1 PROCESS FOR PREPARING TRITYL OLMESARTAN MEDOXOMIL AND
OLMESARTAN MEDOXOMIL
5 Technical field
The present invention relates to an improved process for the synthesis of trityl olmesartan medoxomii and olmesartan medoxomil.
10 Background and prior art
Olmesartan medoxomil is a prodrug that is hydrolysed to otmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 type angiotensin II receptor antagonist, which is by virtue of its pharmacological properties, particularly useful in the 15 treatment of hypertension. The chemical name for olmesartan medoxomil is 4-(1-hydroxy-v 1-methylethyl)-2-propyl-1-[[2-(1H4etrazol-5-yl)[1,1-biphenylH-yl]methyl]-1H-imidazole-5 carboxylic acid(5-methyl-2-oxo-1,3-dioxol-4-yl)methyI ester, and is represented by the following structure (formula I).


20

Olmesartan medoxomil was first disclosed in US patent 5,616,599. The synthetic method employed is depicted in the following reaction Scheme 1, where an imidazole derivative is condensed with a dioxolyl compound, then reacted with a substituted biphenyl methyl


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hafide to obtain trityJ olmesartan medoxomil which is then deprotected to obtain crude olmesartan medoxomil.
Scheme 1

The '599 patent also discloses a process for preparing olmesartan medoxomil in examples 10 18(a) and 78. The process focuses on the coupling reaction between the imidazole derivative and the substituted biphenyl methyl halide, the condensation with the dioxolyl compound and the subsequent deprotection to isolate crude olmesartan medoxomil. Example 18(a) describes the coupling reaction which involves the use of a strong base (sodium hydride). Such strong bases are hazardous and difficult to handle on an industrial 15 scale. The coupling reaction is conducted at a temperature of 60°C. The reaction

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conditions in the coupling step are such that impurities are formed which require the coupled intermediate to be isolated and purified. More specifically, the. coupled intermediate is isolated as a residue which requires purification by column chromatography. The chromatographed product undergoes further isolation steps 5 involving crystallisation in diisopropyl ether. The yield of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyM r{4-[2-(trityltetra2ol-5-yl)phenyl]phenyl}methyl imidazole-5-carboxytate prepared according to example 18(a) is 238.4% w/w. In example 78(a), the product of example 18 is used to produce lithium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetra2ol-5-yl)phenyf]phenyl}-methyirmidazo(e-5-carboxylate. The yield of trityl olmesartan medoxomil 10 prepared according to the process in example 78 is 97.6% w/w. The overall yield of the example 18(a) and example 78 processes is 230% w/w. The overall process is hazardous, tedious, time consuming and involves many steps, including isolation steps.
WO 2004/085428 describes a process for the preparation of olmesartan medoxomil which
15 comprises: a) ring opening the 4,4-dimethyl-2-propyM-[4-{2-(tripheriyf methyltetrazole-5-
yl)phenyl}phenyl]methyl-4,6-dihydrofuran[3,4-d]imidazole-6-one; b) condensing the
resulting 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-{2-(tripheny]methyltetrazole-5-
yl)phenyi}phenyl]methylimidazole-5-carboxylic acid with 4-halomethyl-5-methyl-oxo-1,3-dioxyheterocyclopentene in the presence of alkali; followed by c) deprotection to obtain 20 olmesartan medoxomil.
There is ample literature available on the deprotection of trityl olmesartan medoxomil and purification of olmesartan medoxomil. There are also several other processes reported in the prior art for the preparation of olmesatan medoxomil and its intermediates.
25
The synthesis of olmesartan described in the prior art involves multiple reaction steps, each requiring different conditions, solvents, temperature, etc. This necessitates a discontinuous process and more than one isolation step, which entail longer processing time, lower yields (as product is lost during each isolation step), increased effluent load
30 and increased solvent usage, in comparison with a continuous process. Hence, there is a

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4 constant need to develop more efficient and economical synthetic routes suitable for industrial scale up.
The present inventors have now found a way of synthesizing trityl olmesartan medoxomil 5 and olmesartan medoxomil which avoids the multiple isolation steps used in the previously described processes.
Objects of the invention
10 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 is eco or environmentally friendly.
Another objective of the present invention is to provide a synthesis of trityl olmesartan 15 medoxomil in a single reaction vessel, followed by isolation of the product which can be further detritylated to give olmesartan medoxomil.
Another object of the invention is to provide a one-pot process for the synthesis of olmesartan medoxomil which is carried out without isolating the reaction intermediates 20 thereby avoiding the use of muftiple vessels, large quantity of solvents and additional process steps, thus making the process cost effective.
Summary of the Invention
25 In accordance with the above objectives, the present invention provides a cost effective synthesis of highly pure olmesartan medoxomil.
The synthesis involves an initial coupling of a 4-(1-hydroxy-1-methylethy])-2-propyl-
imidazol-5-carboxylic acid alkyl ester with a trityl biphenyl halide using conditions that
30 minimise the formation of impurities. The product of the coupling reaction is pure enough
to be used in the subsequent synthesis of olmesartan medoxomil without the need for

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isolation and purification of. the coupled product, or of intermediates formed in the subsequent synthesis to prepare olmesartan medoxomii.
In the context of the present invention, the term "one-pot" is intended to mean that the 5 steps referred to are carried out in a single reaction vessel. In the context of the present invention, the term "isolated" is intended to mean that the product/intermediate referred to is not separated as a solid. Thus, the various steps may be carried out in more than one reaction vessel but the intermediate(s) are not necessarily isolated. Alternatively, all the steps may be carried out in a single reaction vessel and none of the intermediates is 10 isolated.
According to a first aspect of the present invention, there is provided a process for the preparation of trityl olmesartan of formula (VI)

(VI)
comprising (a) condensing 4-(1-hydroxy-1-methylethyl)-2-propyl-imida2ol-5-carboxylic acid alkyl ester of formula (II) 20


ROO

wherein R is C1-C6 alkyl with trityl biphenyl bromide of formula (ill)

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(I"

in the presence of a polar aprotic sofvent and a base selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides, and tertiary amines to obtain a compound of formula V,
'' "'%■' ° H". '■&'' '^^^ ^?1 .■C%-

b) deesterifying the compound of formula (V) with a base; and c) reacting the product of 10 step (b) with 4-halomethyl-5-methyl-2-oxc-i,3-dioxolene of formula (IV),

15 wherein X is halogen selected from F or CI or Br or 1, to obtain trityl olmesartan medoxomil of formula (VI).
The process is carried out in the presence of a mild base, such as alkali metal carbonates,
alkali metal hydroxides, alkali metal alkoxides, and tertiary amines. The prior art
20 processes, for example Example 18(a) of US '599, are carried out in the presence of

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7 stronger bases, such as sodium hydride. It has surprisingly been discovered that the use of a mild base leads to the formation of fewer impurities. Thus, there is no need for intermediates in the process to be isolated and purified before being used in the next reactive step. Suitably, the alkali metal carbonate is potassium carbonate. Optionally, the 5 alkali metal hydroxide is sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
It will be appreciated that other trityl biphenyl halides may be used in the process of the present invention, for example trityl biphenyl chloride and trityl biphenyl iodide. 10
In an embodiment, R is a straight or branched chain Ci to C6 alkyl group. For example, R' may be ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl or the tike. Preferably, R is ethyl.
15 In an embodiment, the polar aprotic solvent in step (a) is selected from the group consisting of acetone, tetrahydrofuran, methyl ethyl ketone, acetonitrile, ethyl acetate, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide and mixtures thereof. Preferably, the polar aprotic solvent is dimethyl acetamide.
20 It has also surprisingly been found that the temperature of the reaction mixture in step (a) can affect the formation of impurities. The step (a) process may be carried out at a temperature ranging from 40°C to 55°C, preferably 40°C to 50°C, most preferably 45°C to 50°C. The prior art processes, for example Example 18(a) are carried out at higher temperatures, for example 60°C.
25
The base used in step (b) may be selected from the group consisting of inorganic bases and organic bases. For example, the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates and alkali metal alkoxides. Suitably, the alkali metal carbonate is potassium carbonate. Optionally, the alkali metal hydroxide is
30 sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. Suitably, the organic base is a tertiary amine.

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If necessary, following the coupling in step (c), the reaction mass is neutralized with a suitable acid to obtain trityl olmesartan medoxomil (formula (VI)). The acid may be selected from the group consisting of carboxylic acids and inorganic acids. In an 5 embodiment, the carboxylic acid is formic acid or acetic acid, preferably acetic acid. In another embodiment, the inorganic acid is hydrochloric acid, hydrobromic acid or sulfuric acid, preferably hydrochloric acid.
In an embodiment, steps (a), (b) and (c) are carried out in a single reaction vessel. 10
In another embodiment, neither one of the products of steps (a) or (b) is isolated.
According to another aspect of the present invention, there is provided a process for the preparation of olmesartan medoxomil of formula I 15

comprising preparing trityl olmesartan medoxomil of formula (VI) according to the process described above and d) deprotecting the trityl olmesartan medoxomil (VI) to yield olmesartan 20 medoxomil (I).The overall yield of this process is 240% w/w.
In an embodiment, steps (a), (b), (c) and (d) are carried out in a single reaction vessel.
In another embodiment, steps (a), (b) and (c) are carried out in a single reaction vessel. 25 The trityl olmesartan medoxomil of formula (VI) may be isolated prior to deprotection in

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. 9
step (d). The-isolated trityl olmesartan medoxomil of formula (VI) may be purified prior to deprotection in step (d).
In an embodiment, neither one of the products of steps (a) or (b) is isolated as a solid. 5
In a further embodiment, none of the products of steps (a), (b) or (c) is isolated as a solid.
Deprotection of the trityl olmesartan medoxomil may be carried out according to any conventional method.
10
In an embodiment, the deprotection is carried out in the presence of an acid. Suitable acids are selected from the group consisting of organic carboxyiic acids, sulfonic acids, and inorganic acids. The organic carboxyiic acid may be formic acid, oxalic acid, acetic acid, trimethyl acetic acid or trifluoroacetic acid, preferably acetic acid. The sulfonic acid
15 may be methanesulfonic acid or p-toluene sulfonic acid. The inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, pivalic acid or phosphoric acid, preferably hydrochloric acid.
25 comprising condensing 4-(1-hydroxy-1-methylethyI)-2-propyl-imidazol-5-carboxylic acid alkyi ester of formula (II)
According to another aspect of the present invention, there is provided a process for the 20 preparation of a compound of formula (V)


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wherein R is CrC6 alkyl with trityl biphenyl bromide of formula (III)


5
in the presence of a polar aprotic solvent and a base selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides, and tertiary amines to obtain the compound of formula V. The product of this coupling reaction may be used to produce trityl olmesartan medoxomil and olmesartan medoxomil according to any 10 conventional method. The product of the coupling reaction need not be isolated before being subjected to further steps to produce trityl olmesartan medoxomil or ofmesartan medoxomil.
The above process steps are carried out conveniently in a single pot without changing the 15 reaction vessel.
Detailed description of the invention
The invention will now be described in detail in connection with certain preferred and 20 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 trityl olmesartan medoxomil and olmesartan medoxomil.

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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, 5 reduces enhanced cost associated with multiple reactors, and reduces reaction time and cleanup, thus making the process more economical and industrially viable.
In an embodiment, the present invention provides a method of synthesizing olmesartan medoxomil, which comprises: (a) condensing 4-(1-hydroxy-1-methylethyl)-2-propyl 10 imidazol-5-carboxylic acid alkyl ester of formula (II) where R is Ci-C6 alkyl, with trityl biphenyl bromide of formula (III) in the presence of a polar aprotic solvent and a mild base to obtain a compound of formula V (a first intermediate),
Br N-N


15


(V) (b) deesterifying the resulting intermediate (V) of step (a) to obtain a third intermediate;

20

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(c) reacting the product of step (b) with 4-halomethy!-5-methyl-2-oxol1J3-dioxolene of formula (IV) to obtain trityf olmesartan medoxomif (a third intermediate) of formula VI;



(VI)

10

and (d) deprotecting the trityl olmesartan medoxomil (VI) to yield olmesartan medoxornil.
In a most preferred embodiment, steps (a), (b), (c) and optionally (d) are carried out in a single reaction vessel and without isolating the intermediates formed.
In an embodiment, the process of the present invention for preparing olmesartan medoxomil may also be depicted as in Scheme 2.
Scheme 2

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[Brackets indicate intermediates that could be isolated but are not isolated in the integrated process].
5 The overall synthetic process for the preparation of olmesartan medoxomil of the present invention comprises steps (a), (b), (c) and 99%
Example 2
Preparation of olmesartan medoxomil
25
To dimethyl acetamide (600 ml) was added 4-(1-hydroxy-l-methyiethyJ)-2-propyI imidazol-5-carboxylic acid ethyl ester (100 gms) and powdered potassium hydroxide (50 gms). To this was charged 4-[2-(trityltetrazo!-5-yl)phenyI]benzyl bromide (270 gms) at 45-50°C. The contents were stirred for 5 hours at 45-50°C. Diisopropylethyl amine (200 ml) was charged
30 to the reaction mass at 40-45°C. To this was slowly added a solution of 5-methyl-2-oxo-1,3-dioxane-4-y!)methyl chloride (160 gms) diluted with dimethyl acetamide (320 ml) at 40-

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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. The reaction mass was filtered to remove inorganic
impurities. The reaction mass was charcoalized using charcoal (20 gms) and was stirred
5 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 mi), neutralized with base and extracted in dichloromethane
10 (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 mJ) to give 110 gms of the title compound.
Chromatogrphic purity- > 99%
15 Example 3
Preparation of olmesartan medoxomil
To dimethyl acetamide (800 ml) was added 4-(1-hydroxy-1-methylethyl)-2-propyl imidazol-5-carboxyiic acid ethyl ester (100 gms) and powdered potassium carbonate (200 gms). To
20 this was charged 4-[2-(trityltetrazo!-5-yl)phenyI]benzyl bromide (300 gms) at 45-50°C. The contents were stirred for 8-10 hours at 45-50°C. The insolubles were filtered. The contents were cooled to 5-10°C. Potassium tertiary butoxide (100 gms) was charged at a temperature below 45°C. The reaction was maintained at 40-45°C for 3 hrs. To this was slowly added 5-rnethy!-2-oxo-1,3-dioxane-4-yl) methyl chloride at 40-45°C over a period of
25 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. The reaction mass was filtered to remove inorganics. The reaction mass was charcoalized 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
30 (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

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18 concentrated under reduced pressure. The residue was quenched with water (500 ml), neutralized with base and extracted in dichloromethane (500 ml).The clear dich/orometnane 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 5 of the title compound. Chromatogrphic purity- > 99%
In examples 1 to 3, filtration steps are involved, but the intermediates in the process are not isolated as solids. The filtration steps are used to remove insoluble by-products and impurities; the intermediates remain in solution as the filtrate. The olmesartan medoxomil 10 is isolated as a solid in the final step. These examples exemplify the embodiment in which none of the intermediates (first, second or third) is isolated.
Example 4
Preparation of trityl olmesartan medoxomil 15
To dimethyl acetamide (300 ml) was added 4-(1-hydroxy-1-methylethyl)-2-propyl imidazol-
5-carboxylic acid ethyl ester (50 gms) and powdered potassium hydroxide (25 gms). To
this was charged 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. Diisopropylethyl amine (100 ml) was charged
20 to the reaction mass at 40-45°C. To this was slowly added a solution of 5-methyl-2-oxo-
1,3-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. The reaction mass was filtered to remove inorganics. The
25 reaction mass was charcoalized 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 m!)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.
30
Example 5

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19 Preparation of trityl olmesartan medoxomil
To dimethyl sulphoxide (800 mi), sodium hydroxide powder (50 gms) was added under nitrogen atmosphere and stirred at 20-25°C for 10 minutes. To this, 4-(l-hydroxy-1-5 methylethy]>2-propy1-imidazole-5-ethyl carboxylate (100 gms) was added at 20-25°C. 5-(4'-brornomethyi-biphenyl)-2-y!-1 -trityl tetrazole (270 gms) was added slowly at 20-25°C, and the reaction mass was stirred at20-25°C for 12 hours. Further 10% sodium hydroxide solution (100 ml) was added to the reaction mass at 20-25°C. The temperature of the reaction mass was raised to 40-45°CJ the contents stirred at 40-45°C for 2 hours and 5-
10 methyl^-oxo-I.S-dioxane^ylJmethyl chloride (160 gms) was added slowly at 45-50°C over a period of 45 minutes. The contents were stirred at 45-50°C for 2 hours. The reaction mass was then cooled to 0-5°C, stirred for 1 hour at 0-5°Ct filtered and slurried in water (1.0 It) at 40-45°C for 1 hour, filtered at 40°C and dried at 40°C. To the dried material, ethyl acetate (2.5 It) was added, heated to 50-55°C for complete dissolution, ethyl
15 acetate was distilled off to 1.0 It stage under vacuum at 45-50°C. The contents were cooled to 0-5°C, stirred at 0-5°C for 3 hours, filtered, washed with chilled methanol (100 ml) and dried under vacuum at 40-45°C to give 250 gms of the title compound. Purity by HPLC : > 99%
20 in examples 4 and 5, filtration steps are involved, but the first and second intermediates in the process are not isolated as solids. The filtration steps are used to remove insoluble by-products and impurities; the intermediates remain in solution as the filtrate. The trityl olmesartan medoxomil is isolated as a solid in the final step. These examples exemplify the embodiment in which neither one of the first or second intermediates is isolated. The
25 isolated trityl olmesartan medoxomil is taken on for purification, as exemplified in example 6.
Example 6 Purification 30

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Crude trityi olmesartan medoxomil (140 gms) was dissolved in 1120 ml-of ethyl acetate, distilled up to 560 ml and chilled to 0-5°C . Isopropyl acetate (70 ml) and methanol (35 ml) were charged to the reaction mass. The contents were stirred at 0-5°C for 30 minutes. Pure trityi olmesartan medoxomil was isolated by filtration and was dried under reduced 5 pressure at 45-50°C to give 110 gms of the title compound. Purity by HPLC - > 99%.
Example 7
Preparation of olmesartan medoxomil
10 To 75 % aqueous acetic acid (1000 ml) was slowly added trityi 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 filtered to remove tritanol. The reaction mass was concentrated under reduced pressure. The residue was quenched with water (500 ml), neutralized with a base and extracted in dichloromethane (500 ml).
15 The clear dichloromethane extract was then concentrated under reduced pressure and 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%
It will be appreciated that the invention may be modified within the scope of the appended 20 claims.

21
CLAIMS
1, A process for the preparation of trityl oimesartan medoxomil of formula (VI)

comprising (a) condensing 4-(1-hydroxy--1-methylethyI)-2-propyl-imidazol-5-carboxyIic acid alkyl ester of formula (II)
10
OR
On
wherein R is CfCa alkyl with trityl biphenyl bromide of formula (III)

in the presence of a polar aprotic solvent and a base selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides, and tertiary amines to obtain a compound of formula V,

AMENDED SHEET 1 ived at the EPO on Dec 15,200817:53:36. Page 4 of 15

Si s/12^:608

^$^&lWM£l ™ luonl«»< ^-^^™^^^1VU, U^imUWJOU --—
-m^S J;A^#^V?^^
" SKifflU®; jp|||^i| ' |SgKg7|^2|

(V)
b) deesterifying.the compound of formula (V) with a base; and c) reacting "the product of-5 step (b) with 4~halomethy!-5-methyI"2-oxo-1,3-dioxolene of formula (IV),
{JV>
10 wherein X js halogen selected from. F or CI or Br or I, to obtain trity! olmesartan medoxomil of formula (VI), wherein neither one of the products of steps