FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
l. TITLE OF THE INVENTION: "A process for synthesis of olmesartan
medoxomil "
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to an improved process for the synthesis of olmesartan medoxomil.
Background and prior art:
Olmesartan medoxomil is a prodrug that is hydrolysed to olmesartan during absorption from gastrointestinal tract. Olmesartan is a selective ATI type angitensin II receptor antagonist, which is by virtue of its pharmacological properties, particularly useful in the treatment of hypertension . Chemical name for olmesartan medoxomil is 4-(l-hydroxy-l methylethyl)- 2-propyl-l-[ [ 2-(lH-tetrazol-5-yl)[l, l-biphenyl]-4-yl]methyl] -1H- imidazole-5-carboxylic acid(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester (formula I), and represented by following
structure;

Olmesartan medoxomil was first disclosed in US patent 5,616,599. The synthetic method employed is depicted in following reaction Scheme 1, where imidazole derivative condensed with dioxolyl compound, then reacted with substituted biphenyl methyl halide to obtain trityl olmesartan medoxomil which was deprotected to get crude olmesartan medoxomil.

The '599 patent also discloses two more processes in examples 78 and 79, for preparing olmesartan medoxomil. Both these processes focus on coupling reaction between the imdazole derivative and the substituted biphenyl methyl halide, condensation with dioxolyl compound followed by deprotection to isolate crude olmesartan medoxomil.
WO 2004/ 085428 describes a process for preparation of Olmesartan medoxomil which
comprises; a) 4,4-dimethyl-2-propyl-l-[4-{2-( triphenyl methyltetrazole-5-yl)
phenyl}phenyl]methyl-4,6-dihydrofuran[3,4-d] imidazole- 6-one is ring opened; b) condensing the resulted 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-{2-( triphenyl methyltetrazole-5-yl) phenyl}phenyl]methyl imidazole-5-carboxylic acid with 4-halomethyl-
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5-methyl-oxo-l,3-dioxyheterocyclopentene in presence of alkali followed by; c) deprotection to obtain Olmesartan medoxomil.
There is an ample literature available on the deprotection of trityl olmesartan medoxomil and purification of olmesartan medoxomil. There are several other processes reported in the prior art for the preparation of olmesatan medoxomil and its intermediates.
The synthesis of olmesartan described in the prior arts involves multiple reaction steps, each requiring different conditions, solvents, temperature, etc. This necessitates a discontinuous process and more than one isolation steps, which entails longer processing time, lower yields (as product is lost during each isolation step ), increased effluent load and increased solvent usage, in comparison with a continues process. Hence, there is a constant need to develop more efficient and economical synthetic route suitable for industrial scale up.
Therefore, the present inventors have now found a way of synthesizing olmesartan which avoids the multiple isolation steps used in the previously described processes.
Objects of the invention:
The object of the present invention is to provide an improved process for the synthesis of olmesartan medoxomil, which is economical and suitable for industrial application and eco friendly.
Another objective of the present invention is to provide a synthesis of trityl olmesartan medoxomil in a single reaction vessel and isolation of the product; which can be further detritylated to give olmesartan medoxomil.
Another object of the invention is to provide one-pot process for the synthesis of olmesartan medoxomil without isolating the reaction intermediates thereby avoiding the use of multiple vessels, large quantity of solvents and additional process steps, thus making the process cost effective.
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Summary of the Invention:
In accordance with the above objectives, the present invention discloses cost effective synthesis for preparation of highly pure olmesartan medoxomil, which comprises;
(a) condensing 4-(l-hydroxy-l-methylethyl)-2-propyl imidazol-5-carboxylic acid alkyl ester
of formula (II ) where R is C1-C6 alkyl,

with trityl biphenyl bromide of formula (III),

in a polar aprotic solvent in the presence of base to obtain intermediate of formula V;

(b) hydrolyzing the resulting product of formula V in step (a) where R is C1-C6 alkyl using suitable base to give hydrolysed intermediate (V) where R is H;
(c) reacting the hydrolyzed product of formula V with 4-halomethyl-5-methyl-2-oxo-l,3-dioxolene of formula (IV)
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where X is halogen selected from the group of bromo, chloro, iodo or fluoro; to obtain trityl
olmesartan medoxomil of formula VI : and
(d) deprotecting the compound of formula VI to yield olmesartan medoxomil of formula I.
The above process steps are carried out conveniently in a single pot without changing the reaction vessel.
Detailed description of the invention
While the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention describes a more practical, economical and efficient synthesis for the preparation of highly pure olmesartan medoxomil. This process is particularly advantageous in comparison with known methods because, the reaction is carried out without isolating the intermediates formed by the preceding step, thus reducing the impurity formed and increasing yield and purity of the product. The process of the present invention eliminates the risk of handling hazardous chemicals, enhanced cost associated with multiple reactors, reaction time and cleanup thus making the process more economical and industrially viable.
According to one aspect of the present invention there is provided a method of synthesizing olmesartan medoxomil, which comprises;
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(a) condensing 4-(l-hydroxy-1-methylethyl)-2-propyl imidazol-5-carboxylic acid alkyl ester of formula (II ) where R is C1-C6 alkyl, with trityl biphenyl bromide of formula (III) to obtain a compound of formula V, in a polar aprotic solvent in the presence of base to obtain


intermediate 1;

(b) hydrolyzing the resulting intermediate (v) of step (a) using suitable base where R is C1- C6 alkyl using suitable base to give hydrolysed intermediate (v) where R is H;

( c ) reacting the hydrolyzed product of step (b) with 4- halomenthyl-5-methyl-2oxo-1,3-dioxolene of formula (IV) to obtain (intermediate 2 ) trityl olmesartan medoxomil of formula VI; and

(d) deprotecting the trityl olmesartan medoxomil (VI) to yield olmesartan medoxomil.

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It is an important feature of the present invention that; steps (a), (b),(c) and (d) are carried out in a single reaction vessel without isolating the intermediates formed

[Brackets indicate intermediates that could be isolated but are not isolated in the integrated process].
The overall synthetic process of the present invention is shown as above in Scheme 2 which comprises steps (a), (b) ,(c) and (d) that are carried out in a single reaction vessel.
In step ( a), 4-(l -hydroxy- l-methylethyl)-2-propyl imidazol-5-carboxylic acid alkyl ester of formula (II) is reacted with trityl biphenyl bromide of formula (III) in a polar aprotic solvent in the presence of a base to yield alkyl-4-(l-hydroxy-1-methylethyl)-2-propyll-{4-[2-(trityltetazol-5-yl)phenyl]phenyl}- methylimidazol carboxylate of formula V ( intermediate 1), wherein R is an alkyl group selected from C1 to C6 alkyl group; preferably ethyl group.
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The polar aprotic solvents used in step a) of the process comprises at least one selected from acetone, tetrahydrofuran, methyl ethyl ketone, acetonitrile, ethyl acetate, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide and mixtures thereof , preferably dimethyl formamide and dimethyl acetamide.
Preferred bases for use in step a) of process according to the present invention are inorganic bases such as alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides or organic bases such as tertiary amines.
The reaction is carried out at a temperature from 25-30°C to an elevated temperature such as the reflux temperature of the solvent used, preferably from 40 to 65°C.
In step (b) hydrolysis of Formula V (intermediate 1) is carried out using various inorganic bases such as alkali metal hydroxides, carbonates, alkoxides or organic bases such as tertiary amines; preferably potassium tertiary butoxide and diisopropylethyl amine.
In step(c) the hydrolyzed compound of formula V (intermediate 1), is further condensed with 4-halomethyl- 5- methyl- 2- oxo-1, 3-dioxolene of formula (IV) wherein X is halogen selected from bromo, chloro, iodo and fluoro preferably bromo. The reaction mass is then neutralized with a suitable acid to give trityl olmesartan medoxomil of formula VI (intermediate 2, which is not isolated). The acid used for neutralization is selected from carboxylic acids for example formic acid, acetic acid or inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid.
The reaction mass containing trityl olmesartan medoxomil is treated with an appropriate acid which comprises at least one selected from organic carboxylic and sulfonic acids such as formic acid, oxalic acid, acetic acid, methanesulfonic acid, p-toluene sulfonic acid, trimethyl acetic acid or trifluoroacetic acid and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, pivalic acid or phosphoric acid preferably hydrochloric acid and acetic acid. The pH of the reaction mass is neutralized with organic or inorganic bases. Olmesartan medoxomil is then isolated from the reaction mixture by conventional means. If required it may be further purified from suitable solvent or solvent mixture.
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In another aspect of the present invention, trityl olmesartan medoxomil is prepared in single reaction vessel as described above and isolated by quenching in water. The crude trityl olmesartan medoxomil can be purified further from suitable solvent or solvent mixture.
The trityl olmesartan medoxomil is then deprotected by the methods described above to yield olmesartan medoxomil.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples Example 1
Preparation of olmesartan medoxomil.
To dimethyl acetamide (300 ml ) was added of 4-(l-hydroxy-l-methylethyl)-2-propyl imidazol-5-carboxylic acid ethyl ester (50 gms) and powdered sodium hydroxide (26 gms). To this, 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (135 gms ) was charged at 45-50°C. The contents were stirred for 5 hours at 45-50°C. Charged diisopropylethyl amine (100 ml) to the reaction mass at 40-45°C. A solution of 5-methyl-2-oxo-l, 3-dioxane-4-yl) methyl chloride (80 gms ) diluted with dimethyl acetamide (160 ml) was slowly added to the reaction mass at 40-45°C over a period of 1 hour. The contents were heated to 60-65°C and maintained for 4 hours. The reaction mass was then cooled to 30-35°C and was neutralized with concentrated hydrochloride acid. Reaction mass was filtered to remove inorganic impurities, charcoalized by using charcoal (10 gms) and was stirred for 30 minutes at 40-45°C. The reaction mass was filtered over hyflo. The clear filtrate was acidified with hydrochloric acid (100 ml) slowly at 25-30°C. The contents were stirred at 60°C for 1 hour. The reaction mass was chilled to 0-5°C and was filtered to remove tritanol. The reaction mass was concentrated under reduced pressure. ,The residue was quenched with water ( 500ml ) .neutralized with base and extracted in dichloromethane ( 500 ml ).The clear dichloromethane extract was then concentrated under reduced pressure, stripped off with acetone. The residue thus obtained was isolated from the acetone (250 ml) to give 55 gms of the title compound. Chromatogrphic purity- > 99%
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Example 2
Preparation of olmesartan medoxomil.
To dimethyl acetamide (600 ml) was added of 4-(l -hydroxy- l-methylethyl)-2-propyl imidazol-5-carboxylic acid ethyl ester (100 gms) and powdered potassium hydroxide (50 gms). To this was charged 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (270 gms ) at 45-50°C. The contents were stirred for 5 hours at 45-50°C. Charged diisopropylethyl amine ( 200 ml ) to the reaction mass at 40-45°C. To this was slowly added solution of 5-methyl-2-oxo-l,3-dioxane-4-yl) methyl chloride (160 gms )diluted with dimethyl acetamide (320 ml) at 40-45°C over a period of 1 hour. The contents were heated to 60-65°C and maintained for 4 hours. The reaction mass was then cooled to 30-35°C. and was neutralized with concentrated hydrochloride acid. Reaction mass was filtered to remove inorganic impurities. Reaction mass was charcoalized by using charcoal (20 gms) and was stirred for 30 minutes at 40-45°C. The reaction mass was filtered over hyflo. The clear filtrate was acidified with hydrochloric acid (200 ml) slowly at 25-30°C. The contents were stirred at 60°C for 1 hour. The reaction mass was chilled to 0-5°C and was filtered to remove tritanol. The reaction mass was concentrated under reduced pressure. The residue was quenched with water (1000 ml),neutralized with base and extracted in dichloromethane ( 1000 ml ).The clear dichloromethane extract was then concentrated under reduced pressure, stripped off with acetone. The residue thus obtained was isolated from the acetone ( 500 ml) to give 110 gms of the title compound. Chromatogrphic purity- > 99%
Example 3
Preparation of olmesartan medoxomil.
To dimethyl acetamide (800 ml) was added of 4-(l -hydroxy-l-methylethyl)-2-propyl
imidazol-5-carboxylic acid ethyl ester (100 gms) and powdered potassium carbonate ( 200
gms). To this was charged of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (300 gms ) at
45-50°C. The contents were stirred for 8-10 hours at 45-50°C. Insolubles were filtered. The
contents were cooled to 5-10°C. Charged potassium tertiary butoxide (100 gms ) below
45°C. The reaction was maintained at 40- 45°C for 3 hrs. To this was slowly added 5-methyl-
2-oxo-l, 3-dioxane-4-yl) methyl chloride at 40-45°C over a period of 1 hour. The contents
were heated to 60-65°C and maintained for 4 hours. The reaction mass was then cooled to
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30-35°C and was neutralized with concentrated hydrochloride acid. Reaction mass was filtered to remove inorganic. Reaction mass was charcoalized by using charcoal (10 gms) and was stirred for 30 minutes at 40-45°C. The reaction mass was filtered over hyflo. The clear filtrate was acidified with hydrochloric acid (100 ml) slowly at 25-30°C. The contents were stirred at 60°C for 1 hour. The reaction mass was chilled to 0-5 °C and was filtered to remove tritanol. The reaction mass was concentrated under reduced pressure. The residue was quenched with water ( 500 ml),neutralized with base and extracted in dichloromethane ( 500 ml ).The clear dichloromethane extract was then concentrated under reduced pressure, stripped off with acetone. The residue thus obtained was isolated from the acetone (250 ml) to give 55 gms of the title compound. Chromatogrphic purity- > 99%
Example 4
Preparation of trityl olmesartan medoxomil { 4-(l-hydroxy-lmethylethyl)- 2-propyl-l-[ [ 2-(1H- trityltetrazol-5-yl)[l, l-biphenyl]-4-yl]methyl] -1H- imidazole-5-carboxylic acid(5-methyl-2-oxo-l,3-dioxol-4-yl) methyl ester }.
To dimethyl acetamide (300 ml ) was added of 4-(l-hydroxy-l-methylethyl)-2-propyl imidazol-5-carboxylic acid ethyl ester (50 gms) and powdered potassium hydroxide ( 25 gms). To this was charged of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (135 gms ) at 45-50°C. The contents were stirred for 5 hours at 45-50°C. Charged diisopropylethyl amine ( 100 ml ) to the reaction mass at 40-45°C. To this was slowly added solution of 5-methyl-2-oxo-l,3-dioxane-4-yl) methyl chloride (80 gms )diluted with dimethyl acetamide (160 ml) at 40-45 °C over a period of 1 hour. The contents were heated to 60-65 °C and maintained for 4 hours. The reaction mass was then cooled to 30-35°C. and was neutralized with concentrated hydrochloride acid. Reaction mass was filtered to remove inorganics. Reaction mass was charcoalized by using charcoal (10 gms) and was stirred for 30 minutes at 40-45°C. The reaction mass was filtered over hyflo. The clear filtrate was quenched with purified water( 200 ml )at 25-30°C over a period of 3-4 hours. The contents were stirred at 25-30°C for 30 minutes. Crude trityl olmesartan medoxomil was isolated by filtration, slurried in water (500 ml), centrifuged and dried under reduced pressure at 45-50°C.
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Example 5
Purification
Crude trityl olmesartan medoxomil 140gm was dissolved in 1120 ml of ethyl acetate,
distilled upto 560 ml, chilled to 0-5°C . Isopropyl acetate (70 ml) and methanol (35 ml )were
charged . The contents were stirred at 0-5°C for 30 minutes. Pure trityl olmesartan
medoxomil was isolated by filtration and was dried under reduced pressure at 45-50°C to
give 110 gms of title compound.
Purity by HPLC - > 99%.
Example 6
Preparation of olmesartan medoxomil
To 75 % aqueous acetic acid (1000 ml) was slowly added trityl olmesartan medoxomil (110
gms )[ prepared as described in example 5] at 25-30°C. The contents were stirred at 60°C
for 1 hour. The reaction mass was chilled to 0-5°C and was filtered to remove tritanol. The
reaction mass was concentrated under reduced pressure. The residue was quenched with
water (500 ml), neutralized with base and extracted in dichloromethane (500 ml).The clear
dichloromethane extract was then concentrated under reduced pressure, stripped off with
acetone. The residue thus obtained was isolated from the acetone (250 ml) to give 55 gms of
the title compound.
Chromatogrphic purity- > 99%
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We claim,
1. A process for preparation of olmesartan medoxomil of formula I

comprising the steps of: a) condensing 4-(l-hydroxy-l-methylethyl)-2-propyl imidazol-5-carboxylic acid alkyl ester of formula (II)


where R is C1-C6 alkyl with trityl biphenyl bromide of formula (III).

to obtain intermediate of formula V in a polar aprotic solvent in the presence of
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base, where R is C1-C6 alkyl;


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6. The process as claimed in any of the preceding claims 1 to 5, wherein the said reaction is carried out at temperature ranges from 25 to reflux temperature of the solvent used.
7. The process as claimed in claims 1, 2 &3 wherein the base used in step (b) is selected from the group consisting of inorganic bases such as alkali metal hydroxides, carbonates, alkoxides or organic bases such as tertiary amines.
8. The process as claimed in claim 1, 2, and 3, wherein the said acid in step (c) is selected from carboxylic acids for example formic acid, acetic acid or inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid.
9. The process as claimed in claim 1 and 2, wherein said acid in step (d) is selected from the group consisting of organic carboxylic acids like formic acid, oxalic acid, acetic acid, trimethyl acetic acid or trifluoroacetic acid; sulfonic acids such as methanesulfonic acid, p-toluene sulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, pivalic acid or phosphoric acid preferably hydrochloric acid and acetic acid.
10. A process for preparation of olmesartan medoxomil is substantially as described herein with reference to the foregoing examples 1 to 6.


Abstract:
Disclosed herein is one-pot process for preparation of olmesartan medoxomil, which comprises, condensation of 4-(l-hydroxy-l-methylethyl)-2-propyl imidazol-5-carboxylic acid alkyl ester with trityl biphenyl bromide in a polar aprotic solvent to obtain an intermediate of formula V; hydrolyzing the said intermediate and reacting the hydrolyzed product of formula V with 4-halomethyl-5-methyl-2-oxo-l,3-dioxolene to obtain trityl olmesartan medoxomil; and deprotecting the same to yield olmesartan medoxomil.
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