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

PREPARATION OF OLMESARTAN MEDOXOMIL

INTRODUCTION
The present invention relates to processes for preparing olmesartan medoxomil. In particular embodiments  the present invention provides processes for preparing olmesartan medoxomil  without isolating one or more intermediate compounds.
The drug having the adopted name “olmesartan medoxomil” has a chemical name 2 3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5ylphenyl)benzyl]imidazole-5-carboxylate  cyclic 2 3-carbonate  and is represented by structural Formula I.

Formula I
Olmesartan is a selective angiotensin II receptor antagonist  pharmaceutically used as an antihypertensive for the treatment and prophylaxis of hypertension. It is commercially available in the form of the prodrug olmesartan medoxomil  in products sold using the trademark BENICAR for oral administration as film-coated tablets containing 5 mg  20 mg  or 40 mg of olmesartan medoxomil.
Olmesartan medoxomil and other related imidazole derivatives have been disclosed in U.S. Patent No. 5 616 599. This patent also describes a process for preparation of the imidazole derivatives useful for the synthesis of olmesartan  which involves reaction of diethyl 2-propylimidazole-4 5-dicarboxylate with a Grignard reagent to give ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate  which  on condensation with 4-[2-(trityltetrazole-5-yl)phenyl]benzyl bromide  gives ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazole -5-yl)phenyl] phenyl}methylimidazole-5-carboxylate of Formula IV below  where R is ethyl.
Various modifications in solvents and reagents at different steps are disclosed in the subsequent literature to achieve higher yields and purity of olmesartan medoxomil.
International Application Publication No. WO 2007/017135 discloses a process where ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate is reacted with N-(triphenylmethyl)-5-[4""-(bromomethyl)biphenyl-2-yl]tetrazole  in the presence of a base  using acetonitrile as a solvent  to obtain ethyl-4-(1-hydroxy-1-methylethyl) 2-propyl-1-[[2""-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate.
International Application Publication No. WO 2006/029056 discloses a process for the removal of a trityl group  involving the reaction of trityl olmesartan medoxomil with sulfuric acid  in a mixture of water and acetone  to obtain a solution of olmesartan medoxomil and a precipitate of the triphenylcarbinol salt. The triphenylcarbinol precipitate is removed by filtration  followed by treating the solution with a base to precipitate olmesartan medoxomil.
Additional synthetic methods for olmesartan medoxomil have been described in U.S. Patent Application Publication Nos. 2006/0148870 and 2006/0149078  and in International Application Publication Nos. WO 2006/029057  WO 2004/085428  WO 2006/073518  WO 2006/073519  WO 2007/048361  WO 2007/148344  WO 2008/043996  and others.
Processes of the above-mentioned patents and applications generally involve isolation of various intermediates at different stages  and also involve filtration of the triphenylcarbinol salt  after deprotection of trityl olmesartan medoxomil.
A need exists for improved processes to prepare olmesartan medoxomil.

SUMMARY
Aspects of the present application provide processes for the preparation of olmesartan medoxomil.
The present inventors have found that  after deprotection of the trityl group from trityl olmesartan medoxomil  as an alternative to removing the triphenyl carbinol salt  it can be dissolved in a suitable solvent during workup and then olmesartan medoxomil can be isolated. This provides advantages of cost and ease of conducting the synthesis.
An aspect of the present invention provides a one-pot process for the preparation of olmesartan medoxomil  proceeding without isolation of intermediate compounds formed in various stages of the process  and also not involving filtration of the formed triphenylcarbinol salt after completion of a deprotection reaction.
The present invention provides processes for the preparation of olmesartan medoxomil  which can be practiced on an industrial scale and provide high yields of the product.
In an aspect  the present application provides processes for preparing olmesartan medoxomil  embodiments comprising:
a) reacting alkyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxy-late of Formula II with N-(triphenylmethyl)-5-[4""-(bromomethyl)biphenyl-2-yl]tetrazole of Formula III  where Ph is a phenyl group  in the presence of a base and nonpolar solvent  to form an alkyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2""-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula IV;

Formula II Formula III Formula IV
b) reacting the compound of Formula IV with a base to form trityl olmesartan;
c) reacting trityl olmesartan with 5-methyl-2-oxo-(1 3-dioxolene-4-yl)methyl chloride to form trityl olmesartan medoxomil; and
d) deprotecting trityl olmesartan medoxomil to form olmesartan medoxomil.
In embodiments  one or more sequential steps are carried out without isolating intermediate compounds. In embodiments of the invention  any one or more of steps b)  c)  and d) are carried out without isolating the intermediate compounds formed in the immediately preceding step  followed by isolation of trityl olmesartan medoxomil.
In an aspect  the present invention provides processes for the preparation of olmesartan medoxomil  starting from trityl olmesartan medoxomil  without precipitating a triphenylcarbinol salt.
In an aspect  the present invention provides processes for preparing olmesartan medoxomil  comprising deprotecting trityl olmesartan medoxomil in the presence of an acid  without precipitating a triphenylcarbinol salt.
In an aspect  the present invention provides pharmaceutical compositions comprising olmesartan medoxomil prepared according to a process of the present invention  together with one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION
Aspects of the present application provide processes for the preparation of olmesartan medoxomil. Embodiments of processes comprise:
a) reacting alkyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxy-late of Formula II with N-(triphenylmethyl)-5-[4""-(bromomethyl)biphenyl-2-yl]tetrazole of Formula III  in the presence of a base and non-polar solvent  to form an alkyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2""-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula IV;

Formula II Formula III Formula IV
b) reacting the compound of Formula IV with a base to form trityl olmesartan;
c) reacting trityl olmesartan with 5-methyl-2-oxo-(1 3-dioxolene-4-yl)methyl chloride to form trityl olmesartan medoxomil; and
d) deprotecting trityl olmesartan medoxomil to form olmesartan medoxomil.
Suitably  one or more sequential steps are carried out without isolating the intermediate compounds that are formed. In embodiments of the invention  one or more of steps b)  c)  and d) are carried out without isolating the intermediate compounds formed in the immediately preceding step  followed by isolation of trityl olmesartan medoxomil.
Step a) involves reacting alkyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxy-late of Formula II with N-(triphenylmethyl)-5-[4""-(bromomethyl)biphenyl-2-yl]tetrazole of Formula III  in the presence of a base and nonpolar solvent  to obtain alkyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2""-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula IV.
Non-polar solvents that can be used in step a) include  but are not limited to  hydrocarbons such as hexane  heptane  cyclohexane  methylcyclohexane  toluene  xylene  and any mixtures thereof.
Suitably  the reaction may be carried out with a mixture of a non-polar solvent and water. The content of water can range from about 1 to about 90% by weight of the non-polar solvent.
Suitable bases that can be used for the reaction include  but are not limited to  organic bases such as diisopropylamine and tertiary-butylamine  and inorganic bases such as alkali metal hydroxides  alkali metal alkoxides  and alkali metal carbonates. The alkali metal hydroxides include lithium hydroxide  sodium hydroxide  and potassium hydroxide  alkali metal alkoxides include sodium methoxide  sodium ethoxide  and potassium tertiary-butoxide  and alkali metal carbonates include sodium carbonate and potassium carbonate.
Suitably  aqueous solutions of a base containing about 5% to 50%  or about 10% to 20%  (w/v) of the base can be used.
The reaction may be conducted in the presence of a phase transfer catalyst. Phase transfer catalysts that can be used include  but are not limited to  tetralkylammonium or phosphonium salts  such as tetrabutylammonium bromide  tetrabutylammonium fluoride  and tetrabutylammonium hydrogen sulphate  crown ethers such as 15-crown-5 and 18-crown-6  and the like.
Suitable temperatures for conducting the reaction range from about 25°C to the reflux temperature of the solvent or mixture of solvents used.
Suitably  the compound of Formula IV obtained as a product can be isolated  or the reaction mixture can be directly progressed to the next stage to form trityl olmesartan.
Step b) involves reacting the compound of Formula IV with a base to give trityl olmesartan.
Suitable bases that can be used include  but are not limited to  organic bases such as diisopropylamine and tertiary-butylamine  and inorganic bases such as alkali metal hydroxides  alkali metal alkoxides  and alkali metal carbonates. The alkali metal hydroxides include lithium hydroxide  sodium hydroxide  and potassium hydroxide  alkali metal alkoxides include sodium methoxide  sodium ethoxide  and potassium tertiary-butoxide  and alkali metal carbonates include sodium carbonate and potassium carbonate.
When the reaction is conducted without isolation of the compound obtained in step a) from the reaction mixture  optionally  an additional solvent may be added to the reaction mixture. The added solvent may or may not be the same solvent that is used for the reaction in step a). Additionally  water may be added to the reaction mixture.
The reaction may be carried out at temperatures ranging from about 25°C to the reflux temperature of the solvent or mixture of solvents used.
The product obtained in step b) may be optionally isolated  or the reaction mixture may be progressed directly to step c).
Step c) involves reacting trityl olmesartan with 5-methyl-2-oxo-(1 3-dioxolene-4-yl)methyl chloride to give trityl olmesartan medoxomil.
The reaction is suitably conducted in the presence of a base. The base may be directly added to the reaction mixture obtained from step b) when the reaction is conducted without isolation of the product obtained in step b). The base may be any of inorganic bases such as alkali metal hydroxides  alkali metal alkoxides  and alkali metal carbonates. The alkali metal hydroxides include lithium hydroxide  sodium hydroxide  and potassium hydroxide  alkali metal alkoxides include sodium methoxide  sodium ethoxide  and potassium tertiary-butoxide  and alkali metal carbonates include sodium carbonate and potassium carbonate. Organic bases may also be used  such as diisopropylamine and tertiary-butylamine.
Advantageously  the reaction may be carried out in the presence of a phase transfer catalyst such as a tetralkylammonium or phosphonium salt  such as tetrabutylammonium bromide  tetrabutylammonium fluoride  and tetrabutylammonium hydrogen sulphate  crown ethers like 15-crown-5  18-crown-6  and the like.
The reaction may be carried out at temperatures ranging from about 25°C to the reflux temperature of the solvent or mixture of solvents used.
The product obtained in step c) may be progressed to a deprotection reaction without isolation of the trityl olmesartan medoxomil obtained.
When the trityl olmesartan medoxomil is isolated  the isolation may be accomplished using techniques known in the art  for example  by neutralization using an acid. Optionally  the trityl olmesartan medoxomil obtained can be further purified by recrystallization or slurrying in a suitable solvent.
Suitable organic solvents which can be used for recrystallization or slurrying include  but are not limited to: ketones such as acetone  ethyl methyl ketone  and butanone; nitriles such as acetonitrile and propionitrile; alcohols such as methanol  ethanol  isopropanol  1-butyl alcohol  2-butyl alcohol  and tertiary-butyl alcohol; hydrocarbons such as hexane  heptane  cyclohexane  benzene  xylene  and toluene; halogenated hydrocarbons such as dichloromethane  chloroform  and ethylene dichloride; esters such as ethyl acetate and propyl acetate; and any mixtures thereof in various proportions without limitation.
Step d) involves deprotecting trityl olmesartan medoxomil to give olmesartan medoxomil.
In embodiments  the deprotection reaction is carried out by treating the protected compound with an acid.
Suitable acids that can be used include  but are not limited to  sulfuric acid  acetic acid  hydrochloric acid  nitric acid  phosphoric acid  and the like.
Suitable solvents that can be used include  but are not limited to: alcohols such as methanol  ethanol  isopropanol  1-butyl alcohol  2-butyl alcohol  and tertiary-butyl alcohol; hydrocarbons such as hexane  heptane  cyclohexane  benzene  xylene  and toluene; halogenated hydrocarbons such as dichloromethane  chloroform  and ethylene dichloride; esters such as ethyl acetate and propyl acetate; and any mixtures thereof in various proportions without limitation.
In an aspect  the present invention provides processes for preparing olmesartan medoxomil  starting from trityl olmesartan medoxomil  without isolating a triphenylcarbinol salt.
The term “without isolating” indicates that the triphenylcarbinol salt is not filtered or otherwise removed as a solid  during or after the deprotection reaction.
The deprotection reaction is first carried out in a water-miscible solvent such as: alcohols  including methanol  ethanol  isopropyl alcohol  and n-butanol; ketones  including acetone and methyl ethyl ketone; and nitriles  including acetonitrile and propionitrile; and  after completion of the reaction  a water-immiscible solvent may be added.
Water-immiscible solvents that can be used include  but are not limited to: hydrocarbons such as hexane  heptane  cyclohexane  benzene  xylene  and toluene; esters such as ethyl acetate  isopropyl acetate  isobutyl acetate  and tertiary-butyl acetate; and halogenated hydrocarbons such as dichloromethane and chloroform.
Suitably  the water-immiscible solvent is chosen such that the triphenylcarbinol salt is highly soluble in the solvent  so that after completion of the reaction  the triphenylcarbinol salt remains dissolved in the water-immiscible solvent layer and the product remains in the aqueous layer.
The aqueous layer may be subjected to further treatment  such as treatment with a base for extraction of olmesartan medoxomil.
In embodiments  the water-miscible solvent used is an alcohol and the water-immiscible solvent used is a hydrocarbon.
The product may be extracted from the aqueous layer by treatment with a base.
Suitable bases that can be used for basic hydrolysis include  but are not limited to: alkoxides  including sodium methoxide  sodium ethoxide  potassium methoxide  potassium ethoxide  sodium tertiary-butoxide  potassium tertiary-butoxide  sodium secondary-butoxide  potassium secondary-butoxide  and the like; alkali metal hydroxides  including sodium hydroxide  potassium hydroxide  and lithium hydroxide; alkali metal carbonates  including sodium carbonate  sodium bicarbonate  potassium carbonate  potassium bicarbonate  lithium carbonate  and the like; and alkali metal hydrides  including sodium hydride and the like.
Olmesartan medoxomil that is obtained can be purified by recrystallization or slurrying in a suitable solvent.
Suitable organic solvents that can be used for recrystallization or slurry formation include  but are not limited to: esters such as ethyl acetate  n-butyl acetate  tertiary-butyl acetate  isopropyl acetate  and the like; ketones such as acetone  ethyl methyl ketone  and the like; hydrocarbons such as toluene  xylene  n-hexane  n-heptane  cyclohexane  and the like; nitriles such as acetonitrile  propionitrile  and the like; and any mixtures thereof in various proportions.
Olmesartan medoxomil obtained using a process of the present invention has a purity about 99.5% or higher  or about 99.9% or higher  by weight  as determined using high performance liquid chromatography (HPLC). Among the useful HPLC methods is one described in International Application Publication No. WO 2007/047838.
In an aspect  the present invention provides pharmaceutical compositions comprising olmesartan medoxomil  prepared according to a process of the present invention  together with one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions comprising olmesartan medoxomil  together with one or more pharmaceutically acceptable carriers  may be formulated as: solid oral dosage forms such as  but not limited to  powders  granules  pellets  tablets  and capsules; liquid oral dosage forms such as but not limited to syrups  suspensions  dispersions  and emulsions; and injectable preparations such as but not limited to solutions  dispersions  and freeze dried compositions. Formulations may be in the form of immediate release  delayed release  or modified release. Further  immediate release compositions may be conventional  dispersible  chewable  mouth dissolving  or flash melt preparations  and modified release compositions that may comprise hydrophilic or hydrophobic  or combinations of hydrophilic and hydrophobic  release rate-controlling substances  to form matrix  reservoir  or combination of matrix and reservoir systems. The compositions may be prepared using any of techniques such as direct blending  dry granulation  wet granulation  or extrusion and spheronization. Compositions may be presented as uncoated  film coated  sugar coated  powder coated  enteric coated  or modified release coated.
Pharmaceutically acceptable excipients that can be used in the present invention include  but are not limited to: diluents such as starch  pregelatinized starch  lactose  powdered cellulose  microcrystalline cellulose  dicalcium phosphate  tricalcium phosphate  mannitol  sorbitol  sugar and the like; binders such as acacia  guar gum  tragacanth  gelatin  polyvinylpyrrolidones  hydroxypropyl celluloses  hydroxypropyl methylcelluloses  pregelatinized starches  and the like; disintegrants such as starches  sodium starch glycolate  pregelatinized starches  crospovidones  croscarmellose sodium  colloidal silicon dioxide  and the like; lubricants such as stearic acid  magnesium stearate  zinc stearate  and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic  cationic  or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate-controlling agents such as hydroxypropyl celluloses  hydroxymethyl celluloses  hydroxypropyl methylcelluloses  ethyl celluloses  methyl celluloses  various grades of methyl methacrylates  waxes  and the like. Other pharmaceutically acceptable excipients that can be used include  but are not limited to  film formers  plasticizers  colorants  flavoring agents  sweeteners  viscosity enhancers  preservatives  antioxidants and the like.
In the compositions of present invention olmesartan medoxomil is a useful active ingredient in the range of 20 mg to 350 mg  or 40 mg to 320 mg  per unit dose.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below  which examples are provided only for the purpose of illustration and are not intended to limit the scope of the appended claims in any manner.

EXAMPLE 1: PREPARATION OF OLMESARTAN MEDOXOMIL (FORMULA I).
A. Preparation of ethyl-4-(1-hydroxy-1-methylethyl) 2-propyl-1-[[2""-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate (Formula IV).
A mixture of ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (5.0 g)  potassium carbonate (5.75 g)  and toluene (50 mL) is stirred at 45-50°C for 45 minutes. N-(triphenylmethyl)-5-[4""-(bromomethyl)biphenyl-2-yl]tetrazole (13.2 g) and tetrabutylammonium bromide (1.3 g) are added and the mixture is stirred at 60-70 °C for 10 hours. The insoluble material is removed by filtration and the filtrate is washed with water (2×50 mL) at 60-70°C. The filtrate is distilled under vacuum to produce a syrup. Methanol (25 mL) is added to the residue and stirred for 15 minutes at 25-35°C. The mass is cooled to 0-5 °C and stirred at that temperature for 45 minutes. The precipitated solid is collected by filtration  washed with methanol (10 mL)  and dried at 50-60°C for 6 hours (yield 13.3 g).
B. Preparation of trityl olmesartan medoxomil.
To a solution of the compound of Formula IV (5.0 g) in toluene (40 mL)  dimethylacetamide (10 mL) is added  followed by addition of sodium hydroxide (1.2 g) and N N-diisopropylamine (3.7 g) at 25-35°C. The mixture is stirred at 40-45°C for 4 hours. 5-Methyl-2-oxo-(1 3-dioxolene-4-yl)methyl chloride (1.5 g) and tetrabutylammonium bromide (0.5 g) are added at 40-45°C. The mixture is stirred at 60-70°C for 8 hours. The mass is cooled to 25-35°C  water (50 mL) is added  and the pH is adjusted to about 6-7 by adding 10% aqueous HCl. The layers are separated. The aqueous layer is extracted with toluene (25 mL). The organic layers are combined and washed with water (25 mL). The solvent is distilled under reduced pressure. Methanol (25 mL) is added to the residue. The mixture is cooled to 0-5°C and stirred at that temperature for 45 minutes. The formed solid is filtered  washed with methanol (10 mL) and dried for 45 minutes under vacuum (yield 3.0 g).
C. Preparation of olmesartan medoxomil.
A mixture of trityl olmesartan medoxomil (4.0 g)  methanol (20 mL)  and water (10 mL) is stirred at 25-35°C for 15 minutes. Aqueous HCl (1 mL) is added drop-wise at 25-35°C. The mixture is cooled to 0-5°C. Water (30 mL) is added and the mixture is further stirred at 0-5°C for 1 hour. The insoluble material is removed by filtration and the pH of the filtrate is adjusted to about 3-4 by adding 10% aqueous NaHCO3 at 25-35°C. The mixture is extracted with dichloromethane (3×40 mL). The organic layers are combined and washed with water (40 mL). The solvent is distilled under reduced pressure below 40°C. Ethyl acetate (10 mL) is added to the residue and the mixture is heated to 50-60°C and stirred for 1 hour. The mixture is cooled to 25-35°C. The formed solid is filtered  washed with ethyl acetate (5 mL)  and dried under vacuum at 60-70°C (yield 2.0 g).
Purity by HPLC: 99.8%.

EXAMPLE 2: PREPARATION OF TRITYL OLMESARTAN MEDOXOMIL  WITHOUT ISOLATING THE COMPOUND OF FORMULA IV.
A mixture of ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (10 g)  N-(triphenylmethyl)-5-[4""-(bromomethyl)biphenyl-2-yl]tetrazole (30.1 g)  potassium carbonate (20.1 g)  and dimethylacetamide (80 mL) is stirred at 45-50°C for 7 hours. The insoluble material is removed by filtration. Potassium tertiary-butoxide (9.3 g) is added to the filtrate and the mixture is stirred at 55-60°C for 3 hours. 5-Methyl-2-oxo-(1 3-dioxolene-4-yl)methyl chloride (6.5 g) is added and the mixture is maintained at 55-60°C for 6 hours. The mass is cooled to 25-35°C  toluene (100 mL) and saturated NaCl solution (100 mL) are added  and the pH is adjusted to about 7 by adding 10% acetic acid. The layers are separated. The aqueous layer is extracted with toluene (50 mL). The organic layers are combined and distilled under reduced pressure. Acetonitrile (20 mL) is added to the residue and stirred at 25-35°C for 15 minutes. The mixture is cooled to 0-5°C and stirred at that temperature for 45 minutes. The formed solid is filtered  washed with acetonitrile (20 mL)  and dried for 3 hours under vacuum (yield 13.0 g).

EXAMPLE 3: PREPARATION OF TRITYL OLMESARTAN MEDOXOMIL.
Toluene (180 L) is placed into a reactor and water (3.17 L) is added  followed by addition of ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (18.0 Kg). The mass is stirred for about 10 minutes  heated to about 45°C  and potassium carbonate (25.85 Kg) is added. The temperature of the mass is raised to about 65°C and maintained for about 45 minutes. N-(triphenylmethyl)-5-[4""-(bromomethyl)biphenyl-2-yl]tetrazole (48.9 Kg) and tetrabutylammonium bromide (4.82 Kg) are added at the same temperature and the mixture is stirred at 60-70°C for 10 hours. Reaction completion is verified using thin layer chromatography (TLC). After the reaction is complete  the mass is washed with water (3×120 L) at about 50°C. The mass is cooled to about 25°C and toluene (468 L) and potassium tertiary-butoxide (12.6 Kg) is added  then the mass is maintained at the same temperature for about 1 hour. Water (0.85 L) is added and the mass is maintained at the same temperature for about 2 hours. Reaction completion is verified using TLC  then 5-methyl-2-oxo-(1 3-dioxolene-4-yl)methyl chloride (20 Kg)  tetrabutylammonium bromide (4.82 Kg)  and sodium carbonate (3.96 Kg) are added at 40-45°C. The mass is stirred at about 55°C for about 11 hours. After the reaction is complete  the mass is cooled to about 20°C  water (540 L) is added and the pH is adjusted to about 6-7 by adding 10% aqueous HCl. The layers are separated. The aqueous layer is extracted with toluene (240 L). The organic layers are combined and washed with water (270 L). The solvent is distilled under reduced pressure. Acetone (189 L) is added to the residue and the mixture is heated to about 45°C to produce a solution  then the solution is cooled to about 30°C and maintained for about 20 minutes  followed by cooling to about 2°C and maintaining for about 3 hours. The formed solid is filtered  washed with acetone (54 L)  and dried for about 4 hours. The material obtained is re-crystallized from acetonitrile to yield 34.0 Kg of the title compound.

EXAMPLE 4: PREPARATION OF OLMESARTAN MEDOXOMIL FROM TRITYL OLMESARTAN MEDOXOMIL.
Acetone (46 L) and trityl olmesartan medoxomil (23 Kg) are mixed  heated to 55°C  and maintained for about 20 minutes. The mass is cooled to about 25°C  then further cooled to about 5°C and maintained for about 60 minutes. The solid is filtered and washed with acetone (23 L). The wet solid is dried at about 45°C for about 4 hours. The dry solid and methanol (108.5 L) are stirred at about 25°C for 10 minutes. Aqueous HCl (3.25 Kg) is added and the mixture is stirred at about 25°C for 3 hours. Hexane (104 L) and water (207 L) are added and stirred at about 25°C for 15 minutes. The layers are separated and the aqueous layer is washed with hexane (124 L). Dichloromethane (166 L) is added to the aqueous layer and the pH is adjusted to about 3-4 by adding aqueous NaHCO3 solution (10%  3.0 Kg). The layers are separated and the aqueous layer is extracted with dichloromethane (164 L). The dichloromethane layers are combined and washed with water (104 L). The solvent is distilled under reduced pressure. Acetone (217 L) is added to the residue and the mixture is stirred at about 55°C for 30 minutes. About 80% of the solvent is distilled under reduced pressure. The concentrate is cooled to 25-35°C. The precipitated solid is filtered and dried under vacuum at 50°C  to yield 8.4 Kg of the title compound.
Purity by HPLC: 99.8%.

We Claim:
1. A process for preparing olmesartan medoxomil  comprising:
a) reacting alkyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxy-late of Formula II with N-(triphenylmethyl)-5-[4""-(bromomethyl)biphenyl-2-yl]tetrazole of Formula III  where Ph is a phenyl group  in the presence of a base and non-polar solvent  to form an alkyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2""-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula IV;

Formula II Formula III Formula IV
b) reacting the compound of Formula IV with a base to form trityl olmesartan;
c) reacting trityl olmesartan with 5-methyl-2-oxo-(1 3-dioxolene-4-yl)methyl chloride to form trityl olmesartan medoxomil; and
d) deprotecting trityl olmesartan medoxomil to form olmesartan medoxomil.
2. The process of claim 1  wherein a non-polar solvent comprises a hydrocarbon selected from hexane  heptane  cyclohexane  methyl cyclohexane  toluene  or xylene.
3. The process of claim 1  wherein a non-polar solvent is present together with water.
4. The process of claim 1  wherein either or all of the intermediate of Formula IV formed in step a)  trityl olmesartan formed in b) and trityl olmesartan medoxomil formed in c) are not isolated.
5. A process for preparing olmesartan medoxomil  comprising deprotecting trityl olmesartan medoxomil in the presence of an acid  without precipitating a triphenylcarbinol salt.
6. The process of claim 9  wherein a reaction is initially carried out in a water miscible solvent  followed by addition of a water immiscible solvent.
7. The process of claim 10  wherein a water miscible solvent comprises an alcohol selected from methanol  ethanol  isopropanol  or tertiary-butanol.
8. The process of claim 10  wherein a water immiscible solvent comprises a hydrocarbon selected from hexane  heptane  cyclohexane  benzene  xylene  or toluene.
9. Olmesartan medoxomil prepared by the process of any preceding claim and having purity about 99 percent by weight or greater  as determined using high performance liquid chromatography.
10. A pharmaceutical formulation comprising olmesartan medoximil of claim 17.