WO2012055994A1

WO2012055994A1 - Process for preparing olmesartan medoxomil

Info

Publication number: WO2012055994A1
Application number: PCT/EP2011/068963
Authority: WO
Inventors: Iban JOVÉ MARTÍ; Francisco Marquillas Olondriz
Original assignee: Interquim, S.A.
Priority date: 2010-10-29
Filing date: 2011-10-28
Publication date: 2012-05-03
Also published as: AR083523A1; UY33691A; TW201217363A

Abstract

The invention relates to a process for preparing olmesartan medoxomil by the reaction of sodium 5-(1-hydroxy-1-methylethyl)-2-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylate, obtained by the reaction between ethyl 5-(1-hydroxy-1-methylethyl)-2-propyl-3H-imidazole-4- carboxylate from and 5-(4'-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole followed by saponification, with 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one, deprotection and purification.

Description

Process for preparing olmesartan medoxomil

This invention relates to a process for preparing olmesartan medoxomil (VI). Olmesartan medoxomil (VI) chemically corresponds to (5-methyl-2-oxo-2/-/- 1 ,3-dioxol-4-yl)methyl 4-(2-hydroxypropan-2-yl)-2-propyl-1 -({4-[2-(2H-1 ,2,3,4- tetrazol-5-yl)phenyl]phenyl}methyl)-1 /-/-imidazole-5-carboxylate and it is an Angiotensin II Receptor Blocker. It is used in clinical practice as an antihypertensive. Its structural formula is:

(VI)

BACKGROUND ART

Patent US5616599 describes the synthesis of ethyl 5-(1 -hydroxy-1 - methylethyl)-2-propyl-3-[2'-(1 -trityl-1 /-/-tetrazol-5-yl)biphenyl-4-ylmethyl]-3/-/- imidazole-4-carboxylate, with formula (III)

as an intermediate product in the synthesis of olmesartan medoxomil (VI).

Synthesis of (III) is carried out by the alkylation of the imidazole nitrogen of the compound of formula (I)

(I) with the compound of formula (II)

into Ν,Ν-dimethylformamide using sodium hydride as a base. The purification process comprises several separations with water and ethyl acetate, purification by column chromatography and a final crystallisation. The yield is of 80%.

The article published in J. Med. Chem. (1996), 39(1 ), 323-38 also describes the synthesis of (III) by the same reaction into Ν,Ν-dimethylacetamide using potassium fe/f-butoxide as a base. The purification process also comprises some separations with water and ethyl acetate, purification by column chromatography and a final crystallisation. The yield is of 80%. Similarly, patent application WO2008043996 describes the reaction also in N,N- dimethylacetamide, but using sodium hydroxide, potassium hydroxide or potassium carbonate as a base. The yield in this step is not mentioned because olmesartan medoxomil is synthesised without isolating any intermediate products.

The need for using solvents that are less toxic than Ν,Ν-dimethylacetamide or Ν,Ν-dimethylformamide in the synthesis of intermediate product (III) is therefore evident. Both solvents have toxic effects on reproduction. On the other hand, other inventions reach (III) by the same reaction using less toxic solvents but in the presence of bases involving long reaction times. This is the case in the following inventions: Patent EP1816131 describes obtaining (III) after 7 hours under reflux in acetonitrile using potassium carbonate as a base. The isolation process consists in the cooling, filtering and suspension of the product in water for 1 .5 hours before filtering the intermediate product (III). The yield is of 89%. Patent application WO2007148344 and patent EP1916246 describe the synthesis of (III) in acetone using potassium carbonate and

tetrabutylammonium bromide. The reaction lasts 10-16 hours under reflux. The isolation process consists in filtering the mass to eliminate the salts, distilling the acetone and recrystallising the acetonitrile or methanol. The yield is of 94% for patent application '344 and 80-85% for patent '246.

Patent application WO2007048361 describes the synthesis of (III) in an acetone: polyethyleneglycol mixture in the presence of potash boiling for 1 1 hours. The yield is of 85%.

PCT patent application WO2008043996 describes the synthesis of (III) in dimethyl sulfoxide with sodium hydroxide as a base for 12 hours at room temperature. Intermediate product (III) thus obtained is used in the next step without being isolated.

Although WO2007148344, WO2007048361 , EP1816131 and EP1916246 describe the synthesis of (III) in a less toxic solvent than N, N- dimethylacetamide or Ν, Ν-dimethylformamide, the total reaction time is of 7 to 16 hours. This is why the preparation of (III) in a non-toxic solvent requires shortening the reaction time in order to optimise industrialisation of the process. Patent US5616599 describes the synthesis of 5-methyl-2-oxo-[1 ,3]dioxol-4- ylmethyl 5-(1 -hydroxy- 1 -methylethyl)-2-propyl-3-[2'-(1 -trityl-1 H-tetrazol-5- yl)biphenyl-4-ylmethyl]-3/-/-imidazole-4-carboxylate, with formula (V)

(V) as an intermediate product in the synthesis of olmesartan medoxomil (VI). The synthesis is performed by reacting the intermediate product indicated above (III) with the compound of formula (IV)

(IV) after the saponification of (III) with lithium hydroxide in dioxane to make the lithium salt, of formula (Ill-Li).

(Ill-Li)

Once (Ill-Li) has been isolated it is alkylated with (IV) in N,N- dimethylacetamide using potassium carbonate as a base. The final crystallisation step takes place in diisopropyl ether or in ethyl acetate. The yield is of 87%. Similarly, Patent EP1816131 describes preparing (V) but using sodium hydroxide this time in Ν,Ν-dimethylacetamide to form the sodium salt, with formula (lll-Na).

(IM-Na)

The non-isolated salt (lll-Na) is alkylated with (IV) in N,N-dimethylacetamide using potassium carbonate as a base. Intermediate product (V) thus obtained is used in the next step without being isolated. The yield is of 75%.

The same reaction is described in application WO2008043996 using sodium hydroxide in Ν,Ν-dimethylacetamide to form the salt (lll-Na), which is alkylated with (IV) in Ν,Ν-dimethylacetamide diisopropylethylamine using

diisopropylethylamine or potassium fe/f-butoxide as a base this time. In this application the intermediate product (III) is synthesised in situ starting from (I) and (II), without being isolated.

A similar reaction diagram is followed in Patent EP1916246. Lithium hydroxide is used as a base to obtain salt (Ill-Li) by reflux of (III) in tetrahydrofuran for 15 hours. The alkylation of the previously isolated salt (Ill-Li) with (IV) in N,N- dimethylacetamide in the presence of triethylamine produces (V), with a yield of 75-80%. There is therefore a need for a process for synthesising (V) using less toxic solvents than Ν,Ν-dimethylacetamide or dioxane. Patent application WO2007048361 describes the synthesis of (V) in tetrahydrofuran using potassium hydroxide for 24 hours to prepare the salt, with formula (lll-K).

(Ill-K)

The reaction between the salt (Ill-K) and (IV) is carried out in

methylethylketone and in the presence of potassium iodide for 7.5 hours. The solvent used in the crystallisation is ethanol. The yield is of 86%.

Although WO2007048361 describes the synthesis of (V) in a non-toxic solvent, the reaction time for completion is of 24 hours to form the salt and 7.5 hours for the alkylation step. It is therefore necessary to achieve a process for obtaining (V) that is optimised for industrialisation both by using a non-toxic solvent and by having a shorter reaction time.

Since the solvents N,N-dimethylacetamide, Ν,Ν-dimethylformamide and dioxane, all used in the state of the art as mentioned above, belong to the CMR group (carcinogens, mutagens or reproductive toxicants) ("Regulation (EC) No. 1272/2008 of the European Parliament and Council of 16 December 2008 on the Classification, Labelling and Packaging of Substances and Mixtures, and which modifies and repeals Directives 67/548/EEC and

1999/45/EC and modifies Regulation (EC) No. 1907/2006"), it is convenient to find processes that optimise industrialisation by shortening the manufacturing times, as well as using alternative, safer solvents.

Patent US5616599 describes the deprotection of the trityl derivative (V) in the end product (VI) in aqueous acetic acid at 60°C. Once the reaction has finished, the mixture is cooled, water is added and the triphenylcarbinol is eliminated by filtration. The filtrate is concentrated by low pressure

evaporation, toluene is then added and it is eliminated together with the remaining water and acetic acid, at low pressure. The residue is crystallised from ethyl acetate. The yield of this step is 81 %.

Patent application US20060148870 also describes the deprotection of (V) to produce (VI) in aqueous acetic acid at 60°C. Similarly, patent application WO2007047838 describes the deprotection of (V) to produce (VI) in aqueous acetic acid at 58°C. The process consists in cooling the reaction mixture, adding a sodium chloride solution and the filtrate to eliminate the triphenylcarbinol. Dichloromethane is then added and separated from the aqueous phase. The organic solvent is then distilled and the final waste is crystallised from acetone. The yield of this step is 76%.

Patent EP1916246 also describes the deprotection of (V) to produce (VI) in aqueous acetic acid. Once the reaction has finished, the mixture is cooled, water is added and the triphenylcarbinol is removed by filtration. The acetic acid is distilled and the residue is crystallised from isopropanol.

There are two options described in these four documents for eliminating the acetic acid:

a) Distilling in order to produce an acetic acid-free end product (VI).

Neutralising of the reaction medium due to the enormous amounts of salt generated must be prevented, since deprotection requires large amounts of acetic acid. Toluene or ethyl acetate (when the residue is obtained by distilling acetic acid) must be added in order to ensure the complete removal of acetic acid.

b) Extraction of (VI) from the aqueous acetic acid medium with

dichloromethane (a highly volatile toxic solvent, also within the CMR group). There is therefore a need for a process for synthesising (VI) that does not use aqueous acetic acid solutions and avoids distillations to produce the end product, thus making the process more suited to industrialisation. Patent application WO2007017135 describes the deprotection of (V) in a mixture of ethyl acetate: ethanol, in the presence of HCI at 24-26°C for 3 hours. Once the reaction has finished, water is added and the pH is adjusted to 5 with NaOH. The aqueous phase is separated and extracted with ethyl acetate. The solvent is eliminated under low pressure until it produces a residue, more ethyl acetate is added and it is then distilled again. The solid crystallises from ethyl acetate (75% of yield). At least 20 volumes are required to obtain (VI), volume in this application being the following ratio:

Volume = millilitres (ml) of solvent / grams (g) of solute

Patent application WO2007148344 describes the deprotection of (V) in mixtures of toluene: HCI, ethyl acetate: HCI or heptane: HCI. When toluene or heptane are used the phases are separated and the aqueous phase extracted with ethyl acetate after adjusting the pH of the organic phase to 5.0-6.5 with a potassium carbonate solution. The phases are separated. Ethyl acetate is partially distilled in order to allow the crystallisation of (VI) or it can be distilled entirely and the residue is crystallised from acetone. When ethyl acetate is used as a reaction solvent, the phases are not separated until the pH is adjusted. At least 29 volumes are required to produce (VI).

Patent application WO2008043996 describes the deprotection of (V) in a mixture of Ν,Ν-dimethylacetamide: HCI. The reaction mass is cooled to 0-5°C and the triphenylcarbinol is filtered out. The solvent is distilled. The residue is cooled, neutralised and extracted with dichloromethane. The dichloromethane is removed and the residue is crystallised from acetone. It also describes the deprotection of (V) in an aqueous acetic acid medium. At least 18 volumes are required to produce (VI). When an inorganic acid is used to synthesise (VI), toxic solvents are used (Ν,Ν-dimethylacetamide or dichloromethane, both CMRs) or more than 20 volumes are required to prepare it. There is therefore a need for producing (VI) in a non-toxic solvent, reducing the volumes required and preventing distillations in order to make the process more suitable for industrialisation.

Patent applications US20060258727, US200600741 17, US20070054948 and patent US7528258 describe the deprotection of (V) in a mixture of acetone: water (1 : 1 v/v) in the presence of H₂S0₄ at 40°C. The triphenylcarbinol is precipitated by adding water and is removed by filtration. NaHC0₃ is added to the filtrate and the mixture is cooled to ambient temperature for filtration (VI). The preparation of (VI) described in Patent US7528258 reduces the volumes required during operations when (V) is deprotected using an inorganic acid.

SUMMARY OF THE INVENTION

This invention provides a new and advantageous industrial process for preparing olmesartan medoxomil (VI) according to Diagram 1 :

Diagram 1

(IV)

(V) (VI)

In this application volume = millilitres (ml_) of solvent / grams (g) of solute. The most important features and advantages of this invention compared to the state of the art are:

First step: Synthesis of (III) a) Use of non-toxic solvents (non-CMR): Tetrahydrofuran, dimethyl sulfoxide, acetone, methylethylketone, methyl fe/f-butyl ether, toluene, ethyl acetate, or mixtures thereof.

b) Surprisingly, there is a shortening of reaction times. Indeed, the reaction may even finish in 2 hours, especially when using acetone, dimethyl sulfoxide or tetrahydrofuran as solvents, instead of the 7-16 hours reported in the state of the art when also using non-toxic solvents but using bases other than potassium fe/f-butoxide. The joint use in this invention of potassium tert- butoxide and non-toxic solvents unexpectedly and advantageously shortens the reaction times.

c) Isolation of the product comprises very easy operations, such as cooling the reaction mass, distilling the solvent in the presence of water and filtering it. d) The product is obtained with high yield (95%) and good purity (> 93%).

Second step: Synthesis of (V) a) Use of non-toxic solvents (non-CMR): Tetrahydrofuran, 2- methyltetrahydrofuran, dimethyl sulfoxide, acetone, or mixtures thereof.

b) Shortening of the reaction times to produce the salt, as well as in its alkylation with (IV). Therefore, as well as using non-toxic solvents, it only requires 2 hours to complete the formation of the salt instead of 24 hours, as described in the state of the art, or 2.5 hours for the alkylation step instead of 7.5 hours, as described in the state of the art.

c) Better use of the reagents, since 1.1 equivalents of (IV) are used for each equivalent of (III).

d) The product is obtained with high yield (85%) and good purity (> 95%).

Third step: Synthesis of (VI) a) Use of non-toxic solvents (non-CMR): Methanol, toluene, acetonitrile, or mixtures thereof.

b) The product is crystallised from toluene, which allows eliminating the triphenylcarbinol, which is soluble in this solvent, without loosing the product in the mother liquor. As a result, the process of the present invention requires 14 volumes at the most for this step.

c) The product is obtained with high yields (85% deprotection and 90% recrystallization) and great purity (>99.5%).

Thus, overall and in short, the process of the present invention does not use solvents that are carcinogenic, mutagenic or that have reproductive toxicity effects, it has short reaction times and decreases the amount of solvents to be used, all of which favours industrialisation of the process.

DETAILED DESCRIPTION OF THE INVENTION

This invention has as an object to provide a process for preparing olmesartan medoxomil (VI)

(VI) prising the following steps: alkylation of the compound of formula (I)

with the compound of formula (II)

in the presence of potassium fe/f-butoxide, and in a medium comprising a solvent selected from the group consisting of ethyl acetate, acetone, dimethyl sulfoxide, methylethylketone, methyl fe/f-butyl ether, tetrahydrofuran, toluene, and mixtures thereof;

(ii) saponification of the compound of formula (III) formed in step (i)

in the presence of sodium hydroxide, and in a medium comprising a solvent selected from the group consisting of dimethyl sulfoxide, 2- methyltetrahydrofuran, tetrahydrofuran, and mixtures thereof, to yield the intermediate salt of formula (lll-Na)

(lll-Na) which reacts in situ with the compound of formula (IV)

in the presence of potassium carbonate, and in a medium comprising a solvent selected from the group consisting of acetone, dimethyl sulfoxide, 2- methyltetrahydrofuran, tetrahydrofuran, and mixtures thereof; deprotection of the compound of formula (V) formed in step

(V) in a medium comprising an aqueous solution of a mineral acid selected from the group consisting of hydrochloric, hydrobromic, phosphoric, nitric, and sulphuric acid; and acetone or acetonitrile, followed by separation of the resulting compound (VI) by crystallisation by adding toluene adjusting the pH of the aqueous phase to 4.5-6.0, low pressure elimination of the acetone or acetonitrile, and filtration; and (iv) final purification of (VI) by dissolving it in a medium comprising acetonitrile, or mixtures of acetonitrile with methanol or with acetone under reflux, followed by crystallisation.

In a preferred embodiment, the medium of step (i) comprises a mixture of acetone and dimethyl sulfoxide.

In another preferred embodiment, the reaction of the step (i) is performed under reflux. In another preferred embodiment, the reaction solvent of step (i) is eliminated under low pressure after adding water in order to isolate the product from water.

In another preferred embodiment, (III) is used in the next step of the process without drying. In another preferred embodiment, the medium of step (ii) comprises a solvent selected form the group consisting of dimethyl sulfoxide; a mixture of dimethyl sulfoxide and tetrahydrofuran; a mixture of dimethyl sulfoxide and 2- methyltetrahydrofuran; a mixture of dimethyl sulfoxide and acetone; a mixture of dimethyl sulfoxide, tetrahydrofuran and acetone; and a mixture of dimethyl sulfoxide, 2-methyltetrahydrofuran and acetone.

In another preferred embodiment, the medium of step (ii) comprises a mixture of tetrahydrofuran and dimethyl sulfoxide in order to saponify (III) at a ratio of 2:3.

In another preferred embodiment, the temperature used to saponify (III) in step (ii) is 45-75°C. In another preferred embodiment, the medium of step (ii) comprises a mixture of tetrahydrofuran and dimethyl sulfoxide in order to alkylate (lll-Na) with (IV) at a ratio of 3.7: 1 .5.

In another preferred embodiment, the alkylation temperature between (lll-Na) and (IV) in step (ii) is 60-75°C.

In another preferred embodiment of step (ii), the compound (IV) is added diluted in tetrahydrofuran over (lll-Na) over 1 .5 hours. In another preferred embodiment of step (ii), the compound (IV) is in a proportion of between 1 .0 and 1.5 equivalents with respect to (lll-Na).

In another preferred embodiment, in step (ii) the compound (V) crystallises from ethyl acetate.

In another preferred embodiment, the medium of step (iii) comprises an aqueous solution of hydrochloric acid and acetonitrile. In another preferred embodiment, the deprotection of step (iii) is performed at a temperature between 0 and 25°C. In another preferred embodiment, the deprotection of step (iii) is performed with 4-6 hydrochloric acid equivalents.

In another preferred embodiment, in step (iii) the compound (VI) is crystallised in toluene in order to separate the trityl from the medium when it solubilises in said solvent.

In another preferred embodiment, the pH of step (iii) is adjusted using a base selected from an alkaline carbonate and bicarbonate. In another more preferred embodiment, the base is potassium carbonate, sodium carbonate, bicarbonate or sodium bicarbonate.

In another preferred embodiment of step (iii), the pH is adjusted with a saturated solution of alkaline bicarbonate. In another preferred embodiment of step (iii), the pH is adjusted with a saturated solution of sodium bicarbonate.

In another preferred embodiment, the recrystallisation of (VI) in step (iii) is performed with acetonitrile.

EXAMPLES

Examples 1 -8: Preparation of ethyl 5-(1 -hvdroxy-1 -methylethyl)-2-propyl- 3-r2'-(1 rityl-1H-tetrazol-5-yl)biphenyl-4-ylmethvn-3H-imidazole-4- carboxylate (III)

Example 1

5.19 g of (II) and 2.51 g (1 .1 equivalents) of (I) were suspended in 12.3 ml of acetone. The mixture was cooled to 0-5°C to add 1 .14 g (1 .1 equivalent) of potassium fe/f-butoxide. The mixture was then heated under reflux. At the start of reflux, 0.5 ml of dimethyl sulfoxide were added over about 30 minutes. The reaction was completed in two more hours. The mixture was cooled to ambient temperature in approximately 1 hour. 24.6 ml of water were then added and the acetone was distilled. The mixture was cooled to 0-5°C, it was filtered, washed with water and the resulting solid was dried in a heat cabinet. 6.34 g of (III) were obtained (97% yield). The resulting solid was analysed by HPLC, showing a purity of more than 93%. Example 2

1 .0 g of (I) and 0.47 g (1 .0 equivalents) of potassium fe/f-butoxide were suspended in 5 ml of dimethyl sulfoxide. 2.32 g of (II) (1 .0 equivalents) were then added at ambient temperature over 1 hour. The mixture was stirred for 1 .5 hours at ambient temperature. The mixture was filtered, washed with water and the resulting solid was dried in a heat cabinet. 2.57 g of (III) were obtained (86% yield). The resulting solid was analysed by HPLC, showing a purity of more than 80%.

Example 3

1 .0 g of (I), 2.08 g of (II) (0.9 equivalents) and 0.46 g (1.0 equivalents) of potassium fe/f-butoxide were suspended in 10 ml of tetrahydrofuran. The mixture was then heated to boil for 2 hours. HPLC analysis revealed the formation of 68% of (III). Example 4

5.0 g of (I), 1 1 .6 g of (II) (1 .0 equivalents) and 2.8 g of potassium ferf-butoxide were suspended in 25 ml of methylethylketone. The mixture was heated to 50°C. The reaction was completed after 6.0 hours. HPLC analysis revealed the formation of 60% of (III).

Example 5

1 .0 g of (I), 2.08 g of (II) (0.9 equivalents) and 0.46 g (1 .0 equivalents) of potassium fe/f-butoxide were suspended in 10 ml of methyl ferf-butyl ether. The mixture was brought to the boil. 2 ml of dimethyl sulfoxide were then added over 30 minutes and the reaction was completed in 3.5 hours. HPLC analysis revealed the formation of 59% of (III).

Example 6

5.0 g of (I) and 10.44 g of (II) (0.9 equivalents) were suspended in 25 ml of toluene. The mixture was cooled below 10°C and 2.34 g (1 .0 equivalents) of potassium ferf-butoxide were added. The mixture was heated to 55°C and 5 ml of dimethyl sulfoxide were added. The reaction was completed in 4.0 hours. HPLC analysis revealed the formation of 79% of (III).

Example 7

1 .0 g of (I), 2.08 g of (II) (0.9 equivalents) and 0.46 g (1 .0 equivalents) of potassium ferf-butoxide were suspended in 10 ml of ethyl acetate. The mixture was brought to the boil. The reaction was completed in 2.0 hours. HPLC analysis revealed the formation of 21 % of (III).

Example 8

1 .0 g of (I), 2.32 g of (II) (1 .0 equivalents) and 0.47 g (1 .0 equivalents) of potassium ferf-butoxide were suspended in 10 ml of acetone. The mixture was heated under reflux. The reaction was completed in 2.0 hours. HPLC analysis revealed the formation of 82% of (III). Examples 9-12: Preparation of 5-methyl-2-oxori ,31dioxol-4-ylmethyl ethyl 5-(1 -hvdroxy-1 -methylethyl)-2-propyl-3-r2'-(1 -trityl-1 H-tetrazol-5- yl)biphenyl-4-ylmethvn-3H-imidazole-4-carboxylate (V)

(V)

Example 9

6.20 g of (III) were suspended in a mixture of 15.5 ml of tetrahydrofuran:

dimethyl sulfoxide (2:3, v/v). The mixture was cooled to 17°C in order to add 0.45 g (1.3 equivalents) of sodium hydroxide. The mixture was then heated to 60°C. After two hours 1 .55 g (1 .1 equivalents) of potassium carbonate were added to the mixture. The mixture was heated to 70°C and 1 .41 g of (IV) dissolved in 16.2 ml of tetrahydrofuran were added to the mixture over 1 .5 hours. The reaction was completed in one hour. The mixture was cooled to room temperature. The mixture was then washed three times with a 29% solution of sodium chloride in water. Finally, the organic solvent was distilled and 18.6 ml of ethyl acetate were added. Finally (V) was crystallised from ethyl acetate by cooling. The mixture was cooled to 0-5°C, it was filtered, washed with ethyl acetate and heptane and the resulting solid was dried in a heat cabinet. 5.54 g of (V) were obtained (80% yield). The resulting solid was analysed by HPLC, showing a purity of more than 97%.

Example 10

2.0 g of (III) and 0.18 g (1 .6 equivalents) of sodium hydroxide were suspended in a mixture of 5 ml of dimethyl sulfoxide: 2-methyl tetrahydrofuran (3:2, v/v). The mixture was then heated to 50°C for 1 hour. The mixture was then heated under reflux and 0.46 g of potassium carbonate were added. 0.5 g of (IV) dissolved in 10 ml of 2-methyltetrahydrofuran were added over 1 .25 hours. One hour was necessary to complete the reaction (76% of (V) by HPLC).

Example 11

2.0 g of (III) and 0.18 g (1 .6 equivalents) of sodium hydroxide were suspended in 5 ml of dimethyl sulfoxide. The mixture was stirred for 2 hours at room temperature. The mixture was then heated under reflux and 0.54 g of potassium carbonate were added. 0.58 g of (IV) dissolved in 10 ml of dimethyl sulfoxide were added to the mixture over 30 minutes. 5 hours were necessary to complete the reaction (75% of (V) by HPLC).

Example 12

2.0 g of (III) and 0.18 g (1 .6 equivalents) of sodium hydroxide were suspended in 8 ml of dimethyl sulfoxide. The mixture was stirred for 2 hours at room temperature. The mixture was then heated to 55-60°C and 0.54 g of potassium carbonate were added. The reaction mix was placed under reflux and 0.58 g of (IV) dissolved in 20 ml of acetone were added over 1 .5 hours. 2.75 hours were necessary to complete the reaction (90% of (V) by HPLC). The mixture was filtered to eliminate the salts. The salts were washed with 5 ml of acetone. 20 ml of ethyl acetate and 5 ml of water were added. The aqueous phase was separated. 20 ml of n-heptane were added to the organic phase. The acetone was eliminated by distillation. The mixture was cooled to 0-5°C, the solid formed was filtered and washed twice with 5 ml of n-heptane and dried in a heat cabinet. 1 .34 g of (V) were obtained (60% yield). The resulting solid was analysed by HPLC, showing a purity of 95%.

Examples 13-14: Preparation of (5-methyl-2-oxo-2H-1 ,3-dioxol-4- vDmethyl 4-(2-hvdroxypropan-2-yl)-2-propyl-1 -((4-Γ2-(2Η-1 ,2,3,4-tetrazol-

5-yl)phenvnphenyl>methyl)-1 H-imidazole-5-carboxylate (VI)

Example 13

23.88 g of (V) were suspended in 92 ml of acetonitrile. The mixture was cooled to 5°C in order to add 24.6 ml of 6N HCI. The mixture was stirred for 2 hours at 5°C. 150 ml of toluene were added. The pH was adjusted to 5.7 with potassium bicarbonate. The mixture was filtered in order to eliminate part of the salts generated. The solid was washed with 30 ml of acetonitrile. The phases were separated. The acetonitrile present in the organic phase was distilled. The mixture was cooled and filtered. The solid was washed with toluene and water. (VI) was dried in a heat cabinet. 16.66 g of (VI) were obtained (85% yield).

Example 14

43.0 g of (V) were suspended in 130 ml of acetonitrile. The mixture was cooled to 0-5°C and 35 ml of 6N HCI were added. The mixture was stirred 2.75 hours at 7-8°C. 215 ml of toluene were added. The pH was adjusted to 4.8 with a saturated solution of sodium bicarbonate. The phases were separated. The aqueous phase was re-extracted with a mixture of 215 ml of toluene and 43 ml of acetonitrile. The organic phases were brought together and washed with 43 ml of water. The acetonitrile present in the organic phase was distilled. The mixture was cooled to 0-5°C and filtered. The solid was washed with toluene, water and again with toluene. (VI) was dried in a heat cabinet. 24.67 g of (VI) were obtained (82% yield). Examples 15-17: Purification of (5-methyl-2-oxo-2H-1,3-dioxol-4- vDmethyl 4-(2-hvdroxypropan-2-yl)-2-propyl-1 -((4-Γ2-(2Η-1 ,2,3,4-tetrazol- 5-yl)phenvnphenyl>methyl)-1 H-imidazole-5-carboxylate (VI) Example 15

15.06 g of (VI) were dissolved in 130 ml of acetonitrile under reflux and it was cooled to 0-5°C for filtering, washing with acetonitrile and water and finally drying. The yield was of 93%. Example 16

4.7 g of (VI) were dissolved in 32.9 ml of acetonitrile and 4.7 ml of methanol under reflux. The mixture was cooled to 0-5°C, filtered, washed with acetonitrile and dried in a heat cabinet. The yield was of 80%. Example 17

5.0 g of (VI) were dissolved in 35 ml of acetonitrile and 5 ml of acetone under reflux. The mixture was cooled to 0-5°C, filtered, washed with acetonitrile and dried in a heat cabinet. The yield was of 89%.

Claims

1 . A process for preparing olmesartan medoxomil (VI)

(VI) comprising the following steps:

(i) alkylation of the compound of formula (I)

(I) with the compound of formula (II)

in the presence of potassium fe/f-butoxide, and in a medium comprising a solvent selected from the group consisting of ethyl acetate, acetone, dimethyl sulfoxide, methylethylketone, methyl fe/f-butyl ether, tetrahydrofuran, toluene, and mixtures thereof; (ii) saponification of the compound of formula (III) formed in step (i)

(lll-Na) which reacts in situ with the compound of formula (IV)

in the presence of potassium carbonate, and in a medium comprising a solvent selected from the group consisting of acetone, dimethyl sulfoxide, 2- methyltetrahydrofuran, tetrahydrofuran, and mixtures thereof;

(iii) deprotection of the compound of formula (V) formed in step (ii)

(V) in a medium comprising an aqueous solution of a mineral acid selected from the group consisting of hydrochloric, hydrobromic, phosphoric, nitric, and sulphuric acid; and acetone or acetonitrile, followed by separation of the resulting compound (VI) by crystallisation by adding toluene, adjusting the pH of the aqueous phase to 4.5-6.0, low pressure elimination of the acetone or acetonitrile, and filtration; and

(iv) final purification of (VI) by dissolving it in a medium comprising acetonitrile, or mixtures of acetonitrile with methanol or with acetone under reflux, followed by crystallisation.

2. A process according to claim 1 , wherein the medium of step (i) comprises a mixture of acetone and dimethyl sulfoxide.

3. A process according to claim 1 , wherein the medium of step (ii) comprises a solvent selected from the group consisting of dimethyl sulfoxide; a mixture of dimethyl sulfoxide and tetrahydrofuran; a mixture of dimethyl sulfoxide and 2- methyltetrahydrofuran; a mixture of dimethyl sulfoxide and acetone; a mixture of dimethyl sulfoxide, tetrahydrofuran and acetone; and a mixture of dimethyl sulfoxide, 2-methyltetrahydrofuran and acetone.

4. A process according to claim 1 , wherein the medium of step (iii) comprises an aqueous solution of hydrochloric acid and acetonitrile.

5. A process according to claim 1 , wherein the pH of step (iii) is adjusted using a base selected from alkaline carbonate and bicarbonate.

6. A process according to claim 5, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.