Field of the Invention:

The present invention relates to novel acetone solvate of trityl olmesartan, process for its preparation and an improved process for the preparation of highly pure olmesartan medoxomil. Trityl olmesartan is chemically known as (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(trityltetrazol-5-yl)phenyl] phenyl]methyl imidazole-5-carboxylate having the following structural formula-2,

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 from 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)phenylben2yl 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.

Journal of Medicinal Chemistry 1996, 39, 1, 323-338 reported a process for the preparation of 2-propylimidazole 4,5-dicarboxylic acid. The disclosed process involves condensation of diaminomaleonitrile and trimethyl orthobutyrate in acetonitrile at reflux temperature for 6 hours and the obtained residual compound by column chromatography and then purified residue was refluxed in xylene for 8 hours to provide 2-propylimidazole-4,5-dicarbonitrile, which is further treated with an aqueous hydrochloric acid at reflux, followed by lengthy workup process provides the 2-propylimidazole-4,5-dicarboxylic acid. The said process involves the usage of column purification and lengthy workup process makes it not suitable for commercial scales. There is a need in the art for economically and commercially viable process for the preparation of 2-propylimidazole 4,5-dicarboxylic acid.

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.

Brief Description of the Invention:

The present invention relates to a novel solvate of trityl olmesartan, process for its preparation and an improved process for the preparation of highly pure trityl olmesartan compound of formula-2 as well as its use in the preparation of highly pure olmesartan medoxomil.

The first aspect of the present invention is to provide novel acetone solvate of trityl olmesartan compound of formula-2. The novel acetone solvate of trityl olmesartan of the present invention is used to prepare high pure olmesartan medoxomil compound of formula-1.

The second aspect of the present invention is to provide a process for the .preparation of novel acetone solvate of trityl olmesartan, which comprises of stirring the trityl olmesartan in acetone for a sufficient period of time and isolating the acetone solvate of trityl olmesartan.

The third aspect of the present invention is to provide a novel crystalline form of trityl olmesartan acetone solvate. The novel crystalline form of the present invention is used to prepare high pure olmesartan medoxomil compound of formula-1.

The fourth aspect of the present invention is to provide a process for the preparation of crystalline form of trityl olmesartan acetone solvate, which comprises of reacting the 4-(l -hydroxy-l -methylethyl)-2-propyl-l -(4-(2-trityltetrazol-5yl)phenyl] .phenyl)methyl imidazol-5-carboxylic acid compound of formula-3 with 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene compound of formula-4 in presence of a suitable base in acetone in presence or absence of a phase transfer catalyst, followed by isolation of the acetone solvated form of trityl olmesartan from acetone.

The fifth aspect of the present invention is to provide a process for the preparation highly pure trityl olmesartan, which comprises of stirring the trityl olmesartan acetone solvate in a suitable solvent to provide the pure trityl olmesartan.

The sixth aspect of the present invention is to provide highly pure olmesartan medoxomil compound of formula-1, which comprises of contacting acetone solvated .form of trityl olmesartan with an acid in a suitable solvent and with or without water, to obtain a solution of olmesartan medoxomil, followed by separation of the by product and then treating the solution with a base to provide the highly pure olmesartan medoxomil.

The seventh aspect of the present invention is to provide an improved process for the preparation of 4-(l-hydroxy-l-methyl ethyl)-2-propyl-l-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl) methylimidazole-5-carboxylic acid compound of fonnula-3, which comprises of reacting dimethyl-2-propyl(4-(2-(trityltetrazol-5-yl)phenyl)phenyl)methyl imidzole-4,5-dicarboxylate compound of formula-5 with Grignard reagent in a suitable solvent to provide the methyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-(2-tritylterazole-5-yl)phenyl]-phenyl methyl imidazole-5-carboxylate compound of •formula-6, followed by its hydrolysis in presence of a suitable base and a solvent to provide the compound of formula-3, characterized in that the grignard reaction takes place at a temperature of less than 0°C.

The eighth aspect of the present invention is to provide one pot process for the preparation of 2-propyl-lH-imdazole-4,5-dicarboxylic acid compound of formula-7, which comprises of reacting the diaminomalenonitrile with tnmethylorthobutyrate in a
suitable alcoholic solvent to provide 5-propyl-lH-pyrrole-2,3-dicarbonitrile compound of formula-8, which on in-situ reaction with a suitable acid provides the compound of formula-7.

Brief Description of the Drawings:

Figure-1: Illustrates the Powder X-ray diffractogram of trityl olmesartan acetone solvate
Detailed Description of the Invention:

The present invention relates to novel solvate of trityl olmesartan, a process for its preparation and an improved process for the preparation of highly pure trityl olmesartan compound of formula-2.

The first aspect of the present invention provides a novel acetone solvate of trityl olmesartan compound of formula-2.

Formula-2

The present invention also provides the use of novel acetone solvated form of trityl olmesartan. The novel acetone solvate of the present invention is used to prepare highly pure olmesartan medoxomil compound of formula-1
Formula-1

The second aspect of the present invention provides a process for the preparation of trityl olmesartan acetone solvate, which comprises of stirring the trityl olmesartan in acetone for a sufficient period of time at a temperature from 0 to 35°C, preferably 0-5°C and isolating the acetone solvate of trityl olmesartan by filtration.

The third aspect of the present invention provides novel crystalline form of trityl olmesartan acetone solvate. The novel crystalline form of the present invention is characterized by its powder X-ray diffractogram having characteristics 2 theta peaks at 6.05,10.22, 10.68, 12.04, 14.31, 15.76,18.06, 19.28,20.69,21.36, 24.12, 29.02, 30.21 ± 0.2 degrees 20. The novel acetone solvated form of the trityl olmesartan of the present invention here in designated as "crystalline form-M". The PXRD of crystalline form-M of the present invention is represented in figure-1.

The reported/prior art processes for the preparation of olmesartan medoxomil involve a number of recrystallisations in a final stage to get the desired purity required for formulation. The usage of novel acetone solvated form or crystalline form M of trityl olmesartan in preparation of olmesartan avoids the number of recrystallisations in the final stage and also provides highly pure olmesartan medoxomil when compared to the prior art.

The fourth aspect of the present invention provides a process for the preparation of crystalline form-M of trityl olmesartan acetone solvated form, which comprises of reacting the 4-(l-hydroxy-l-methylethyl)-2-propyl-l-(4-(2-trityltetrazol-5yl)phenyl) phenyl)methyl imidazol-5-carboxylic acid compound of formula-3.

Formula-3 with 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene compound of formula-4.

Formula-4 in presence of a suitable base selected from sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably sodium carbonate in acetone .in presence or absence of a phase transfer catalyst selected from tetra butyl ammonium bromide, tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, preferably tetra butyl ammonium bromide, followed by isolation of the acetone solvated form of trityl olmesartan from acetone.

The fifth aspect of the present invention provides a process for the preparation highly pure trityl olmesartan, which comprises of

a) Suspending the trityl olmesartan acetone solvate in a suitable solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol; ester solvents like ethylacetate, methyl acetate, isopropylaceatate, ketone solvent like acetone; nitrile solvents like acetonitrile, hydrocarbon solvents like toluene, heptane, cyclohexane and hexane,

b) stirring the suspension,

c) filtering, washing the solid,

d) frying the solid to get highly pure trityl olmesartan.

The sixth aspect of the present invention provides a highly pure olmesartan medoxomil compound of formula-1, which comprises of the following steps; a) contacting acetone solvated form of trityl olmesartan 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, sulfiiric acid, sulfiirous acid, p-toluene sulfonic acid, nitric acid, nitrous acid, phosphoric acid and carbonic acid; and binary acids such as hydrochloric acid, hydrobromic acid and hydrocyanic acid, hydrocholoric acid, sulfuric acid, paratoluene sulfonic acid, especially acetic acid is preferred. Preferably in an amount of 1 to about 8 equivalents, in a suitable solvent selected from acetone, acetonitrile at a temperature range from 10 to 65 °C to obtain a solution of olmesartan medoxomil with unwanted triphenol carbinol as a solid,

b) adding water to the above solution,

c) separating the triphenyl carbinol from the above solution of olmesartan medoxomil by filtration,

d) treating the solution of olmesartan medoxomil with a suitable base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or its aqueous solution, preferably sodium bicarbonate to provide the highly pure olmesartan medoxomil compound of formula-1.

The seventh aspect of the present invention is to provide an improved process for the preparation of 4-(I-hydroxy-1-methyl ethyl)-2-propyl-l-(4-[2-(trityltetrazol-5-yl)phenyl]phenyl) methylimidazole-5-carboxylic acid compound of formula-3,

Formula-3 which comprises of the following steps;
a) reacting the dimethyl-2-propyl(4-(2-(trityltetrazol-5-yl)phenyl]phenyl)methyl imidzole-4,5-dicarboxylate compound of formula-5.


,

Formula-5 with a grignard reagent selected from methyl magnesium chloride or methylmagenesium bromide in a suitable solvent selected from toluene, tetrahydrofuran, followed by quenching the reaction mixture with a suitable aqueous acid, to provide methyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-(2-tritylterazole-5-yl)phenyl]-phenyl methyl imidazole-5-carboxylate compound of formula-6, characterized in that addition of grignard reaction and maintenance of the reaction is carried out at the temperature of -30 to -50°C, preferably at -35°C to -38°C and the quenching with an acid is carried out at a temperature of-5 to -10°C,

Formula-6 b) hydrolyzing the compound of formula-6 in-situ in presence of a suitable alkali metal base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like preferably sodium hydroxide with or without water in a suitable solvent selected from ketone solvents like acetone; nitrile solvents like acetonitrile; alcoholic solvent selected from methanol, ethanol, isopropanol and butanol or mixtures thereof, followed by extracting the reaction mixture with a suitable hydrocarbon solvent selected from toluene, cylcohexane, heptane or hexane; ester solvents like ethyl acetate, methyl acetate or isopropyl acetate, to provide the compound of formula-3.

The said compound of formula-3 is used in the preparation of olmesartan medoxomil compound of formula-1 provides the highly pure olmesartan medoxomil which is free of impurity at 1.13 RRT (Impurity-X).

As per the prior art processes, 4-(l-hydroxy-1-methyl ethyl)-2-propyl-l-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl) methylimidazole-5-carboxylic acid, a key intermediate of olmesartan medoxomil was prepared by treating dimethyl-2-propyl(4-(2-(trityltetrazol-.5-yl)phenyl]phenyl)methyl imidzole-4,5-dicarboxylate with methylmegnesium chloride in toluene at temperature ranges from 25 to 50°C to provide the methyl-4-(l-hydroxy-1-methylethyl)-2-propyl-1 -[4-(2-tritylterazole-5-yl)phenyl]-phenyl methyl imidazole-5-carboxylate which on hydrolysis with a base to provide the corresponding acid compound and the same has been further converted into olmesartan medoxomil by medoxomil condensation followed by removal of triphenyl protecting group. When we carried out the above grignard reaction at room temperature as per the prior art we observed that 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-(2-tritylterazole-5-yl)phenyl]-phenyl methyl imidazole-5-carboxylic acid contaminated with some unknown impurities and the same have been reacted vdth reagent in subsequent steps in the preparation of olmesartan medoxomil and analyzed by HPLC. Along with olmesartan some impurity compound observed at the RRT of 1.13 having a molecular weight of 503, herein designated as "Impurity-X", which is the derivative of the impurity observed in the grignard reaction.

The impurity X is not removable/washable by conventional purification methods and hence we the present inventors have tried to control the same at the origin itself i.e., during Grignard reaction, by varying the process parameters. After conducting various experiments and finally it was concluded, that the adding grignard reagent at a temperature of -30 to -50°C and maintaining the grignard reaction at a temperature range of -30 to -50°C, followed by extraction of the reaction mixture with a suitable solvent after the hydrolysis step removed/controlled the impurity-X in the final compound.

The eighth aspect of the present invention one pot process for the preparation of 2-propyl-lH-imdazole-4,5-dicarboxylic acid compound of formula-7 with high yields and purity, which is a key intermediate in synthesis of olmesartan medoxomil compound of formula-1

Formula-7
which comprises of reacting the diaminomalenonitrile with trimethylorthobutyrate in a
suitable alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol and
butanol or mixtures thereof at a temperature of 25°C to reflux temperature of the solvent
to provide the 5-propyl-lH-pyrrole-2,3-dicarbonitrile compound of formula-8.

Formula-8
which on in-situ reaction with a suitable acid selected form hydrochloric acid, sulfuric
acid, hydrobromic acid, followed by isolation of 2-propyl-lH-imidazole-4,5-dicarboxalic
acid compound of formula-7 from suitable solvent like water.

As per the prior art, the process for the preparation of compound of formula-7 involves the usage of acetonitrile as a solvent for the condensation of diaminomalenonitrile with trimethylorthobutyrate leads to less yields and poor quality of the material. The prior art also involves the isolation of compound formula-8 after tedious work up procedure from the reaction mixture. The present invention provides the simple process with the usage of alcoholic solvent as well as avoids the tedious workup procedure and does not involve the isolation of nitrile compound of formula-8.

The compoimd of formula-7 can be converted into dialkyl 2-propyl-lH-imdazole-4,5-dicarboyxlate compound of formula-9

Formula-9

Wherein R is selected from CM alkyl;
by treating it with a suitable alcohol like methanol, ethanol or isopropanol in presence of
a suitable acid catalyst selected thionyl chloride, sulfuric acid or by conventional methods
known in the art.

The dimethyl-2-propyl(4-(2-(trityltetrazol-5-yl)phenyl]phenyl)methyl imidzole-4,5-dicarboxylate compound of formula-5 can be prepared by the methods known in the art.
XRD analysis of acetone solvated form of trityl olmesartan was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.0457min.

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 µm or equivalent; Flow rate: 1.0 ml/min; wavelength: 210 nm;

Temperature: 35°C; Load: 10 1; Run time: 45 min; and using acetonitrile and water in the ratio of 75:25 v/v as a diluent.

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:

Example-1: Preparation of acetone solvated form of trityl olmesartan:

A mixture of tritylolmesartan (50 grams) and acetone (100 ml) was stirred for an 20 minutes at 25-30°C. The reaction mixture was then cooled to 0-5°C and stirred for an hour. The solid filtered, washed with acetone and dried to get the title compound. Yield: 45 grams Purity by HPLC: 98.75%

ExampIe-2: Preparation of crystalline form M of trityl olmesartan:

4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene (13.2 grams) was added to a mixture of 4-( 1 -hydroxy-1 -methylethyl)-2-propyl-1 -(4-(2-trityltetrazol-5yl)phenyl] phenyl)methyl imidazol-5-carboxylic acid compound of formula-3 (40 grams), sodium carbonate (4 grams), tetrabutylammonium bromide (3.72 grams) and acetone (400 ml) at 25-30°C. The reaction mixture was heated to 40-45°C and stirred for 4 hours. The reaction mixture was filtered through hyflow and washed with acetone. The filtrate was completely distilled off under reduced pressure at 50-55°C and then cooled to 25-35°C. Acetone (40 ml) was added to the above reaction mixture and stirred for 45 nunutes at 25-35°C. The reaction mixture was cooled to 0-5°C and stirred for an hour. The solid formed was filtered, washed and dried at 60-70°C to get crystalline form M of trityl olmesartan. Yield: 37 grams •Purity by HPLC: 98.86 %

Example-3: Preparation of acetone solvate trityl olmesartan:

4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene (9.9 grams) was added to a mixture of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-(4-(2-trityltetrazol-5yl)phenyl]phenyl)methyl imidazol-5-carboxylic acid compound of formula-3 (30 grams), sodium carbonate (3 grams), tetrabutylammonium bromide (2.8 grams) and acetone (75 ml) at

25-30°C. The reaction mixture was heated to 40-45°C and stirred for 4 hours. The
reaction mixture was cooled to 25-35°C and then to 0-5°C. The reaction mixture was
stirred for an hour at 0-5 °C. The solid was filtered, washed with acetone and dried at
50-60°C to get the title compound.

Yield: 28 grams

Purity by HPLC: 98.02 %

ExampIe-4: Preparation of highly pure trityl olmesartan:

A mixture of tritylolmesartan acetone solvate (25 grams) and ethylacetate (50 ml) was stirred for 30 minutes at 25-30°C. The solid was filtered, washed with ethylacetate and dried at 50-55°C to get the title compound. Yield: 22 grams Purity by HPLC: 98.83%
Example-5: Preparation of highly pure olmesartan medoxomil compound of formuIa-1 from acetone solvate of trityl olmesartan:

Aqueous acetic acid (1200 ml acetic acid in 1800 of water) was added to acetone solvated form of trityl olmesartan (100 grams) at 25-3 5°C. The reaction mixture was heated to 60-65°C and stirred for 15 minutes at 60-65°C. The reaction mixture was cooled to 25-35°C and water (1500 ml) was added to it. The reaction mixture was cooled to 5-10°C and stirred for 45 minutes. The unwated triphenyl carbinol was filtered off and washed with aqueous acetic acid. Methylene chloride (1000 ml) was added to the above filtrate and stirred for 15 minutes at 25-30°C. The organic and aqueous layers were separated and extracted the aqueous layer with methylene chloride. Added a mixture of 5% solution of sodium chloride and sodium bicarbonate and separated the organic and aqueous layers. The organic layer was washed with 5% sodium chloride solution and solvent from the organic layer was distilled off under reduced pressure at below 65°C. The reaction mixture was cooled to 40°C and acetone (50 ml) to it. The reaction mixture was cooled to 0-5 °C and stirred for 2 hours. The solid filtered, washed with chilled acetone and dried at 55-65°C to get the high pure olmesartan medoxomil. Yield: 58 grams; Purity by HPLC: 99.81%

Example-6: Preparation of 2-propyl-lH-iiiiidazoIe-4,5-dicarboxylic acid:

A mixture of diaminomaleononitrile (10 grams), trimethylorthobutyrate (17.8 grams) and methanol (20 ml) was heated to reflux and stirred until the reaction was completed. The solvent from the reaction mixture was distilled off imder reduced pressure at below 60°C.

The reaction mixture was cooled and acidified with hydrochloric acid. The reaction mixture was heated to reflux and stirred at reflux imtil the completion of the reaction and isolating the title compoimd from water. The solid formed was filtered, washed with water and dried to get the title compound. Yield: 16 grams: Melting point: 260-270°C

Example-?: Preparation of dimetliyl 2-propyl-lH-imidazole-4,5-dicarboxylate:

Thionyl chloride (15 grams) was added to a mixture of 2-propyl-lH-imidazole-4,5-dicarboxylic acid in methanol (30 ml) and heated to reflux then stirred until the completion of reaction. The reaction mixture was cooled to 0-5°C and quenched with water. The reaction mixture was basified with aqueous sodium hydroxide and stirred for 15 minutes. The solid was filtered, washed with water and dried to get the title compound Yield: 11 grams Melting point: 142-148°C

Example-8: Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyI-l-{4-[2-(trityltetrazol-5-yl)phenyl]phenyI) methylimidazole-5-carboxylic acid:

Methyl magnesium chloride (186 ml) was added to a mixture of dimethyl-2-propyl(4-(2-(trityltetrazol-5-yl)phenyl]phenyl)methyl imidazole-4,5-dicarboxylate (100 grams) in toluene (600 ml) at -35 to -30°C and stirred for 3 hours. Aqueous acetic acid was added to the reaction mixture at below -5°C then stirred at 25-30°C. The layers were separated and extracted the aqueous layer with toluene. The organic layer washed with aqueous sodium chloride solution then the organic layer was distilled off under reduced pressure at below 55°C. Dissolve the residue in acetone and aqueous sodium hydroxide (10 grams in 300 ml of water) at 25-30°C and stirred for 4 hours. The reaction mixture was washed with cyclohexane. Ethyl acetate (400 ml) and aqueous sodium chloride (200ml) was added to the separated aqueous layer, stirred and layers were separated. Extracted the aqueous layer with ethylacetate. Cyclohexane (750 ml) was added to the organic layer and acidified with aqueous acetic acid then stirred for an hour. The solid was filtered, washed with a mixture of ethylacetate and cyclohexane and dried to get the title compound Yield: 85 grams

Example-9: Preparation of trityl olmesartan medoxomil:

4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene (13.2 grams) was added to a mixture of 4-( 1 -hydroxy-1 -methylethyl)-2-propyl-1 -(4-(2-trityltetrazol-5yl)phenyl] phenyl)methyl imidazol-5-carboxylic acid obtained as per the example-8 (40 grams), sodium carbonate (4 grams), tetrabutylammonium bromide (3.72 grams) and acetonitrile (400 ml) at 25-30°C. The reaction mixture was heated to 40-45°C and stirred for 4 hours. The reaction mixture was filtered through hyflow and washed with acetone. The filtrate was completely distilled off imder reduced pressure at 50-55°C and then cooled to 25-35°C. Acetonitrile (40 ml) was added to the above reaction mixture and stirred for 45 minutes at 25-35°C. The reaction mixture was cooled to 0-5°C and stirred for an hour. The solid formed was filtered, washed and dried at 60-70°C to get the title compound. Yield: 35.6 grams

ExampIe-10: Preparation of highly pure olmesartan medoxomil:

Aqueous acetic acid (120 ml acetic acid in 180 of water) was added to trityl olmesartan (10 grams) obtained as per example-9 at 25-35°C. The reaction mixture was heated to 60-65°C and stirred for 15 minutes at 60-65°C. The reaction mixture was cooled to 25-35°C and water (150 ml) was added to it. The reaction mixture was cooled to 5-10°C and stirred for 45 minutes. The unwated triphenyl carbinol was filtered off and washed with aqueous acetic acid. Methylene chloride (100 ml) was added to the above filtrate and stirred for 15 minutes at 25-30°C. The organic and aqueous layers were separated and extracted the aqueous layer with methylene chloride. Added a mixture of 5% solution of sodium chloride and sodium bicarbonate and separated the organic and aqueous layers. The organic layer was washed with 5% sodium chloride solution and solvent from the organic layer was distilled off under reduced pressure at below 65°C.

The reaction mixture was cooled to 40°C and acetone (50 ml) to it. The reaction mixture was further cooled to 0-5°C and stirred for 2 hours. The solid was filtered, washed with chilled acetone and dried at 55-65°C to get the high pure olmesartan medoxomil. Yield: 5.7 grams Purity by HPLC: 99.81%; Impurity at 1.13 RRT: 0.07%

1. Acetone solvate of trityl olmesartan

2. A process for the preparation of acetone solvated form of trityl olmesartan comprising of stirring the trityl olmesartan in acetone for a sufficient period of time to produce its solvated form.

3. Crystalline form M of trityl olmesartan acetone solvate characterisized by its PXRD spectrum having characteristics 2 theta peaks at 6.05, 10.22, 10.68, 12.04, 14.31,

15.76, 18.06, 19.28, 20.69, 21.36, 24.12, 29.02, 30.21 ± 0.2 degrees 29 ± 0.2 degrees
20.

4. Use of trityl olmesartan acetone solvate and crystalline form M of trityl olmesartan in the preparation of highly pure olmesartan medoxomil compound of formula-1.

5. A process for the preparation of crystalline form-M trityl olmesartan, which
comprises of reacting the 4-(l-hydroxy-l-methylethyl)-2-propyl-l-(4-(2-trityltetrazol-
5yl)phenyl] phenyl)methyl imidazol-5-carboxylic acid compound of formula-3 in presence of a suitable base selected from sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, in acetone in presence or absence of a phase transfer catalyst selected from tetra butyl ammonium bromide, tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, followed by isolating the crystalline form-M of the acetone solvated form of trityl olmesartan from acetone.

6. A process for the preparation of highly pure trityl olmesartan, which comprises of

a) Suspending the trityl olmesartan acetone solvate in a suitable solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol; ester solvents like ethylacetate, methyl acetate, isopropylaceatate, ketone solvent like acetone; nitrile solvents like acetonitrile, hydrocarbon solvents like toluene, heptane, cyclohexane and hexane,

b) stirring the suspension,

c) filtering, washing the solid,

d) drying the solid to get highly pure trityl olmesartan.

7. A process for the preparation of highly pure olmesartan medoxomil compound of
formula-1,


a) contacting acetone solvated form of trityl olmesartan with an 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 and hydrocyanic acid, to obtain a solution of olmesartan
medoxomil withunwanted triphenol carbinol as a solid,

b) adding water to the above solution,

c) separating the triphenyl carbinol from the above solution of olmesartan
medoxomil by filtration or centrifugation,

d) treating the solution of olmesartan medoxomil with a suitable base selected from
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
sodium bicarbonate, potassium bicarbonate or its aqueous solution, to provide the
highly pure olmesartan medoxomil compound of formula-1.

8. One pot process for the preparation of 2-propyl-lH-imdazole-4,5-dicarboyxlate compound of formula-7 with high yields and purity,

subsequently treating the compound of formula-8 in-situ with a suitable acid selected form hydrochloric acid, sulfuric acid, hydrobromic acid, followed by isolation of 2-propyl-lH-imidazole-4,5-dicarboxalic acid compound of formula-7 form a suitable solvent.

9. An improved process for the preparation of 4-( 1 -hydroxy-1 -methyl ethyl)-2-propyl-1 –(4-[2-(trityltetrazol-5-yl)phenyl]phenyl) methylimidazole-5-carboxylic acid compound of formula-3,

which comprises of the following steps;

a. reacting the dimethyl-2-propyl(4-(2-(trityltetrazol-5-yl)phenyl]phenyl)methyl imidzole-4,5-dicarboxylate compound of formula-5

with a grignard reagent selected from methyl magnesium chloride or methylmagenesium bromide in a suitable solvent selected from toluene, tetrahydroufran to provide the methyl-4-(l-hydroxy-1-methylethyl)-2-propyl-1-

[4-(2-tritylterazole-5-yl)phenyl]-phenyl methyl imidazole-5-carboxylate compound of formula-6, characterized in that addition of grignard reaction and maintenance of the reaction is carried out at the temperature of -30 to -50°C, preferably at -35°C to -38°C and the quenching with an acid is carried out at a temperature of -5 to -10°C,

b. hydrolyzing the compound of formula-6 in-situ in presence of a suitable alkali metal base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like preferably sodium hydroxide with or without water in a suitable solvent selected from ketone solvents like acetone; nitrile solvents like acetonitrile; alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol, followed by extracting the reaction mixture with a suitable solvent hydrocarbon solvent selected from toluene, cylcohexane, heptane or hexane; ester solvents like ethyl acetate, methyl acetate and isopropyl acetate, to provide the compound of formula-3.

10. An improved process for the preparation of 4-(l-hydroxy-1-methyl ethyl)-2-propyl-l-(4-[2-(trityltetrazol-5-yl)phenyl]phenyl) methylimidazole-5-carboxylic acid compound of formula-3,

with methyl magnesium chloride in toluene, followed by quenching the reaction
mixture with a suitable aqueous acid to provide the methyl-4-( 1-hydroxy-1-
methylethyl)-2-propyl-l-[4-(2-tritylterazole-5-yl)phenyl]-phenyl methyl
imidazole-5-carboxylate compound of formula-6, characterized in that addition of grignard reaction and maintenance of the reaction is carried out at the temperature at -35°C to -38°C and the quenching with an acid is carried out at a temperature of-5to-10°C,

b. hydrolyzing the compound of formula-6 in-situ in presence of aqueous sodium hydroxide in acetone, followed by extracting the reaction mixture with cylcohexane to provide the compound of formula-3.