesartan compound of formula-8,

which comprises of recrystallizing the trityl olmesartan from a mixture of ketone solvent like acetone and ester solvent like ethyl acetate at a temperature ranges from 0 to reflux temperature, preferably 30 to 70°C and more preferably 55-60°C to provide the high pure trityl olmesartan compound of formula-S. The ratio of ethyl acetate and acetone employed for recrystallization is in the ratio of 1 to 99: 99:1. The trityl olmesartan

obtained is having the purity greater than 98% by HPLC, preferably greater than 99% by HPLC.
In preferred embodiment of the present invention, the purification of trityl olmesartan comprising of
a) Suspending the trityl olmesartan in a mixture of ethylacetate and acetone,
b) heating the suspension,
c) cooling the reaction mixture,
d) filtering off the solid to provide the high pure trityl olmesartan .
The second aspect of the present invention provides an improved process for the preparation of olmesartan medoxomil compound of formula-1, which comprises of the following steps,
a) treating the trityl olmesartan compound of formula-8 or its solvates with a suitable acid selected from organic acid such as acetic acid, formic acid, benzoic acid, oxalic acid; oxoacids such as perchloric acid, chloric acid, chlorous acid, hypochlorous acid, sulfuric acid, sulfurous acid, p-toluene sulfonic acid, nitric acid, nitrous acid, phosphoric acid and carbonic acid; and binary acids such as hydrochloric acid, hydrobromic acid; or their aqueous solution, preferably aqueous acetic acid, at a temperature range from 10 to 65 °C to obtain a solution of olmesartan medoxomil with unwanted triphenol carbinol as a solid,
b) quenching the reaction mixture with water and stirred,
c) filtering off the unwanted triphenol carbinol,
d) adding suitable solvent such as acetone to the filtrate,
e) basifying the reaction mixture with ammonia,
f) stirring the reaction mixture and filtering off the solid,
g) dissolving the obtained solid in a suitable solvent like methylene chloride followed by washing it with water,
h) isolating the highly pure olmesartan medoxomil using suitable solvent like acetone.

The third aspect of the present invention provides an improved process for the preparation of olmesartan medoxomil compound of formula-1, which comprises of the following steps;
a) Reacting dimethyl-2-propylimidazole-4,5-dicarboxylate compound of formula-2

Fonnula-4
b) reacting the diester compound of formula-4 with grignard reagent such as
methylmagnesium chloride in a suitable solvent like toluene to provide the methyl-4-
(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2-(2-trityltetrazole-5-yl)phenyl]-phenyl]
methyl imidazole-5-carboxylate compound of formula-5,

I
in presence of a suitable base like sodium carbonate and a phase transfer catalyst like tetrabutylammonium bromide (TBAB) in a suitable solvent like acetone, followed by purifying the obtained trityl olmesartan medoxomil using mixture of acetone and ethyl acetate provides the pure trityl olmesartan medoxomil compound of formula-8,


Formula-8
d) reacting the trityl olmesartan medoxomil compound of formula-8 with suitable aqueous acid such as acetic acid, followed by removing the unwanted solid and isolating the olmesartan medoxomil by basifying the filtrate using ammonia in presence of a suitable solvent like acetone,
e) dissolving the obtained solid in a suitable solvent followed by washing it with water,
f) isolating the high pure Olmesartan medoxomil compound of formula-1 using a suitable solvent like acetone.
The present invention further provides the usage of ammonia as a base to increase the basicity or decrease the acidity of the reaction mixture which is obtained after the deprotection of trityl group from trityl olmesartan followed by filtration of unwanted solid in presence or absence of a suitable solvent.
The related substance of acetone solvated form of trityl olmesartan and olmesartan medoxomil were analyzed by HPLC using the following conditions: Column: ZORBAX Phenyl, 250 X 4.6 mm, 5 )im or equivalent; Flow rate: 1.0 ml/min; wavelength: 210 run; Temperature: 35°C; Load: 10 nl; Run time: 45 min; and using acetonitrile and water in the ratio of 75:25 v/v as a diluents.

The present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
ExampIe-1: Preparation of dimethyl 2-propyH-[4-[2-(2-trityltetrazol-5-
yl)phenyl]phenyl]methyl imidazole-4,5-dicarboxylate compound of formula-4:
A mixture of dimethyl-2-propylimidazole-4,5-dicarboxylate compound of formula-2 (100 grams), 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide compound of formula-3 (296 grams), potassium carbonate (119 grams) in dimethyl formamide (100 ml) and acetone (500 ml) was heated to reflux temperature. The reaction mixture was stirred up to reaction completion and solvent was distilled off completely from the reaction mixture. The reaction mixture was cooled to 25-30°C, acetone (150 ml) and water (1000 ml) were added to it then stirred for 60 minutes. The obtained solid was filtered, washed with water and then the wet solid was recrystallized from acetone to provide the title compound. Yield: 285 grams; Purity by HPLC: 98.15%
Example-2: Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(2-trityltetra2ol-5-yl)phenyl]phenyl] methyl imidazole-5-carboxylic acid:
Methyl magnesium chloride (186 ml) was added to dimethyl-2-propyl-1-[4-(2-(2-trityltetrazol-5-yl)phenyl]phenyl)methyl imidazole-4,5-dicarboxylate (100 grams) in toluene (600 ml) at -35 to -30°C and stirred up to completion of the reaction. The reaction mixture was quenched with aqueous acetic acid (15% solution) at below -5°C then stirred at 25-30°C. The organic and aqueous layers were separated and the aqueous layer was extracted with toluene and added to organic layer. The organic layer washed with aqueous sodium chloride solution, then distilled off organic layer under reduced pressure at below 55°C. The obtained residue was dissolved in acetone (400 ml) and aqueous sodium hydroxide (10 grams in 300 ml of water) was added at 25-30°C and stirred up to completion of the reaction. The reaction mixture was washed with cyclohexane. Ethyl acetate (400 ml) and aqueous sodium chloride (200 ml) was added to the separated aqueous layer, stirred then the organic and aqueous layers were separated. Cyclohexane

(750 ml) was added to the organic layer and acidified with aqueous acetic acid then stirred for an hour. The solid obtained was filtered, washed with a mixture of ethylacetate and cyclohexane and dried to get the title compound Yield: 85 grams; Purity by HPLC: 96.08%
ExainpIe-3: Preparation of trityl olmesartan:
4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene (34 grams) was added to a mixture of 4-(l-hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2-(2-trityltetrazol-5yl)phenyl] phenyl] methyl imidazol-5-carboxylic acid (100 grams), sodium carbonate (10 grams), tetrabutylammonium bromide (9.3 grams) and acetone (1 L) at 25-30°C. The reaction mixture was heated to 35-40°C and stirred up to completion of reaction. The reaction mixture was filtered and washed with acetone. The filtrate was completely distilled off under reduced pressure at 50-55°C. Acetone was to the residue, stirred and filtered off the solid. The obtained wet solid was recrystallized from a mixture of acetone (200 ml) and ethyl acetate (75 ml) to get the pure trityl olmesartan. Yield: 80 grams
ExampIe-4: Preparation of highly pure olmesartan medoxomil:
Tritylolmesartan (100 grams) was added to aqueous acetic acid (400 ml in 200 ml of water) at 40-45°C and stirred up to the completion of reaction at 40-45°C. The reaction mixture was cooled to 25-35°C and water (600 ml) was added. The reaction mixture was cooled to 0-5°C and stirred for 60 minutes. The unwanted solid was filtered off and washed with aqueous acetic acid. Acetone (100 ml) was added to the above filtrate, cooled to 15-20°C and basified with aqueous ammonia. The reaction mixture temperature was raised to 25-30°C and filtered, washed the solid with water. The obtained solid was dissolved in methylene chloride (1500 ml) then washed with water. The solvent was distilled off completely and acetone (200 ml) was added to the obtained residue. The reaction mixture was heated to reflux and stirred for 30 minutes. The reaction mixture was cooled to 25-30°C and stirred for an hour. The obtained solid was filtered, washed with acetone and then dried to get the titie compound. Yield: 56 grams Purity by HPLC: 99.87%

Example-5: Purification of olmesartan medoxomil:
A mixture of olmesartan medoxomil (100 grams) and acetone (1800 ml) was heated to reflux temperature and filtered. The solvent from the filtrate was distilled off completely imder reduced pressure at below 55°C, The obtained residue was recrystallized from acetone to get pure olmesartan medoxomil. Yield: 92 grams Purity by HPLC: 99.92 %
ExampIe-6: Purification of trityl olmesartan:
A mixture of acetone (200 ml), ethyl acetate (75 ml) and tritylolmesartan (100 grams) was heated to 55-60°C and stirred for 45 minutes. The reaction mixture was cooled to 0-5 °C and stirred for an hour. The solid formed was filtered, washed with acetone and then dried to get pure trityl olmesartan. Yield: 95 grams Purity by HPLC: 99.59%

We Claim:
1. A process for the purification of trityl olmesartan compound of formula-8, which comprises of recrystallizing it from a mixture of acetone and ethylacetate at a suitable temperature to provide the high pure trityl olmesartan compound of formula-8.
2. The process according to claim 2, wherein the ethylacetate and acetone in the ratio of 1:99 to 99:1.
3. The process according to claim 1, wherein the recrystallisation temperature ranges from 0 to 70°C.
4. A process for the purification of trityl olmesartan comprises of the following steps,

a) Suspending the trityl olmesartan in a mixture of ethylacetate and acetone,
b) heating the suspension,
c) cooling the reaction mixture,
d) filtering the solid to provide the high pure trityl olmesartan .

5. The process according to claim 1 or 4, wherein the trityl olmesartan obtained having purity greater than 99% by High performance liquid chromatography.
6. Improved process for the preparation of highly pure olmesartan medoxomil compound of formula-1, which comprises of the following steps,

a) treating the trityl olmesartan compound of formula-8 or its solvates with a suitable acid selected from organic acid such as acetic acid, formic acid, benzoic acid, oxalic acid; oxoacids such as perchloric acid, chloric acid, chlorous acid, hypochlorous acid, sulfuric acid, sulfurous acid, p-toluene sulfonic acid, nitric acid, nitrous acid, phosphoric acid and carbonic acid; and binary acids such as hydrochloric acid and hydrobromic acid; or their aqueous solution, at a temperature range from 10 to 65 °C to obtain a solution of olmesartan medoxomil with unwanted triphenol carbinol as a solid,
b) quenching the reaction mixture with water and stirred.

c) filtering off the unwanted triphenol carbinol,
d) adding suitable solvent such as acetone to the filtrate,
e) basifying the reaction mixture with ammonia,
f) stirring the reaction mixture and filtering off the solid,
g) recrystallizing the obtained solid using a suitable solvent selected from methylene chloride or acetone or mixture thereof provides highly pure olmesartan compound of formula-1.
7. Improved process for the preparation of highly pure olmesartan medoxomil
compound of formula-1, which comprises of the following steps,
a) treating the trityl olmesartan compound of formula-8 with aqueous acetic acid at a temperature range from 10 to 65 °C to obtain a solution of olmesartan medoxomil with unwanted triphenol carbinol as a solid,
b) filtering off the unwanted triphenol carbinol,
c) adding acetone to the reaction mixture
d) basifying the reaction mixture with ammonia,
e) stirring the reaction mixture and filtering off the solid,
f) dissolving the obtained solid in methylene chloride followed by washing it with water,
g) isolating the highly pure olmesartan medoxomil using acetone.

8. The usage of ammonia as a base to increase the basicity or decrease the acidity of the reaction mixture which is obtained after the deprotection of trityl group from trityl olmesartan followed by filtration of unwanted solid in presence or absence of a suitable solvent.
9. Improved process for the preparation of olmesartan medoxomil compound of formula-1, which comprises of the following steps;
a) Reacting dimethyl-2-propylimidazole-4,5-dicarboxylate compound of formula-2


with 4-[2-(2trityltetrazole-5-yl)phenyl]benzyl bromide compound of formuIa-3

Formula-3 in presence of a suitable alkali base such as potassium carbonate and in a suitable mixture of acetone and dimethyl formamide to provide the diester compound of formula-4,
Fonnula-4 b) reacting diester compound of formula-4 with grignard reagent such as methylmagnesium chloride in a suitable solvent like toluene provides the methyl-4-( 1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2(2-trityltetrazole-5-yl)phenyl]-phenyl] methyl imidazole-5-carboxylate compound of formula-S,


Formula-5 which on in-situ hydrolysis with aqueous sodium hydroxide in a suitable solvent such as acetone provides the monoacid compound of formula-6,

Formula-8 d) reacting the trityl olmesartan medoxomil compound of formula-8 with suitable aqueous acid, followed by removing the unwanted solid and isolating the

olmesartan medoxomil by basifying the filtrate using ammonia in presence of a suitable solvent like acetone,
e) dissolving the obtained solid in a methylene chloride followed by washing it with water,
f) isolating the highly pure olmesartan medoxomil using acetone.
10. The process according to claim 6,7& 9, wherein the olmesartan medoxomil obtained having purity greater than 99.50% by High performance liquid chromatography.