FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]

IMPROVED PROCESS FOR THE PREPARATION OF OLMESARTAN
MEDOXOMIL AND INTERMEDIATES THEREOF
Applicant Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road,
Near Dinesh Hall,
Ahmadabad 380 009.
Gujarat, India

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

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester, the key intermediate for the preparation of olmesartan medoxomil.
BACKGROUND OF THE INVENTION
Olmesartan medoxomil (I) is a powerful angiotensin II receptor antagonist and widely used for the treatment of hypertension and related diseases and conditions.

U.S. Patent No. 5,616,599 (the '599 patent) discloses a process for the preparation of olmesartan medoxomil comprising:
• condensing 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 H-imidazole-5-carboxylic acid ethyl ester (II) with 4-[2-(trityitetrazol-5-yl)phenyl]benzyl bromide (III) in presence of sodium hydride and dimethyl formamide to obtain amorphous ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylme-thyl]imidazol-5-yl carboxylate (IV);
• hydrolyzing ethyl 4-{1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyl-tetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) in presence of lithium hydroxide in dioxane to obtain corresponding lithium salt of the acid, which is then reacted with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene in

presence of potassium carbonate and dimethyl acetamide to get trityl olmesartan nedoxomil (V) and
deprotecting trityl olmesartan medoxomil (V) in presence of acetic acid and water followed by recrystallization in ethyl acetate to obtain olmesartan medoxomil (I).

U.S. Patent No. 5,616,599 also discloses process for the preparation of 4-(l-hydroxy-1-methylethyl)-2-propyl-1H-imidazoie-5-carboxylic acid ethyl ester (II). The process comprises reacting 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (lla) with methyl magnesium bromide in tetrahydrofuran to obtain 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) followed by recrystallization from diisopropylether. The process produces the potential impurities "methoxy impurity" and "dehydro impurity" in the intermediate stage which is also difficult to remove from the pharmaceutically active compound i.e. olmesartan medoxomil (I).


U.S. Patent No. 7,563,814 discloses, the impurities "methoxy impurity" and "dehydro impurity" as the precursors of impurities OLM-Me and OLM-eliminate and are formed during the Grignard reaction of 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (Ha). The patent provides a process for preparing olmesartan medoxomil (I) having low level of impurities by selecting the intermediate trityi olmesartan medoxomil (V) with low level impurities. The patent does not disclose the process to reduce "methoxy impurity" and "dehydro impurity" in the prior stage itself.
J.P. Patent No. 4,260,241 discloses process for preparing 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) by using methylmagnesium chloride as a Grignard reagent in a specific solvent like tetrahydrofuran and aromatic solvent. The patent discloses replacement of methylmagnesiumbromide of a Grignard reagent with methylmagnesiumchloride and the drawback of using methylmagnesiumbromide as a Grignard reagent gives low yield and purity.
J.P. Patent No. 4,185,182 discloses process for preparing 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) with a methyl Grignard reagent prepared in dibutyl ether solvent and hydrolyzing the reaction product.
There is a need for the process for preparing olmesartan medoxomil (I) with reduced level of impurities. The present invention provides an improved process for the preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid

ethyl ester (II), the key intermediate for the preparation of olmesartan medoxomil (I). The process produces 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxyfic acid ethyl ester (II) in a good yield and purity by controlling the potential impurities "methoxy impurity" and "dehydro impurity" in the intermediate stage itself. Highly pure 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) can be employed as a useful intermediate to yield high purity of olmesartan medoxomil (I) thereof which may be scaled up for large scale synthesis. The process is simple, industrially feasible, and economical and gives better yield and purity.
SUMMARY OF THE INVENTION
In one embodiment, the specification discloses the process for the preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) comprising:
a) reacting 2-propyl-1 H-imidazole-4,5-carboxylic acid diethyl ester (lla) with solvent;
b) adding methyl magnesium bromide prepared in solvent selected from aromatic solvent or ether which is not tetrahydrofuran and dibutyl ether or mixture of aromatic solvent and ether to the reaction mixture of step a);
c) acidifying the reaction mixture of step b);
d) isolating 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II).
In another embodiment, the specification discloses the process for the preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) comprising:
a) reacting 2-propyl-1 H-imidazole-4,5-carboxylic acid diethyl ester (lla) with solvent;
b) adding methyl magnesium bromide prepared in toluene to the reaction mixture of step a);
c) acidifying the reaction mixture of step b);

d) isolating 4-(1-hydroxy-1-methylethy))-2-propy)-lH-imidazole-5-carboxy!ic acid ethyl ester (II).
In yet another embodiment, the specification discloses 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxyiic acid ethyl ester (II) containing less than or equal to 0.1% of methoxy impurity and dehydro impurity.
In yet another embodiment, the specification discloses use of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) for the preparation of olmesartan medoxomil (I).
In yet another embodiment, the specification discloses process for the preparation of olmesartan medoxomil (I) comprising:
a) reacting trityl olmesartan medoxomil (V) with aqueous acid;
b) adding water to the reaction mixture of step a);
c) quenching the reaction mixture of step b) in aqueous ionic salt solution;
d) extracting the reaction mixture of step c) with the mixture of organic solvent;
e) separating aqueous layer and organic layer;
f) treating the organic layer with base;
g) adding acid to the organic layer;
h) isolating olmesartan medoxomil (I).
DETAILED DESCRIPTION OF THE INVENTION
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires

otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The present invention may, however, be embodied in many different forms and should not be construed as limited to the aspects set forth herein. In addition and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.
As used herein, the term "methoxy impurity" refers to 4-(1-Methoxy-1-methylethyl)-2-propyl-1 H-imidazole-5-carboxylic acid ethyl ester of the formula:

As used herein, the term "dehydro impurity" refers to Ethyl-4-(prop-1-en-2yl)-2-propyl-1H-imidazole-5-carboxylate of the formula:

As used herein, the term "degradation impurity (la)" refers to 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazole-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of the formula:


In one embodiment, the specification discloses the process for the preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) comprising:
a) reacting 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (Ma) with solvent;
b) adding methyl magnesium bromide prepared in solvent selected from aromatic solvent or ether which is not tetrahydrofuran and dibutyl ether or mixture of aromatic solvent and ether to the reaction mixture of step a);
c) acidifying the reaction mixture of step b);
d) isolating 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II).
The process for the preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) comprises reacting 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (IIa) with solvent to obtain clear solution. The solution is cooled to a temperature at about -25°C to -35°C, more preferably to a temperature at about ~28°C to -32°C. The process comprises adding methyl magnesium bromide prepared in solvent or mixture of solvent to the reaction mass. The reaction mass is further maintained at the temperature of about -5°C to -15°C, more preferably at the temperature of about -8°C to -10°C and quenched with acid. The reaction mass is extracted with the organic solvent like toluene and ethyl acetate. The organic layer is separated from the aqueous layer. Activated charcoal is added to the separated organic layer and the reaction mass is filtered. The filtrate is

distilled under vacuum to isolate 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II). 4-{1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) may be further recrystallized from diisopropyl ether.
Solvent used in step a) may include, but are not limited to, ethers, such as diethyl ether, dimethyl ether, diisopropyl ether, and tert-butyl methyl ether; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane, ethyl benzene; or mixtures thereof. The most preferable solvent is toluene.
Solvent used in step b) may include, but are not limited to, aromatic solvent such as benzene, toluene or xylene; ethers such as tetrahydrofuran, dibutyl ether, tert-butyl methyl ether, isopropyl ether, diethyl ether, dimethyl ether or diisopropyl ether; or mixture of aromatic solvent and ether. The most preferable solvent is toluene.
Acid used in step c) may include but are not limited to hydrochloric acid, hydrobromic acid, acetic acid and the like. The preferable acid is hydrochloric acid.
In another embodiment, the specification discloses the process for the preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) comprising:
a) reacting 2-propyl-1 H-imidazole-4,5-carboxylic acid diethyl ester (lla) with solvent;
b) adding methyl magnesium bromide prepared in toluene to the reaction mixture of step a);
c) acidifying the reaction mixture of step b);
d) isolating 4-(1~hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II).
The process for the preparation of 4-( 1 -hydroxy-1 -methylethyl)-2-propyl-1 H-imidazole-5-carboxylic acid ethyl ester (II) comprises reacting 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (lla) with solvent to obtain clear solution. The solution is cooled to a temperature at about -25°C to -35°C, more preferably to a

temperature at about -28°C to -32°C. The process further comprises adding methyl magnesium bromide prepared in toluene to the reaction mass. The reaction mass is further maintained at the temperature of about -5°C to -15°C, more preferably at the temperature of about -8°C to -10aC and quenched with acid. The reaction mass is extracted with the organic solvent like toluene and ethyl acetate. The organic layer is separated from the aqueous layer. Activated charcoal is added to the separated organic layer and the reaction mass is filtered. The filtrate is distilled under vacuum to isolate 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II). 4-(1-hydroxy-1-methylethyl)-2-propy[-1H-imidazole-5-carboxylic acid ethyl ester (II) may be further recrystallized from diisopropyl ether.
Solvent used in step a) may include, but are not limited to, ethers, such as diethyl ether, dimethyl ether, diisopropyl ether, and tert-butyl methyl ether; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane, ethyl benzene; or mixtures thereof. The most preferable solvent is toluene.
Acid used in step c) may include but are not limited to hydrochloric acid, hydrobromic acid, acetic acid and the like. The preferable acid is hydrochloric acid.
The process for preparing GRIGNARD reagent i.e. methyl magnesium bromide solution in toluene comprises replacing the solvent tetrahydrofuran completely by toluene. The process comprises taking methyl magnesium bromide in the solvent tetrahydrofuran. Nitrogen gas purging is given to the reaction mass for 3-4 hours followed by stirring. Toluene is added to the reaction mass and distilled under vacuum. The reaction mass is stripped with toluene and distilled under vacuum. Toluene is further added to the reaction mass to obtain methyl magnesium bromide solution in toluene. The advantage of using toluene over tetrahydrofuran is that, toluene is a non-polar solvent and controls the formation of methoxy impurity and dehydro impurity during the reaction.

The starting material 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (lla) can be prepared as per the process known in the art.
(n yet another embodiment, the specification discloses 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) containing less than or equal to 0.1% of methoxy impurity and dehydro impurity, more preferably less than 0.05%,
In yet another embodiment, the specification discloses use of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) for the preparation of olmesartan medoxomif (I).
The process comprises reacting 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) with 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) in presence of base and solvent to obtain ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyl-tetrazol-5-yl)-4- biphenyl methyl] imidazol-5-yl carboxylate (IV) which on hydrolysis in presence of potassium hydroxide and solvent gives its corresponding potassium salt. Potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1 -[2'-(N-triphenylmethyltetrazol-5-yl)-4- biphenyi- methyl] imidazol-5-yl carboxylic acid (VI) on reaction with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene gives trityl olmesartan medoxomil (V) which on further reaction with acid gives olmesartan medoxomil (I).
In yet another embodiment, the specification discloses process for the preparation of olmesartan medoxomil (I) comprising:
a) reacting trityl olmesartan medoxomil (V) with aqueous acid;
b) adding water to the reaction mixture of step a);
c) quenching the reaction mixture of step b) in aqueous ionic salt solution;
d) extracting the reaction mixture of step c) with the mixture of organic solvent;
e) separating aqueous layer and organic layer;
f) treating the organic layer with base;
g) adding acid to the organic layer;

h) isolating olmesartan medoxomil (I).
It has been observed that the process of the present invention yields olmesartan medoxomil (I) with low level of degradation impurity (la) and minimize the particle size of olmesartan medoxomil (I):

Addition of acetic acid during extraction process of olmesartan medoxomil (I) controls the degradation impurity (la) below 0.15% and minimize the particle size of olmesartan medoxomil (I) and yields stable olmesartan medoxomil (I).
The process comprises reacting trityl olmesartan medoxomil (V) with aqueous acid solution. The acid includes acetic acid, trifluoroacetic acid or hydrochloric acid, preferably acetic acid. The reaction mass is maintained at 25-30°C. Water is added to the reaction mass. The reaction mass is filtered and quenched with aqueous ionic salt solution i.e. sodium chloride solution. The reaction mass is further extracted with a mixture of organic solvents of type I and type II. Type I solvent includes dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, ethyl acetate, methyl acetate and isopropyl acetate and type II solvent includes methanol, ethanol, isopropanol, N,N-dimethyl formamide, N,N- dimethyl acetamide and dimethyl sulfoxide. The preferable organic solvent is mixture of dichloromethane and methanol. The organic layer is separated from organic layer. The organic layer is further washed with aqueous basic solution to minimize the degradation impurity (la) which is generated during detritylation. The base includes, but are not limited to,

carbonates like sodium carbonate, potassium carbonate and the like; bicarbonates like sodium bicarbonate, potassium bicarbonate and the like; or hydroxide like sodium hydroxide, potassium hydroxide and the like. The preferable base is bicarbonate. The organic layer is dried over sodium sulfate or magnesium sulfate, preferably sodium sulfate. Acid is added to the obtained organic mixture in the organic layer. The acid includes, but is not limited to, organic acid like C1-C3 carboxylic acid, preferably, acetic acid. The organic layer is distilled under vacuum at 35-45°C to isolate olmesartan medoxomil (I). The solid obtained is crystallized from an ester solvent selected from a group consisting of ethyl acetate, methyl acetate, ethyl lactate, methyl formate, preferably ethyl acetate to obtain pure olmesartan medoxomil (I).
During isolation of olmesartan medoxomil (I) from organic layer containing acetic acid, it minimizes the particle size of olmesartan medoxomil (I) and reduces number of times milling which also gives increase in the impurity level during stability. Olmesartan medoxomil (I) prepared according to the process of present invention has particle size D90from about 25μm to about 75μm.
The following examples illustrate certain specific aspects and embodiments of the present invention in greater detail, and are not intended to limit the scope of the invention.
REFERENCE EXAMPLE 4-{1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester
(ID
100 ml tetrahydrofuran and 5.0 gm 2-propyl-1H-irnidazole-4,5-carboxylic acid diethyl
ester (Ha) were charged in round bottom flask at 27.5±2.5°C and stirred for 10 minutes to obtain clear solution. The reaction mass was cooled at -30±2.5°C. 44.17 ml of methyl magnesium bromide solution in tetrahydrofuran was added to the reaction mass at -30±2.5°C. The temperature was raised to 0±2.5°C and the reaction mass was stirred for 1.5 hour. 10.0 gm ammonium chloride and 50 ml of water were

charged in another round bottom flask and the above reaction mass was added to it at 25±5°C. The reaction mass was extracted twice with 50 ml ethyl acetate at 25-30°C. The organic layer and aqueous layer were separated. The organic layer was washed with 225 ml saturated sodium chloride. The organic layer was distilled out to obtain 4-(1-hydroxy-1 -methylethyl)-2-propyl-1 H-imidazole-5-carboxylic acid ethyl ester (II) as oil. Purity: 73.10%
Content of Dehydro Impurity: 2.56% Content of Methoxy Impurity: 1.00%
EXAMPLE 1
Preparation of 2-propyl-1 H-imidazole-4,5-dicarbonitrile
240 ml acetonitrile, 40.0 gm diaminomalonitrile and 65.1 ml trimethyl ortho butyrate were charged to the round bottom flask and stirred at 25-30°C. The reaction mass was heated up to reflux temperature (78-83°C). The reaction mass was further distilled. 240 ml toluene was charged to the reaction mass and distilled up to the reaction mass achieves the temperature 100-110°C. The reaction mass was further distilled under mild vacuum below 80°C. The reaction mass is stripped with 40 ml diisopropyl ether at 57+2.5°C. Further, 80 ml diisopropyl ether and 80 ml hexane were added to the reaction mass and was stirred for 10 minutes at 55-60°C. The reaction mass was cooled to 25-30°C, stirred, filtered and washed with the mixture of diisopropyl ether and hexane. The wet solid was dried to obtain 2-propyl-1H-imidazole-4, 5-dicarbonitrile. Dry weight: 49.2 gm
EXAMPLE 2
Preparation of 2-propyl-1 H-imidazole-4, 5-dicarboxylic acid
320 ml concentrated hydrochloric acid and 160 ml water was charged in round bottom flask and stirred at 25-30°C. 48.0 gm 2-propyl-1H-imidazole-4, 5-dicarbonitrile was added to the above reaction mixture and heated up to reflux temperature. After the completion of the reaction, the reaction mass was cooled at

25-30°C and stirred for 1.0 hour. The solid was filtered, washed with water and the
wet solid was dried at 50-55X to obtain 2-propyl-1H-imidazole-4, 5-dicarboxylic
acid.
Dry weight: 43.2 gm
EXAMPLE 3
Preparation of 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (lla)
100 ml methylene dichloride, 1.0 ml dimethyl formamide and 10.0 gm 2-propyl-1H-imidazole-4, 5-dicarboxylic acid were added to the round bottom flask and stirred at 25-30°C. 9.2 ml thionyl chloride was added to the above reaction mass and heated up to the reflux temperature. 4.6 ml of thionyl chloride was added to the reaction mass at reflux temperature. After completion of the reaction, the reaction mass was cooled to 25-30°C. The reaction mass was quenched into 100 ml ethanol for 10-15 minutes and stirred for 2.0 hours. The reaction mass was distilled under vacuum below 45°C. 100 ml of ethyl acetate was added to the reaction mass followed by washing with 100 ml saturated sodium bicarbonate solution. The organic layer was separated followed by washing with 100 ml water. Further 1.0 gm activated charcoal was added to the separated organic layer. The reaction mass was filtered and the filtrate was distilled under vacuum. 25 ml hexane was added to the reaction mass at 40-45°C and stirred for 10 minutes. The reaction mass was cooled to 25-30°C. The solid was filtered and washed with 10 ml hexane. The wet solid was dried at 50-55°C for 6 hours to obtain 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (lla). Dry weight: 9.6 gm
EXAMPLE 4
4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester
(II) [By using methyl magnesium bromide in toluene: tetrahydrofuran (3:1)]
100 ml toluene and 5.0 gm 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (lla) were charged to the round bottom flask and stirred at 25-30°C to obtain clear solution. The reaction mass was cooled at -30±2.5°C. 132 ml methyl magnesium bromide in the mixture of toluene and tetrahydrofuran (3:1) was added to the reaction

mass and the temperature was raised to 0±5°C. 100 ml aqueous acetic acid was charged at 0±5°C in another round bottom flask and the above reaction mass was added to it. The reaction mass was stirred at 25-30°C. The organic layer and aqueous layer were separated. The aqueous layer was washed with toluene. The organic layer was washed with 50 ml saturated sodium chloride. The organic layer was separated from aqueous layer and was distilled to obtain 4-(1-hydroxy-1-methylethyl)-2-propyl-1 H-imidazole-5-carboxylic acid ethyl ester (II). The residue was dissolved in 25 ml ethyl acetate and 0.5 gm activated charcoal was charged to it. The reaction mass was stirred for 15 minutes, filtered, washed with ethyl acetate and distilled. The residue was stripped with 5,0 ml diisopropyl ether. Further 15.0 ml of diisopropyl ether was added to the reaction mass and stirred. The reaction mass was cooled at 25-30°C, stirred, filtered and washed with diisopropyl ether. The residue was dried below 45°C to obtain 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II). Purity: 98.03%
Content of Dehydro Impurity: Not detected Content of Methoxy Impurity: 0.1%
EXAMPLE 5
Preparation of 4-{1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic
acid ethyl ester (II)
250 ml toluene and 25.0 gm 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (lla) were charged to the round bottom flask and stirred at 25-30°C to obtain the clear solution. The reaction mass was cooled at -30±2.5°C. 524.3 ml methyl magnesium bromide solution in toluene was added to the reaction mass. The temperature of the reaction mass was raised to -10±2.5°C. 125 ml of concentrated hydrochloric acid and 375 ml water was added to the another round bottom flask and the above reaction mass was added to it at 0±5°C. The reaction mass was stirred at 0-50C. The organic and aqueous layers were separated. The aqueous layer was washed with 125 ml toluene. The pH of the reaction mass was adjusted to 3.0 to 3.5 by sodium hydroxide solution. The organic layer and aqueous layer were separated.

The aqueous layer was extracted twice with toluene. Organic and aqueous layers were separated. 250 ml of ethyl acetate was charged to the aqueous layer. The pH was adjusted 7.0-7.5 by using sodium hydroxide solution. The reaction mass was heated at 25-30°C and stirred. Organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with 125 ml saturated sodium chloride solution. Organic and aqueous layers were separated. 2.5 gm activated charcoal was added to the reaction mass. The reaction mass was filtered and distilled to obtain residue of 4-(1-hydroxy-1-methylethy!)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II). The residue was stripped with 25 ml diisopropyl ether. 75 ml diisopropyl ether was added to the residue and reaction mass was cooled at 25-30°C and stirred for 1.0 hour. The reaction mass was filtered and the wet solid was dried to obtain pure 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II). Dry weight: 17.6 gm Purity: 99.16%
Content of Dehydro Impurity: Not detected Content of Methoxy Impurity: Not detected
Preparation of methyl magnesium bromide in toluene:
524.3 ml of 1.5 M methyl magnesium bromide in tetrahydrofuran was taken in round bottom flask and nitrogen gas purging was given to the solution for 3-4 hours under stirring at 25-30X. 250 ml toluene was added to the solution and was distilled under vacuum below 35°C up to thick mass is obtained. The thick mass was stripped with 250 ml toluene and further 250 ml of toluene was added to it to obtain methyl magnesium bromide in toluene.
EXAMPLE 6
Preparation of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-
triphenylmethyl-tetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV)
1050 ml N,N-dimethyl acetamide and 150 gm 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylic acid ethyl ester (II) were charged In round bottom flask and

stirred to get clear solution. 107.8 gm potassium carbonate and 330.6 gm 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) were added to the above reaction mass and temperature was raised to 40-45°C. The reaction mass was cooled to 25-30°C. 6000 ml water was added to the reaction mass at 5-10°C. The reaction mass was extracted twice with 750 ml methylene dichloride and the organic and aqueous layers were separated. Organic layer was washed thrice with 750 ml water and organic layer was distilled below 50°C. 1500 ml methanol was charged to the reaction mass at 40-45°C and the solvent was distilled under vacuum below 45°C to obtain slurry, The slurry was stirred at 40-45°C for 5-10 minutes and cooled to 25-30DC. The solid mass was filtered and washed twice with 150 ml methanol. The wet material was dried to obtain ethyl 4-{ 1 -hydroxymethylethyl)-2-propyl-1 -[2'-{N-triphenylmethyl-tetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl carboxylate (IV). Dry weight: 365-395 gm
EXAMPLE 7
Preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5yl)
phenyl} phenyl} methylimidazole-5-carboxylic acid potassium salt (VI)
3000 ml isopropyl alcohol and 43.94 gm potassium hydroxide were charged in round bottom flask and the reaction mass was heated at 35-40°C to obtain clear solution. 375.0 gm ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyl-tetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl carboxylate (IV) was added to the above solution and the reaction mass was distilled under vacuum below 45°C. 3000 ml ethyl acetate was added to the thick mass and stirred for 15-20 minutes. The reaction mass was cooled at 25-30°C. The solid mass was filtered and washed twice with 375 ml ethyl acetate and suck dried to obtain wet solid of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5yl) phenyl} phenyl} methylimidazole-5-carboxyfic acid potassium salt (VI).
EXAMPLE 8
Preparation of Preparation of trityl olmesartan medoxomil (V)

3187.5 ml acetone, 104.8 gm 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene and 9.11 gm potassium iodide was charged to the round bottom flask and the reaction mass was heated at 45-50°C. 660 gm wet 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5yl) phenyl} phenyl} methylimidazole-5-carboxylic acid potassium salt (Vl).and 38.0 gm of activated charcoal was added to the above reaction mass and stirred for 15-20 minutes. The reaction mass was filtered and washed with 375 ml acetone. The filtrate was distilled under vacuum below 45°C. The reaction mass was stripped twice with 375 ml methanol. 2250 ml was added to the thick mass at 40-45°C and the reaction mass was stirred at 40-45°C. The reaction mass was cooled to 5-10°C. The solid was filtered and washed twice with 375 ml methanol. The wet solid was dried under vacuum to obtain trityl olmesartan medoxomil (V). Dry weight; 320-355 gm
Purification of Preparation of trityl olmesartan medoxomil (V)
2345 ml ethyl acetate and 335 gm trityl olmesartan medoxomil (V) were charged in the round bottom flask. The reaction mass was heated at 50-55°C to get clear solution. The reaction mass was cooled to 0-5°C till solid formation was observed. The solid was filtered and washed with 335 ml ethyl acetate and dried under vacuum to obtain pure trityl olmesartan medoxomil (V). Dry weight: 290-325 gm
EXAMPLE 9
Preparation of Olmesartan medoxomil (I)
1125 ml of acetic acid and 375 ml water was charged in round bottom flask. 200 gm trityl olmesartan medoxomil (V) was added to the above solution at 25-30°C. 400 ml water was added to the reaction mass at 25-30°C. The by product was filtered and the filtrate was quenched in sodium chloride solution at 25-30°C. The product was extracted thrice with 1000 ml mixture of methylene dichloride and methanol (9:1).

The organic layer was separated from the aqueous layer. The organic layer was washed twice with sodium bicarbonate solution. The organic layer was separated and washed thrice with 1000 ml water. The organic layer was treated with 100 gm sodium sulfate and 200 ml acetic acid was added to it. The organic layer was distilled under vacuum below 40°C. After distillation, 400 ml ethyl acetate was charged twice and distilled under vacuum till thick mass was obtained. 1200 ml ethyl acetate was added to the thick mass. The suspension was stirred at 40-45°C for 10-15 minutes. The suspension was cooled to 25-30°C and the solid was filtered, washed with 200 ml ethyl acetate to obtain wet crude solid of olmesartan medoxomil (I).
Purification of Olmesartan Medoxomil (I)
600 ml ethyl acetate and 119.5 gm of crude olmesartan medoxomil (I) were charged
in round bottom flask and the reaction mass was heated at 75-80°C. The reaction
mass was cooled at 25-30°C and stirred for 1.0 hour. The solid was filtered and
washed with 200 ml ethyl acetate. The wet solid was dried under vacuum at 45±5°C
to obtain pure olmesartan medoxomil (I).
Dry weight: 105-118.5 gm
Olmesartan degradation impurity (la): 0.08%
Purity: 99.75%
Particle size: D (0.90) = 28.82 micron

We claim:
1. A process for the preparation of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-
imidazole-5-carboxylic acid ethyl ester (II) comprising:
a) reacting 2-propyl-1H-imidazole-4,5-carboxylic acid diethyl ester (Ha) with solvent;
b) adding methyl magnesium bromide prepared in solvent selected from aromatic solvent or ether which is not tetrahydrofuran and dibutyl ether, or mixture of aromatic solvent and ether to the reaction mixture of step a);
c) acidifying the reaction mixture of step b);
d) isolating 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II).
2. A process for the preparation of 4-{1-hydroxy-1-methylethyl)-2-propyl-1H-
imidazole-5-carboxylic acid ethyl ester (II) comprising:
a) reacting 2-propyl-1H-imidazole-4, 5-carboxylic acid diethyl ester (lla) with solvent;
b) adding methyl magnesium bromide prepared in toluene to the reaction mixture of step a);
c) acidifying the reaction mixture of step b);
d) isolating 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II).

3. 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) containing less than or equal to 0,1% of methoxy impurity and dehydro impurity.
4. 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) prepared according to claim 1 and 2 , containing less than or equal to 0.1% of methoxy impurity and dehydro impurity.
5.The process of claim 1 and 2,wherein the solvent of step (a) includes ethers, such as diethyl ether, dimethyl ether, diisopropyl ether, and tert-butyl methyl ether;

hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane, ethyl benzene; or mixtures thereof.
6. The process of claim 5, wherein the solvent is toluene.
7. The process of claim 1, wherein the solvent of step (b) includes aromatic solvent such as benzene, toluene or xylene; ethers such as tetrahydrofuran, dibutyl ether, tert-butyl methyl ether, isopropyl ether, diethyl ether, dimethyl ether or diisopropyl ether; or mixture of aromatic solvent and ether.
8. The process of claim 7, wherein the solvent is toluene.
9. The process of claim 1 to 4, further comprises conversion of 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (II) for the preparation of olmesartan medoxomil (I).