FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Olmesartan medoxomil of formula I.

Formula 1

BACKGROUND OF THE INVENTION

Olmesartan medoxomil is chemically known as 4-(l-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]-methyl]-lH-imidazole-5-carboxylic acid, (5-methy 1-2-oxo-l,3-dioxol-4-yl)methyl ester. Olmesartan medoxomil is an AT1-subtype angiotensin II receptor antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Olmesartan medoxomil blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATi receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. Olmesartan medoxomil is used for the treatment of hypertension and is marketed under the brand name Benicar®.

Olmesartan and its pharmaceutically acceptable esters and salts are disclosed in US 5,616,599.

US '599 also discloses a process for the preparation of Olmesartan medoxomil (I), by condensing 4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (II) with 5-[4'-(bromomethyl)[l,l'-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (III) in the presence of sodium hydride and N,N-dimethylformamide, followed by isolation using column chromatography to produce trityl Olmesartan ethyl ester (IV), which is further treating with lithium hydroxide monohydrate in the presence of dioxane to produce lithium salt of trityl Olmesartan (IVa). Lithium salt (IVa) is reacted with 4-chloromethyl-5-methyl-l,3-dioxol-2-one (V) in the presence of potassium carbonate and N,N-dimethylacetamide to produce trityl Olmesartan medoxomil (VI), which is de-tritylated in the presence of aqueous acetic acid to produce Olmesartan medoxomil (I). The process is as shown in Scheme-I below:


The major disadvantage with the above process is that the formation of undesired impurities during the condensation of 4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (II) with 5-[4'-(bromomethyl)[l,r-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (III). Column chromatography is used to remove the impurities. Employing column chromatography technique is tedious and laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.

EP 1 916 246 discloses a process for the preparation of trityl Olmesartan medoxomil (VI) by condensing trityl Olmesartan lithium salt (IVa) with 4-chloromethyl-5-methyl-l,3-dioxol-2-one (V) in the presence of tertiary amine selected from trietylamine, N-methylmorpholine, diisopropylethylamine in an organic solvent.

US 2009/0281327 A1 discloses the condensation of trityl Olmesartan dihydrate (IVb) with 4-chloromethyl-5-methyl-l,3-dioxol-2-one (V) in the presence of a base and a catalyst selected from PTC or alkyl iodides to produce trityl Olmesartan medoxomil (VI).

The process is as shown in Scheme-II below:

Scheme-II

WO 2007/048361 Al discloses the condensation of trityl Olmesartan potassium salt (IVc) with (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyI chloride (V) in the presence of

potassium iodide (KI) in methyl ethyl ketone to produce trityl Olmesartan medoxomil
(VI).
The process is as shown in Scheme-Ill below:

Hence, there is a need to develop a process, which provides isolation of trityl Olmesartan ethyl ester (IV) without column chromatography, which reduces the impurities to obtain pure trityl Olmesartan ethyl ester (IV).

The present invention also directed to a process, wherein condensation of a salt of trityl Olmesartan (IVd) with 4-halomethyl-5-methyl-l,3-dioxol-2-one (V) in the presence of
alkyliodide without using any base.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Olmesartan medoxomil (I) of high purity on commercial scale.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Olmesartan medoxomil of formula (I)

which comprises,

(i) condensing ethyl 4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate of formula (II),

Formula II

with 5-[4'-(bromomethyl)[ 1,1 '-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole of formula (III),

in the presence of a base in a solvent to produce a reaction mixture containing trityl Olmesartan ethyl ester of formula (IV),

(ii) treating the reaction mixture obtained in step (i) with a solvent to isolate trityl
Olmesartan ethyl ester (IV),

(iii) treating compound IV of step (ii) with base in the presence of solvent to
produce a compound of formula (IVd),
Formula IVd

wherein, M represents sodium, lithium, cesium etc;

(iv) reacting the compound (IVd) with 4-halomethyl-5-methyl-l,3-dioxol-2-one of formula (Va),

Formula Va

wherein X represents halide selected from CI, Br, F & I; in the presence of an alkali halide in a solvent to produce trityl Olmesartan medoxomil (VI),

(v) de-tritylation of tntyl Olmesartan medoxomil (VI) to produce Olmesartan medoxomil (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Olmesartan medoxomil of formula (I).

The process comprises, condensation of ethyl 4-(l -hydroxy- 1-methy lethyl)-2-propylimidazole-5-carboxylate (II) with 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) in the presence of a base in a solvent to produce trityl Olmesartan ethyl ester (IV).
The base used in the above reaction is selected from an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like; organic base such as diethylamine, triethylamine, tert-butylamine, diisopropylamine, and the like. The solvent used in the above reaction is selected from N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, acetone, toluene, ethyl acetate or mixtures thereof. The reaction is carried out at a temperature of about 30-100°C for a period of about 30min to 40 hours.

After completion of the reaction, solvent selected from acetone, ethyl acetate, water, acetonitrile or mixtures thereof is added and cooled the reaction mass to 0 to 10°C,
followed by stirring for 30min to 2 hrs. Filtered the slurry containing trityl Olmesartan ethyl ester (IV), followed by washing with water and dried the product.

Treating trityl Olmesartan ethyl ester (IV) with base in a solvent to produce corresponding salt of trityl Olmesartan (IVd).The base used in the above reaction is selected from an alkali metal hydroxide selected from sodium hydroxide, lithium hydroxide, cesium hydroxide etc. The solvent used in the above reaction is selected from tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, water, ethyleneglycol or mixtures thereof. The reaction is carried out at a temperature of about 15-100°C.
After completion of the reaction, reaction mixture is concentrated to produce salt of trityl Olmesartan (IVd) as a residue, which is used as such in the next reaction. Alternatively, residue containing salt of trityl Olmesartan (IVd) is dissolved in a organic solvent selected from ethyl acetate, butyl acetate, methyl acetate, methylene chloride, ethylene chloride or mixtures thereof. The resulting solution is washed with sodium chloride solution, followed by removing the organic solvent to produce a salt of trityl Olmesartan (IVd), which is optionally crystallized from solvent selected from acetonitrile acetone, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof.

Reacting the salt of trityl Olmesartan (IVd) with 4-halomethyl-5-methyl-l,3-dioxol-2-one (Va), wherein the halo represents CI, Br, F & I, in the presence of an alkali halide in a solvent to produce trityl Olmesartan medoxomil (VI).

The solvent used in the above reaction is selected from tetrahydrofuran, N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, ethyl acetate, toluene, acetone, methanol, ethanol, isopropanol, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof. The alkali halide is selected from sodium chloride, sodium bromide, sodium iodide, lithium chloride, cesium chloride, and the like.

This reaction is optionally carried out in the presence of a phase transfer catalyst (PTC), selected from tetraethylammonium-p-toluenesulfonate, tetrapropylammonium trifluoromethane sulfonate, tetraphenylphosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride,

benzyltriethylammonium chloride, benzyltrirnethylamrnonium chloride,
benzyltriphenylphosphonium chloride, benzytributylammonium chloride,
butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl
ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium
bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide,
methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide,
phenyltrimethylammonium chloride, tetrabutylammonium hydroxide,
tetrabutylammonium perchlorate, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctylammonium bromide, tetraphenylphosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride, wherein tetrabutylammonium salts and particularly tetrabutylammonium halides, e.g. the bromides are especially preferred. The reaction is carried out at a temperature of about 15-40°C, for a period of about 1 to 5 hrs.

After completion the reaction, solvent selected from ethyl acetate, butyl acetate, methyl acetate, toluene, xylenes, methylene chloride, ethylene chloride or mixtures thereof and water is added to the reaction mass and separated the layers. Organic layer is concentrated to remove the solvent to 1/3 volume and second solvent selected from diisopropyl ether, acetonitrile, hexanes, diethyl ether or mixtures thereof; is added to the concentrated mass containing trityl Olmesartan medoxomil (VI). Filtered the resulting solid and dried under reduce pressure. Alternatively, organic layer containing trityl Olmesartan medoxomil (VI) is completely concentrated to residue and used as such in the de-tritylation step.

Trityl Olmesartan medoxomil (VI) is detritylated in the presence of an aqueous acid to produce Olmesartan medoxomil (I).

The acid used in the de-tritylation reaction is selected from carboxylic acids such as formic acid, acetic acid, oxalic acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid; inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid or mixtures thereof.
The reaction is carried out at a temperature of about 10 to 100°C, for a period of about 30 min to 5 hrs. After completion of the reaction, reaction mixture is filtered to remove the by product trityl alcohol through hyflo. The filtrate containing Olmesartan medoxomil (I) is diluted with water and extracted with organic solvent selected from methylene chloride, ethylene chloride, ethyl acetate, butyl acetate, methyl acetate, toluene, xylenes or mixtures thereof. The organic layer is diluted with water and adjusted the pH to 7.0 to 7.5 using base selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, pyridine, alkyl amine etc. Organic layer is separated and partially concentrated under reduced pressure under heating. The resulting concentrated mass containing Olmesartan medoxomil (I) is stirred with a solvent selected from acetonitrile, THF, acetone, methanol, ethanol, isopropanol, ethyl acetate or mixtures thereof, and filtered to produce crude Olmesartan medoxomil (I).

Olmesartan medoxomil (I) crude obtained by the above process is purified by known methods, for example recrystallization by dissolving in a solvent selected from methanol, ethanol, isopropanol, methylene chloride, tetrahydrofuran, acetone, acetonitrile, ethyl acetate or mixtures thereof; and precipitating pure Olmesartan medoxomil (I) by cooling the solution to about 0-30°C, or by adding an anti solvent selected from cyclohexane, n-hexane, heptane, diisopropyl ether, etc. The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE:

Stage I:

Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[[2'-[N-(triphenylmethyl)-
tetrazol-5-yl] [1,1-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxy-lic acid, ethyl
ester (Trityl Olmesartan acid, ethyl ester):

Method A:

4-(l -Hydroxy- l-methylethyl)-2-propylimidazole-5- carboxylic acid, ethyl ester (200 g) was dissolved in N,N-dimethylacetamide (1000 ml) at 25-30°C and powdered anhydrous potassium carbonate (144 g), 5-[4'-(bromomethyl)[l,r-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (464.20 g) were added at 25-30°C. The temperature of the above suspension was raised to 35-40°C and stirred till completion of the reaction. Thereafter, acetone (1400 ml) was added to the reaction mass at 35-40°C. The slurry was cooled to 20-25°C and DM water (600 ml) was added slowly in -15 min at 20-25°C. The slurry was cooled to 2-5°C and stirring was continued at 2-5°C for 1 h. The product was filtered and washed with pre-cooled 20% v/v aqueous acetone (400 ml) followed by DM water (3000 ml) and dried to afford trityl Olmesartan acid, ethyl ester (530 g).

Method B:

4-(l-Hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylic acid, ethyl ester (200g) was dissolved in N,N-dimethylacetamide (1000 ml) at 25-30°C and powdered anhydrous potassium carbonate (143.75 g), 5-[4'-(bromomethyl)[l,r-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (464.20g) were added at 25-30°C. The temperature of the above suspension was raised to 35-40°C and stirring was continued till completion of the reaction. Thereafter, acetone (1000 ml) was added followed by ethyl acetate (800 ml) to the reaction mass at 35-40°C. The slurry was cooled to 2-5°C and stirring was continued at 2-5°C for lh. The product was filtered and washed with pre-cooled 20% v/v aqueous acetone (5.70 Lt, 5-10°C). Thereafter, the cake was washed with DM water (3000 ml) and dried to afford trityl Olmesartan acid, ethyl ester (530 g).

Method C:

4-(l-Hdroxy-l-methylethyl) 2-propylimidazole-5- carboxylic acid, ethyl ester (200g) was dissolved in N,N-dimethylacetamide (300 ml) and acetone (1000 ml) followed by powdered anhydrous potassium carbonate (143.75 g), 5-[4'-(bromomethyl)[l,r-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole (464.20g) were added at 25-30°C. The temperature of the aboye suspension was raised to 35-40°C and stirring was continued at reflux temperature till completion of the reaction. Thereafter, ethyl acetate (1400 ml) was added followed by water (600 ml) to the reaction mass at 35-40°C. The slurry was cooled to 2-5°C and stirring was continued at 2-5°C for lh. The product was filtered and washed with pre-cooled 20% v/v aqueous acetone (5.70 Lt, 5-10°C) followed by water (3000 ml) and dried to afford trityl Olmesartan acid, ethyl ester (540 g).

Stage II:

Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyI-l-[[2'-[N-(triphenylmethyl)-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxy-lic acid, sodium salt (trityl Olmesartan sodium salt):

Method A:

Trityl Olmesartan acid, ethyl ester (450g) was dissolved in tetrahydrofuran (2700 ml) at 25-35°C. The reaction mixture was cooled to 15-20°C, followed by a pre-cooled solution of sodium hydroxide (prepared by dissolving 31.40 g of sodium hydroxide in 1125 ml of DM water, 15-20°C) was added at 10-20°C and the contents were stirred till completion of the reaction. The reaction mass was concentrated under reduced pressure (50-30 mm Hg) at below 20°C till no more tetrahydrofuran distills out. The concentrated reaction mass was dissolved in ethyl acetate (4.50 Lt) at 25°C and washed with saturated sodium chloride solution. The organic layer was concentrated till no more ethyl acetate distills out at below 40°C under reduced pressure. The concentrated mass containing trityl Olmesartan sodium as a viscous liquid was directly taken for preparation of trityl Olmesartan Medoxomil.

Method B:

Trityl Olmesartan acid, ethyl ester (450g) was dissolved in tetrahydrofuran (2700 ml) at 25-35°C. The reaction mixture was cooled to 15-20°C, followed by a pre-cooled solution of sodium hydroxide (prepared by dissolving 31.40 g of sodium hydroxide in 1125 ml of DM water, 15-20°C) was added at 10-20°C and the contents were stirred at 15-20°C till completion of the reaction. The reaction mass was washed with saturated sodium chloride solution. The organic layer was concentrated at below 40°C under reduced pressure (50-30 mm Hg) till no more tetrahydrofuran distills out. The concentrated mass was dissolved in ethyl acetate (4.50 Lt) at 25-30°C and washed with saturated sodium chloride solution. The organic layer was concentrated at below 40°C under reduced pressure till no more ethyl acetate distills out. The concentrated mass containing trityl Olmesartan sodium as a viscous liquid is directly taken for preparation of trityl Olmesartan Medoxomil.

Method C:

Trityl Olmesartan acid, ethyl ester (450g) was dissolved in tetrahydrofuran (2700 ml) at 25-35°C. The reaction mass was cooled to 15-20°C, followed by a pre-cooled solution of sodium hydroxide (prepared by dissolving 31.40 g of sodium hydroxide in 1125 ml of DM water, 15-20°C) was added at 10-20°C and the contents were stirred at 15-20°C till completion of the reaction. The reaction mass was washed with saturated sodium chloride solution. The organic layer was concentrated at below 40°C under reduced pressure (50-30 mm Hg). Ethyl acetate (1350 ml) was added to the concentrated mass and distillation was continued till no more ethyl acetate distills out. The concentrated mass containing trityl Olmesartan sodium as a viscous liquid is directly taken for preparation of trityl Olmesartan Medoxomil.

Method D:

Trityl Olmesartan acid, ethyl ester (l0g) was dissolved in tetrahydrofuran (60 ml) at 25-35°C. The reaction mixture was cooled to 10-15°C, followed by pre-cooled solution of sodium hydroxide in methanol (prepared by dissolving 0.56 g of sodium hydroxide in 10 ml of methanol, 10-15°C), DM water (2.5 ml) were added at 10-15°C. The contents were stirred at 10-15°C till completion of the reaction. The reaction mixture was concentrated at below 20°C under reduced pressure (50-30 mm Hg). The concentrated mass containing
trityl Olmesartan sodium as a viscous liquid is directly taken for preparation of trityl Olmesartan Medoxomil.

Method E:

Trityl Olmesartan acid, ethyl ester (l0g) was dissolved in tetrahydrofuran (60 ml) at 25-35°C. The reaction mixture was cooled to 10-15°C, followed by pre-cooled solution of sodium hydroxide in methanol (prepared by dissolving 0.56 g of sodium hydroxide in 10 ml of methanol, 10-15°C) was added and the contents were stirred till completion of the reaction. The reaction mixture was concentrated at below 30°C under reduced pressure (50-30 mm Hg). The concentrated mass containing trityl Olmesartan sodium as a viscous liquid is directly taken for preparation of trityl Olmesartan Medoxomil.

Method F:

Trityl Olmesartan acid, ethyl ester (l0g) was dissolved in tetrahydrofuran (60 ml) at 25-35°C and diluted with ethanol (10 ml). Thereafter, the reaction mixture was cooled to 10-15°C, and aqueous sodium hydroxide solution (0.56 g of NaOH dissolved in 2.5 ml water) was added at 10-15°C. The contents were stirred at 10-15°C till completion of the reaction. The reaction mixture was concentrated at below 30°C under reduced pressure (50-30 mm Hg). The concentrated mass containing trityl Olmesartan sodium as a viscous liquid is directly taken for preparation of trityl Olmesartan Medoxomil.

Method G:

Trityl Olmesartan acid, ethyl ester (450g) was dissolved in tetrahydrofuran (2700 ml) at 25-35°C. The reaction mixture was cooled to 15-20°C, followed by a pre-cooled solution of sodium hydroxide (prepared by dissolving 31.40 g of sodium hydroxide in 1125 ml of DM water, 15-20°C) was added at 10-20°C and the contents were stirred till completion of the reaction. The reaction mass was washed with saturated sodium chloride solution. The organic layer was concentrated at below 40°C under reduced pressure (50-30 mm Hg). Ethyl acetate (1350 ml) was added to the concentrated mass and distillation was continued till no more ethyl acetate distills out. Acetonitrile (3.15 It) was added to the concentrated mass, stirred for 2h at 20-25°C to produce crystals and cooled to 0-5°C,
then stirred for 30 min. The solid was filtered, washed with acetonitrile and dried to produce trityl Olmesartan sodium salt as white crystalline powder (405 g).

Method H:

Trityl Olmesartan acid, ethyl ester (lOg) was dissolved in tetrahydrofuran (60 ml) at 25-35°C. The reaction mixture was cooled to 10-15°C, followed by a pre-cooled solution of sodium hydroxide in water (prepared by dissolving 0.56 g of sodium hydroxide in 2.5 ml of water). Ethanol (10 ml) was added to the reaction mixture and the contents were stirred at 15-20°C till completion of the reaction. The reaction mixture was concentrated at below 20°C under reduced pressure (50-30 mm Hg). Acetonitrile (70 ml) was added to the concentrated mass and stirring was continued for lh at 20-25°C. The resulting slurry was cooled to 0-5°C and stirred for 30 min. The product was filtered and washed with pre-cooled acetonitrile to yield trityl Olmesartan acid, sodium salt as white crystalline powder (9.0 g).

Stage III:

Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[[2'-[N-(triphenylmethyl)-tetrazoI-5-yl][14'-biphenyl]-4-yl]methyl]-l/J-imidazole-5-carboxy-lic acid, (5-methyI -2-oxo-l,3-dioxol-4-yI)methyl ester (trityl Olmesartan medoxomil):

Method A:

The concentrated mass obtained in Stage II option C was dissolved in N,N-dimethylacetamide (900 ml) at 25-35°C, followed by 4-chloromethyl-5-methyl-l,3-dioxol-2-one (92.5% purity by GC, 109 g) and sodium iodide (13.30g) were added at 25-35QC. Thereafter, the reaction mixture was stirred at 30-35°C till completion of the reaction. Ethyl acetate (4.50 It) and DM water (4.50 It) followed by sodium metabisulphite (9 g) were added at 30-35°C and the reaction mass was stirred at the same temperature for -15 min. The layers were separated and the organic layer was washed with -20% w/w aqueous sodium chloride solution at 30-35°C. The organic layer was concentrated at 30-40°C under reduced pressure till the reaction mass volume is 1800 ml and diisopropyl ether (2.25 Lt) was added at 30-40°C. The slurry was cooled to 0-5°C

and stirred for 30 min. The product was filtered, washed with diisopropyl ether and dried under reduced pressure to obtain trityl Olmesartan Medoxomil as white powder (427.50 g) having >99% of HPLC purity.

Method B:

Trityl Olmesartan sodium salt (350 g) was dissolved in N,N-dimethylacetamide (1050 ml) at 25-35°C and 4-chloromethyl-5-methyl-l,3-dioxol-2-one (92.5% purity by GC, 82.70 g) followed by sodium iodide (10.50g) were added. Thereafter, the reaction mixture was stirred at 30-35°C till completion of the reaction. Ethyl acetate (3.50 It), DM water (3.50 It) followed by sodium metabisulphite (7 g) were added at 30-35°C and stirring was continued at the same temperature for -15 min and the layers were separated. The organic layer was washed with -20% w/w aqueous sodium chloride at 30-35°C. The organic layer was concentrated at 30-40°C under reduced pressure till the reaction mass volume is 1400 ml and diisopropyl ether (1.75 Lt) was added. The slurry was cooled to 0-5°C and stirred for 30 min. The product was filtered, washed with diisopropyl ether and dried under reduced pressure to obtain trityl Olmesartan Medoxomil as white powder (350 g).

Method C:

Trityl Olmesartan sodium salt (25 g) was dissolved in acetone (250 ml) at 25-35°C and 4-chloromethyl-5-methyl-l,3-dioxol-2-one (92.5% purity by GC, 6.0 g), sodium iodide (0.75 g) and tetrabutylammonium bromide (0.25 g) were added. Thereafter, the reaction mixture was stirred at 30-35°C till completion of the reaction. The reaction mass was concentrated at below 35°C under reduced pressure. Ethyl acetate (250 ml), water (250 ml) and sodium metabisulphite (0.25 g) were added to the reaction mass at 30-35°C and stirred for 15 min. The layers were separated and the organic layer was washed with -20% w/w aqueous sodium chloride at the same temperature. The organic layer was concentrated at 30-40°C under reduced pressure till the reaction mass volume is 100 ml and diisopropyl ether (125 mlt) was added. The slurry was cooled to 0-5°C and stirred for 30 min. The product was filtered, washed with diisopropyl ether and dried under reduced pressure to obtain trityl Olmesartan Medoxomil as white powder (25 g).

Method D:

Trityl Olmesartan sodium salt (25 g) was dissolved in acetone (250 ml) at 25-35°C and 4-chloromethyl-5-methyl-l,3-dioxol-2-one (92.5% purity by GC, 6.0 g), sodium iodide (0.75 g) were added. The reaction mixture was stirred at 30-35°C till completion of the reaction. The reaction mass was concentrated at below 35°C under reduced pressure, then ethyl acetate (250 ml), water (250 ml) and sodium metabisulphite (0.25 g) were added and stirred for 15 min. The layers were separated and the organic layer was washed with -20% w/w aqueous sodium chloride at 30-35°C. The organic layer was concentrated at 30-40°C under reduced pressure till the reaction mass volume is 100 ml and diisopropyl ether (125 mlt) was added. The slurry was cooled to 0-5°C and stirred for 30 min. The product was filtered, washed with diisopropyl ether and dried under reduced pressure to obtain trityl Olmesartan Medoxomil as white powder (25 g).

Method E:

Trityl Olmesartan sodium salt (25 g) was dissolved in acetone (250 ml) at 25-35°C followed by 4-chloromethyl-5-methyl-l,3-dioxol-2-one (92.5% purity by GC, 6.0 g) and sodium iodide (0.75 g) were added at 25-35°C. Thereafter, the reaction mixture was stirred at 30-35°C till completion of the reaction. The reaction mass was concentrated at below 35°C under reduced pressure followed by methylene chloride (250 ml), water (250 ml) and sodium metabisulphite (0.25 g) were added at 30-35°C and stirred for 15 min. The layers were separated and washed the organic layer with water (100 ml) at 30-35°C. The organic layer was concentrated at 30-40°C under reduced pressure. The concentrated mass is directly subjected to de-tritylation reaction to produce Olmesartan medoxomil.

Method F:

Trityl Olmesartan sodium salt (5 g) was dissolved in acetone (50 ml) at 25-35°C followed by 4-chloromethyl-5-methyl-l,3-dioxol-2-one (92.5% purity by GC, 1.20 g) and sodium iodide (50 mg) were added. Thereafter, the reaction mixture was stirred at 30-35°C till completion of the reaction. The reaction mass was concentrated at below 35°C under reduced pressure and acetonitrile (30 ml) was added, and then distillation was continued to collect 15 ml of the distillate. Thereafter, the slurry was cooled to 0-5°C and stirred for

III. The product was filtered, washed with pre-cooled acetonitrile and dried to yield trityl Olmesartan Medoxomil (4.6 g).

Stage IV:

Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[[2'-(1H-tetrazol-5-yl] [1,1'-biphenyl]-4-yl]methyl]-lH-imidazole-5-carboxylic acid, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester (Olmesartan medoxomil):

Method A:

The concentrated mass as obtained in Stage III Method E was dissolved in 75% v/v aqueous acetic acid (125 ml) at 25-30°C and the contents were stirred till completion of the reaction. The by-product, trityl alcohol was filtered through hyflo and washed with 75% v/v aqueous acetic acid (25 ml). Methylene chloride (250 ml) was added to the filtrate followed by DM water (250 ml) was added at 20-30°C and stirred at the same temperature for 15 min. The layers were separated and the aqueous layer was extracted with methylene chloride (125 ml) at 20-30°C. The combined organic extract was washed with DM water at 20-30°C. Water (25 ml) was added to the organic layer and its pH was adjusted to 7.30-7.50 with 5% w/w aqueous sodium bicarbonate at the same temperature and stirred for 15 min. The organic layer was separated and-concentrated at 30-40°C under reduced pressure. Acetone (125 ml) was added to the concentrated mass and distillation was continued at 30-40°C under reduced pressure (150-300 mm Hg) till the reaction mass volume is 50 ml. The resulting slurry was cooled to 0-5°C and stirring was continued at the same temperature for 1 h. The product was filtered, washed with pre-cooled acetone and dried to afford Olmesartan Medoxomil (12.50 g).

Method B:

Trityl Olmesartan Medoxomil (275g) was suspended in 75% v/v aqueous acetic acid (1375 ml) at 25-30°C and stirred the contents till completion of the reaction. The by product, trityl alcohol was filtered through hyflo and washed with 75% v/v aqueous acetic acid (275 ml). Methylene chloride (2.75 It) was added to the filtrate followed by DM water (4.125 It) was added at 20-30°C. The reaction mass was stirred at the same temperature for 15 min. The layers were separated and extracted the aqueous layer with
methylene chloride (2.75 It) at 20-30°C. The combined organic extract was washed with DM water. DM water (275 ml) was added to the organic layer at 20-30°C and its pH was adjusted to 7.30-7.50 with 5% w/w aqueous sodium bicarbonate solution and stirred for 15 min. The organic layer was separated and concentrated at 30-40°C under reduced pressure till the mass volume is 300 ml. Thereafter, acetone (1375 ml) was added to the concentrated mass and distillation was continued under reduced pressure at 30-40°C till the mass volume is 275 ml. The resulting suspension was cooled to 0-5°C and stirring was continued at the same temperature for 1 h. The product was filtered, washed with pre-cooled acetone and dried to yield Olmesartan Medoxomil (157 g) as white powder having >99.5% of HPLC purity. This crude product was crystallized from acetone to yield Olmesartan Medoxomil as white crystalline powder (146 g) having >99.7% of HPLC purity.

Stage IV:

Purification of crude Olmesartan medoxomil

Method A:

Olmesartan Medoxomil crude (25g) was dissolved in acetone (375 ml) at reflux temperature, carbon (1.25 g) was added and stirring was continued for 30 min at this temperature. The contents were cooled to 45-50°C and the carbon was filtered through hyflo. The residue was washed with hot acetone (25 ml). Ethyl acetate (50 ml) was added to the filtrate and concentrated at below 40°C under reduced pressure to a volume of 90 ml. Thereafter, the resulting crystals were cooled to 0-5°C and stirred for 30 min at this temperature. The product was filtered, washed with ethyl acetate and dried to afford Olmesartan Medoxomil (22.5 g) as white crystalline powder having >99.7% of HPLC purity.

Method B:

Olmesartan Medoxomil crude (25g) was dissolved in acetone (375 ml) at reflux temperature, carbon (1.25 g) was added and stirring was continued for 30 min at this temperature. The contents were cooled to 45-50°C and the carbon was filtered through hyflo. The residue was washed with hot acetone (50 ml). Methylene chloride (25 ml) was added to the filtrate and concentrated to a volume of 90 ml at below 40°C under reduced pressure. Thereafter, the resulting crystals were cooled to 0-5°C and stirred for 30 min at this temperature. The product was filtered, washed with ethyl acetate and dried to afford Olmesartan Medoxomil (22.5 g) as white crystalline powder having >99.7% of HPLC purity.

Method C:

Olmesartan Medoxomil crude (25g) was dissolved in acetone (375 ml) at reflux temperature, carbon (1.25 g) was added and stirring was continued for 30 min at this temperature. The contents were cooled to 45-50°C and the carbon was filtered through hyflo. The residue was washed with hot acetone (25 ml). Ethyl acetate (50 ml) was added to the filtrate and concentrated at below 40°C under reduced pressure to a volume of 90 ml. Thereafter, the resulting crystals were cooled to 0-5°C and stirred for 30 min at this temperature. The product was filtered, washed with ethyl acetate and dried to afford Olmesartan Medoxomil (22.5 g) as white crystalline powder having >99.7% of HPLC purity.

The obtained Olmesartan medoxomil (20 g) was suspended in DM water (400 ml) at 25-30°C and stirring was continued for 1 hour at this temperature. The product was filtered, washed with DM water and dried under reduced pressure to afford Olmesartan medoxomil (192 g) having acetone content <1500 ppm.

WE CLAIM

1. A process for the preparation of Olmesartan medoxomil of formula (I),
Formula I which comprises:

(i) condensing ethyl 4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate of formula (II), Formula II with 5-[4'-(bromomethyl)[ 1,1 '-biphenyl]-2-yl]-N-(triphenylmethyl)tetrazole of formula (III),

Formula III in the presence of a base in a solvent to produce a reaction mixture containing trityl Olmesartan ethyl ester of formula (IV),

(ii) treating the reaction mixture obtained in step (i) with a solvent to isolate trityl
Olmesartan ethyl ester (IV),

(iii) treating the compound of formula IV obtained in step (ii) with a base in the presence of a solvent to produce a compound of formula (IVd),

wherein, M represents sodium, lithium, cesium etc;

(iv) reacting the compound (IVd) with 4-halomethyl-5-methyl-l,3-dioxol-2-one of formula (Va), Formula Va wherein X represents halide selected from CI, Br, F & I;
in the presence of an alkali halide in a solvent to produce trityl Olmesartan
medoxomil (VI),

(v) de-tritylation of trityl Olmesartan medoxomil (VI) to produce Olmesartan medoxomil (I).

2. The process according to claim 1, wherein the base used in step (i) is selected from an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like; organic base such as diethylamine, triethylamine, tert-butylamine, diisopropylamine or mixtures thereof.

3. The process according to claim 1, wherein the solvent used in step (i) is selected from N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, acetone, toluene, ethyl acetate or mixtures thereof.

4. The process according to claim 1, wherein the solvent used in step (ii) is selected from acetone, ethyl acetate, water, acetonitrile or mixtures thereof.

5. The process according to claim 1, wherein the base used in step (iii) is selected from an alkali metal hydroxide selected from sodium hydroxide, lithium hydroxide, cesium hydroxide or mixtures thereof.

6. The process according to claim 1, wherein the solvent used in step (iii) is selected from tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, water, ethylene glycol or mixtures thereof.

7. The process according to claim 1, wherein the alkali halide used in step (iv) is selected from sodium chloride, sodium bromide, sodium iodide, lithium chloride, cesium chloride or mixtures thereof.

8. The solvent used in step (iv) is selected from tetrahydrofuran, N,N-dimethyl acetamide, N,N-dimethylformamide, N,N-dimethyl sulfoxide, ethyl acetate, toluene, acetone, methanol, ethanol, isopropanol, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof.

9. The process according to claim 1, wherein de-tritylation step (v) is carried out in the presence of acid or aqueous acid.

10. The process according to claim 9, wherein acid is selected from carboxylic acids such as formic acid, acetic acid, oxalic acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid; inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid or mixtures thereof.