FIELD OF INVENTION

The present invention relates to an improved process for the manufacture of Olmesartan and its pharmaceutically acceptable salts and esters thereof, as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions.

BACKGROUND OF INVENTION

In medicine olmesartan medoxomil, chemically described as Olmesartan medoxomil, 4-( 1 -hydroxy-1 -methylethyl)-2-propyl-1 -[[2'-( 1H-tetrazol-5-yl) [ 1, 1 '-biphenyl]-4yl] methyl|-1H-imidazole-5-carboxylic acid has the formula as given below:

It is widely used for the treatment of hypertension and related diseases and conditions due to its ability to inhibit the angiotensin-converting enzyme. As an angiotensin II receptor antagonist, olmesartan medoxomil avoids the side-effects of calcium antagonists, shows high stability and obvious curative effects.

US 5,616,599 discloses processes for the preparation of olmesartan medoxomil involving inter alia reacting (5-methyl-2-oxo-l,3-dioxolcn-4-yl)methyl-4-(l-hydroxy- 1 -methylethyl)-2-propylimidazole-5-carboxylate and 4-[2-trityltetrazol-5- yl)phenyl]benzyl bromide in N,N-dimethyl acetamide in the presence of potassium carbonate or reacting ethyl-4-(l -hydroxy- l-methylcthyl)-2-propylimidazole-5-carboxylate and 4-[2-trityltetrazol-5-yl)phcnyl]benzyl bromide in N,N- dimethylformamide in the presence of sodium hydride. In example 70, the alkylation of ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate with 4'-bromomethylbiphenyl-2-carbonitriIe in N,N-dimethyl acetamide and in the presence of potassium tert -butoxide is disclosed. Common to all the processes disclosed is that the alkylated product is subjected to a column chromatography in order to obtain an acceptable purity. For the preparation of an ester, the product obtained is described to be hydrolyzcd by means of an alkali metal hydroxide, the salt is isolated and further esterified. In the last step, the trityl protection group is removed by treating the trityl medoxomil ester in acetic acid.

The process of detritylation of trityl olmesartan medoxomil is disclosed in col-193, example: 78(b). In this process the precipitated triphenyl carbinol is removed by filtration.

US 7,528,258 B2 discloses a process for preparing olmesartan medoxomil comprises the steps of: Contacting trityl olmesartan medoxomil with an acid in a water miscible organic solvent, with or without water, to obtain a solution of olmesartan medoxomil and a precipitate of triphenyl carbinol; filtering the precipitate of triphenyl carbinol from the solution of olmesartan medoxomil; and contacting the solution of olmesartan medoxomil with a base to obtain olmesartan medoxomil.

In J. Med. Chcm., 39 (1996), 323-338 the alkylation step between 4-[2-trityltetrazol-5-yl)-phenyl|benzyl bromide or its analogues and the imidazole intermediate is described to have been performed in N,N-dimethyl acetamide and in the presence of potassium tert-butoxide. Ethyl acetate and water is added to the reaction mixture and the product is extracted into Ethyl acetate. The purification of the product is achieved by the use of flash column chromatography (Ethyl acctatc/hexane, 1:2) and optionally by an additional crystallization from Isopropyl ether, hexane, Ethyl acetate or mixtures thereof.

In HP 0 796 852 B1 the authors disclose a safer and easier preparation of 5-substituted tetrazoles without the use of Bu3SnN3. The process comprises reacting nitrile with an inorganic azide salt in an aromatic hydrocarbon solvent in the presence of an amine salt.

In WO 2004/085428 there is described a new process for the preparation of olmesartan medoxomil. In the process the ring in 4,4-dimethyl-2-propyl-l-{4-[2-(triphenyl-methyl-tertazole-5-yl)phenyl]phenyl}methyl-4,6-dihydrofuran-[3,4d]imidazole-6-one is opened, and the resulting 4-( 1-hydroxy-1-methylethyl)-2-propyl-I-{4-|2-(triphcnyl-methyl-tertazole-5yl)-phenyl]phenyl}methylimidazole-5-carboxylic acid is subsequently condensed with 4-halo-methyl-5-methyl-2-oxy-l,3-dioxyheterocyclopentene under the action of alkali. After deprotection of the triphenylmethyl protecting group, olmesartan medoxomil is obtained.

WO 2007/048361 discloses a method of removing the triphenylmethyl protecting group from the precursors of antihypertensive drugs of general formula I, wherein R is a mctabolically designed.

WO 2007/047838 also discloses another process for the preparation of Olmesartan which is depicted in the following scheme:

A general shortcomings of the prior art methods resides in that processes proposed involve, apart from applying column chromatography, additional isolation steps, which arc acknowledged to decrease yield and rendering processes cumbersome.

In view of the shortcoming of the prior art an object of the present invention resides in providing an alternative process for obtaining olmesartan medoxomil, which may be rapidly carried out, is economical and provides the desired compound in high purity.

OBJECTIVE OF THE INVENTION

The main object of the present invention is to provide a process for the preparation of Olmesartan medoxomil with high purity.

In another object of the present invention is to perform the alkylation and esterification reaction in presence of a catalyst.

Another embodiment of the invention provides a process for preparing olmesartan medoxomil, comprising deprotection of trityl olmesartan medoxomil in the presence of an acid and further isolating the pure olmesartan medoxomil by slurrying with toluene and heptane or hcxane.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of olmesartan medoxomil. The main aspect of the present invention provides a process for the preparation olmesartan which comprises:

a) reacting diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate with 5-(4'-(bromomethyl)biphenyl-2-yl)-l -trityl- 1H-tetrazole to give diethyl 2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxylate in presence of base and catalyst,

b) reacting the obtained diethyl 2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxylate with methylmagnesium halide to yield ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-l- ((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-
carboxylatc,

c) hydrolyzing the ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1 H-imidazole-5-carboxylate to obtain trityl olmesartan salt,

d) cstcrifying the salt of trityl olmesartan with 4-halo-methyl-5-methyl-2-oxo-1,3-dioxolane in an organic solvent in the presence of catalyst and optionally in the presence of additional base to obtain tirtyl olmesartan medoxomil followed by,

e) deprotection of the trityl olmesartan medoxomil to give Olmesartan medoxomil.

The present invention also relates to a process for preparing Olmesartan medoximil comprising

a) deprotecting trityl olmesartan medoximil in presence of an acid and water mixture in water miscible solvent,

b) adjusting the pH from 4.0 to 4.5,

c) extracting the residue with ethylacetate or methylene dichloride,

d) evaporating the ethyl acetate layer to give residue containing triphenyl carbinol and olmesartan medoximil,

e) refluxing the residue in a mixture of water immiscible solvents,

f) isolating olmesartan medoximil by filtration.

DETAILED DESCRIPTION OF THE INVENTION

In a specific embodiment, the present invention provides a process for the preparation of olmesartan medoxomil which involves condensing diethyl-2-propyl-1H-imidazole-4,5-dicarboxylate with 5-(4'-(bromomethyl)biphenyl-2-yl)-l-trityl-1H-tetrazole in presence of a catalyst Viz polyethylene glycol 400 using base in an organic solvent to obtain diethyl 2-propyl-1 -((2'-( 1 -trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxylate followed by reaction with methyl magnesium halide to obtain ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l -trityl- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate. The resultant grignard reaction product is hydrolyzed to obtain trityl olmesartan which is isolated as its sodium salt. Esterification of sodium salt of trityl olmesartan with 4-halomethyl-5-methyl-2-oxo-l,3-dioxolene in an organic solvent in the presence of base and Polyethylene glycol 400 gives trityl olmesartan medoxomil followed by deprotection yields olmesartan medoxomil.

The alkylation reaction is carried out in the presence of base selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkali metal hydrides such as sodium hydride, potassium hydride or lithium hydride, alkali metal alkoxides such as sodium methoxide, sodium ethoxidc, potassium tert-butoxide or lithium methoxide, more preferably potassium carbonate.

The alkylation reaction is carried out in inert organic solvent selected from aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as tetrahydrofuran or dioxane, alcohols such as methanol, ethanol, or tert-butanol, amides such as N,N-dimethylacetamide, N,N-dimethylformamide or jV-methyl-2-pyrrrolidinone, ketones such as acetone or methyl ethyl ketone, nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, more preferably acetone.

It has been unexpectedly found that in the preparation of olmesartan medoxomil the alkylation step goes to completion very quickly and also gives higher yields with low level of impurities. This has been accomplished by employing polyethylene glycol 400 as catalyst.

The ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5- yl)biphcnyl-4-yl)methyl)-1H-imidazole-5-carboxylate is hydrolyzed with bases that arc selected from potassium hydroxide, sodium hydroxide etc in alcohols like ethanol, methanol and isopropyl alcohol and ethers like dioxane, tetrahydrofuran to yield trityl olmesartan as salt.

The esterification of trityl olmesartan with medoxomil halide is conducted in an organic solvent selected from N,N-dimethylformamide or N,N-dimcthylacetamide, halogcnatcd aliphatic hydrocarbons such as methylene chloride, ketones such as acetone or methyl isobutyl ketone, ethers such as tetrahydrofuran, dioxane, aromatic hydrocarbons such as toluene, xylene more preferably N,Ndimcthylacctamide.

The esterification is preferably carried out in the presence of polyethylene glycol 400 as catalyst and optionally bases are employed which are selected from organic amine base such as triethylamine, pyridine, N/-methyl morpholine, an alkali metal carbonate such as sodium carbonate or potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide.

The deprotection of the obtained trityl olmesartan medoxomil is carried out as per the methods reported in the literature.

In another embodiment of the invention, the deprotection of trityl omlesartan is carried out in the presence of acid and water mixture in a water miscible organic solvent. After the reaction is completed, the pH of the organic layer is adjusted to 4-5 by using a base and extracted with suitable solvent. Then the organic layer is washed with water followed by 10% sodium chloride solution. The solvent is distilled off under vacuum. The obtained residue containing triphenyl carbinol, as byproduct is refluxed with toluene and heptane/hexane mixture. After the completion of reflux, the solution is cooled and filtered to get pure olmesartan medoxomil, free from trityl carbinol which is further purified by cthylacctate to get the pharmaceutical grade olmesartan medoxomil.

EXAMPLES

Exam ple-1

Preparation of diethyl 2-propyI-l-((2'-(l-trityl-lII-tetrazol-5-yl)biphenyl-4- yl)methyl)-1H-imidazole-4,5-dicarboxylate 50 g of diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate was dissolved in 400 ml of acetone, 120.5 g of 5-(4'-(bromomethyl)biphenyl-2-yl)-l-trityl-1H-tetrazole, 82 g of potassium carbonate and 5 ml of polyethylene glycol-400 were added. Reaction mass was heated to reflux and maintained for 3 hours. Reaction completion was confirmed using thin layer chromatography. After reaction was completed, acetone was distilled off completely from the reaction mass and cooled to room temperature. 400 ml water was added to the reaction mass and stirred for 2 hours. The solid was filtered and washed with 100 ml of water. 200 ml of ethyl acetate was added to wet mass, re fluxed for 30 min and cooled to 10-15°C. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 60°C to get 134 g of title compound. Purity by HPLC: 99%.

Example-2

Preparation of diethyl 2-propyl-l-((2'-(l-trityl-1H-tctrazol-5-yl) biphenyl-4-yl) mcthyl)-1H-imidazole-4,5-dicarboxylate 10 g of diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate was dissolved in 80 ml of acetone, 24 g of 5-(4'-(bromomethyl)biphcnyl-2-yl)-l-trityl-1H-tetrazole, 10.5 g of sodium carbonate and 1 ml of polyethylene glycol-400 were added. Reaction mass was heated to reflux and maintained for 10 hours. Reaction completion was confirmed using thin layer chromatography. After reaction was completed, acetone was distilled off completely from the reaction mass and cooled to room temperature.

80 ml water was added lo the reaction mass and stirred for 2 hours. The solid was filtered and washed with 20 ml of water. 40 ml of ethyl acetate was added and refluxed for 30 min and cooled to 10-15°C. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 60°C to get 16 g of title compound. Purity by HPLC: 97%.

Example-3

Preparation of diethyl 2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4- yl)methyl)-1H-imidazolc-4,5-dicarboxylate 10 g of diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate was dissolved in 80 ml of acetone, 24 g of 5-(4'-(bromomethyl)biphenyl-2-yl)-l-trityl-1H-tetrazole, 4.6 g of sodium hydroxide and 1 ml of polyethylene glycol-400 were added. Reaction mass was heated to reflux and maintained for 12 hours. Reaction completion was confirmed using thin layer chromatography. After reaction was completed, acetone was distilled off completely from the reaction mass and cooled to room temperature. 80 ml water was added to the reaction mass and stirred for 2 hours. The solid was filtered and washed with 20 ml of water. 40 ml of ethyl acetate was added, refluxed for 30 min and cooled to 10-15°C. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 60°C to get 8.5 g of title compound. Purity by HPLC: 97.9%.

Example-4

Preparation of diethyl 2-propyl-l-((2'-(l-trityl-1H-tctrazol-5-yI) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxylate 10 g of diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate was dissolved in 80 ml of acetonitrile, 24 g of 5-(4'-(bromomethyl)biphenyl-2-yl)-l-trityl-1H-tctrazole, 16.2 g of potassium carbonate and 1 ml of polyethylene glycol-400 were added.

Reaction mass was heated to reflux and maintained for 6 hours. Reaction completion was confirmed using thin layer chromatography. After reaction was completed, acctonitrile was distilled off completely from the reaction mass and cooled to room temperature. 80 ml water was added to the reaction mass and stirred for 2 hours. The solid was filtered and washed with 20 ml of water. 40 ml of ethyl acetate was added and were refiuxed for 30 min and cooled to 10-15°C. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 60°C to get 16.5 g of title compound. Purity by HPLC: 96.9%.

Example-5

Preparation of diethyl 2-propyl-l-((2'-(l-trityl-1H-tctrazol-5-yl) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxylate 10 g of diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate was dissolved in 80 ml of Dimethyl formamidc, 24 g of 5-(4'-(bromomethyl)biphenyl-2-yl)-l-trityl-1H-tctrazolc, 16.2 g of potassium carbonate and 1 ml of polyethylene glycol-400 were added. Reaction mass was maintained at 60°C for 10 hours. Reaction completion was confirmed by TLC. After reaction was completed, DMF was distilled off completely from the reaction mass and cooled to room temperature. 80 ml water was added to the reaction mass and stirred for2 hours. The solid was filtered and washed with 20 ml of water. 40 ml of ethyl acetate was added and were refiuxed for 30 min and cooled to 10-15°C. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 60°C to get 20 g of title compound. Purity by 11 PLC: 99.2%.

Example-6

Preparation of diethyl 2-propyl-l-((2'-(l-trityl-1H-tctrazol-5-yl) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxyIate 10 g of diethyl 2-propyl-1H-imidazoIe-4,5-dicarboxylate was dissolved in 80 ml of Dimethyl acetamide, 24 g of 5-(4'-(bromomethyl)biphenyl-2-yl)-l-trityl-1H-tetrazole, 16.2 g of potassium carbonate and 1 ml of polyethylene glycol-400 were added. Reaction mass was maintained at 60°C for 10 hours. Reaction completion was confirmed by TLC. After reaction was completed, DMA was distilled off completely from the reaction mass and cooled to room temperature. 80 ml water was added to the reaction mass and stirred for 2 hours. The solid was filtered and washed with 20 ml of water. 40 ml of ethyl acetate was added and were refluxed for 30 min and cooled to 10-15°C. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 60°C to get 20 g of title compound.

Example-7

Preparation of diethyl 2-propyI-l-((2'-(l-trityl-1H-tctrazol-5-yl) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxylatc 10 g of diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate was dissolved in 80 ml of Methyl isobutyl ketone, 24 g of 5-(4'-(bromomcthyl)biphenyl-2-yl)-l-trityl-1H-tctrazole, further added 16.2 g of potassium carbonate and 1 ml of polyethylene glycol-400. Reaction was maintained at 60°C for 6 hours. Reaction completion was confirmed using thin layer chromatography. After reaction was completed, Methyl isobutyl ketone was distilled off completely from the reaction mass and cooled to room temperature. 80 ml water was added to the reaction mass and stirred for 2 hours. The solid was filtered and washed with 20 ml of water. 40 ml of ethyl acetate was added and were refluxed for 30 min and cooled to 10-15°C. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 60°C to get 27.5 g of title compound.

Example-8

Preparation of diethyl 2-propyI-l-((2'-(l-trityl-1H-tctrazol-5-yl) biphenyi-4-yl) methyl)-1H-imidazole-4,5-dicarboxylate 10 g of diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate was dissolved in 80 ml of acetone, 24 g of 5-(4'-(bromomethyl)biphenyl-2-yl)-l-trityl-1H-tetrazole, 10 g of sodium bicarbonate and 1 ml of polyethylene glycol-400 were added. Reaction mass was heated to reflux and maintained for 5 hours. Reaction completion was confirmed using thin layer chromatography. After reaction was completed, acetone was distilled off completely from the reaction mass and cooled to room temperature. 80 ml water was added to the reaction mass and stirred for 2 hours. The solid was filtered and washed with 20 ml of water. 40 ml of ethyl acetate was added and were refluxed for 30 min and cooled to 10-15°C. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 60°C to get 5 g of title compound.

Example-9

Preparation of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5- yl) biphenyl-4-yl) methyl)-1H-imidazole-5-carboxylic acid ethyl ester 150 g of diethyl 2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-4,5-dicarboxylate was dissolved in 1500 ml of methylene dichloride solution was added to 360 ml of methyl magnesium chloride in tetrahydrofuran (3 moles) at 0-5°C and maintained for 2 hours at 0-5°C. Reaction completion was confirmed using thin layer chromatography. Reaction mass was quenched in 1500 ml of 10% aqueous ammonium chloride solution. Organic layer was separated and aqueous layer was extracted with 2x300 ml of methylene dichloride.

Combined organic layers washed with 600 ml 10% sodium chloride solution. The solvent was distilled off at a temperature of 40°C under vacuum to get 150 g of title compound. Purity by HPLC: 90.6%.

Example-10

Preparation of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazoI-5- yl) biphenyl-4-yl) methyl)-1H-imidazole-5-carboxylic acid sodium salt 150 g of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl)-1H-imidazole-5-carboxylic acid ethyl ester was added to 8.2 g of sodium hydroxide and 750 ml of isopropyl alcohol. The mixture was stirred at 35-40°C for 5 hours. After reaction completion, distilled off solvent completely under vacuum at below 50°C. 600 ml acetonitrile was added to the residue and stirred for 10 hours at room temperature. Cooled the contents to 0-5°C and maintained for 2 hours. The solid was filtered and washed with 150 ml chilled acetonitrile. The solid was dried at 40°C to get 135 g of title compound. Purity by HPLC: 97.8%.

Example-11

Preparation of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tctrazol-5- yl) biphcnyI-4-yl) methyl)-1H-imidazole-5-carboxylic acid ethyl ester 20 g of diethyl 2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-li/-imidazole-4,5-dicarboxylate was dissolved in 200 ml of Toluene solution was added to 48 ml of methyl magnesium chloride in tetrahydrofuran (27%) at 0-5°C and maintained for 2 hours at 0-5°C. Reaction completion was confirmed by TLC. Reaction mass was quenched in 200 ml of 10% aqueous ammonium chloride solution. Organic layer was separated and aqueous layer was extracted with 2x40 ml of Toluene. Combined organic layers washed with 80 ml 10% sodium chloride solution. The solvent was distilled off at a temperature of 60°C under vacuum to get 15 g of title compound. Purity by IIPLC: 93.4%.

Example-12

Preparation of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5- yl) biphenyl-4-yl) methyI)-1H-imidazole-5-carboxylic acid ethyl ester 10 g of diethyl 2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-4,5-dicarboxylate was dissolved in 100 ml of diisopropylether solution was added to 24 ml of methyl magnesium chloride in tetrahydrofuran (27%) at 0-5°C and maintained for 2 hours at 0-5°C. Reaction completion was confirmed by TLC. Reaction mass was quenched with 100 ml of 10% aqueous ammonium chloride solution. Organic layer was separated and aqueous layer was extracted with 2x40 ml of methylene dichloride. The combined organic layer was washed with 40 ml of 10% sodium chloride solution. The solvent was distilled off at a temperature of 60°C under vacuum to get 6 g of title compound. Purity by HPLC: 93.0%.

Examplc-13

Preparation of 4-(2-hydroxypropan-2-yI)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5- yl) biphenyl-4-yI) methyl)-1H-imidazoIe-5-carboxylic acid ethyl ester:

10 g of diethyl 2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-4,5-dicarboxylate was dissolved in 100 ml of tetrahydrofuran solution was added to 24 ml of methyl magnesium chloride in tetrahydrofuran (27%) at 0-5°C and maintained for 2 hours at 0-5°C. Reaction completion was confirmed by TLC. Reaction mass was quenched with 100 ml of 10% aqueous ammonium chloride solution. Aqueous layer was extracted with 2x50 ml of methylene dichloride.

Combined organic layers washed with 40 ml 10% sodium chloride solution. The solvent was distilled off at a temperature of 60°C under vacuum to get 15 g of title compound.

Purity by HPLC: 85.4% Example-14 Preparation of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5- yl) biphenyl-4-yl) methyI)-1H-imidazole-5-carboxylic acid sodium salt:

150 g of diethyl 2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-4,5-dicarboxylate was dissolved in 1500 ml of methylene dichloride solution was added to 360 ml of methyl magnesium chloride in tetrahydrofuran (27%) at 0-5°C and maintained for 2 hours at 0-5°C. Reaction completion was confirmed using thin layer chromatography. Reaction mass was quenched by pouring 1500 ml of 10% aqueous ammonium chloride solution. Organic layer was separated and aqueous layer was extracted with 2 * 300 ml of methylene dichloride. Combined organic layers washed with 600 ml 10% sodium chloride solution. The solvent was distilled off at a temperature of 40°C under vacuum. 8.2 g of sodium hydroxide and 750 ml of isopropyl alcohol were added to the obtained solid. The mixture was stirred at 35-40°C for 5 hours. After reaction completion, distilled off solvent completely under vacuum at below 50°C. 600 ml acetonitrile was added to the residue and stirred for 10 hours at room temperature. Cooled the contents to 0-5°C and maintained for 2 hours. The solid was filtered and washed with 150 ml chilled acetonitrile. The solid was dried at 40°C to get 135 g of title compound. Purity by HPLC: 97.8%.

Example-15

Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)mcthyl 4-(2-hydroxypropan-2- yI)-2-propyl-l-((2,-(l-trityl-1H-tetrazol-5-yI)biphenyl-4-yl)methyl)-1H- imidazole-5-carboxylate 47 g of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl) biphenyl-4-yl)methyI)-1H-imidazolc-5-carboxylic acid sodium salt was added in 280 ml of N,N-dimethyl acetamide, 9.8 g of 4-Chloromethyl-5-methyl-l,3 dioxolene-2-one and polyethylene glycol-400. Reaction maintained for 16 hours at room temperature. Reaction completion was confirmed using thin layer chromatography. Reaction mass was quenched into a mixture of 500 ml water and 400 ml of ethyl acetate. Organic layer was separated and aqueous layer was extracted with 2x 100 ml of ethyl acetate. Combined organic layers washed with 200 ml 10% sodium chloride solution. The solvent was distilled off at a temperature of 50°C under vacuum. 100 ml ethyl acetate was added to the residue and stirred for 10 hours at room temperature. Cooled the contents to 0-5°C and maintained for 2 hours. The solid was filtered and washed with 50 ml chilled ethyl acetate. The solid was dried at 50°C to get 41 g of title compound. Purity by HPLC: 98.9%

Example-16

Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 4-(2-hydroxypropan-2- yl)-2-propyl-l-((2'-(l-triryl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H- imidazole-5-carboxylate 10 g of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityI-1H-tetrazol-5-yI) biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylic acid sodium salt was added in 60 ml of N,N-dimethyl formamidc, 2 g of 4-Chloromcthyl-5-methyl-l,3 dioxolene-2-one and 1 ml of polyethylene glycol-400. Reaction maintained for 22 hours at room temperature.

Reaction completion was confirmed using thin layer chromatography. Reaction mass was quenched in 150 ml water and 150 ml of ethyl acetate. Organic layer was separated and aqueous layer was extracted with 2><20 ml of ethyl acetate. Combined organic layers washed with 50 ml 10% sodium chloride solution. The solvent was evaporated at a temperature of 50°C under vacuum. 20 ml ethyl acetate was added to the residue and stirred for 10 hours at room temperature. Cooled the contents to 0-5°C and maintained for 2 hours. The solid was filtered and washed with 10 ml chilled ethyl acetate. The solid was dried at 50°C to get 8.5 g of title compound. Purity by HPLC: 99.0% Exam ple-17

Preparation of (5-methyl-2-oxo-l,3-dioxoI-4-yI)methyl 4-(2-hydroxypropan-2-yl)-2-propyI-l-((2'-(l-trityl-1H-tetrazol-S-yl)biphenyI-4-yl)methyI)-1H-imidazole-5-carboxylate 10 g of 4-(2-hydroxypropan-2-yl)-2-propyl- l-((2'-(l-trityl-1H-tetrazol-5-yl) biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylic acid sodium salt was added in 60 ml of acetonitrile, 2 g of 4-Chloromethyl-5-methyl-l,3 dioxolene-2-one and 1 ml of polyethylene glycol-400. Reaction maintained for 30 hours at room temperature. Reaction completion was confirmed using thin layer chromatography. Salts were filtered. Solvent was evaporated at a temperature of 50°C under vacuum. 20 ml ethyl acetate was added to the residue and stirred for 10 hours at room temperature. Cooled the contents to 0-5°C and maintained for 2 hours. The solid was filtered and washed with 10 ml chilled ethyl acetate. The solid was dried at 50°C to get 6 g of title compound. Purity by HPLC: 99.1%.

Example-18

Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yI)methyl 4-(2-hydroxypropan-2-yl)-2-propy 1-1 -((2 '-(1 -trityl- 1H-tetrazol-5-y l)biphcny 1-4-y I) methyl)-1H-imidazolc-5-car boxy late 10 g of 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l -trityl-1H-tetrazol-5-yl) biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylic acid sodium salt was added in 60 ml of methyl isobutyl ketone, 2 g of 4-Chloromethyl-5-methyl-l,3 dioxolene-2-one and 1 ml of polyethylene glycol-400. Reaction maintained for 30 hours at room temperature. Reaction completion was confirmed using thin layer chromatography. Salts were filtered. Solvent was evaporated at a temperature of 50°C under vacuum. 20 ml ethyl acetate was added to the residue and stirred for 10 hours at room temperature. Cooled the contents to 0-5°C and maintained for 2 hours. The solid was filtered and washed with 10 ml chilled ethyl acetate. The solid was dried at 50°C to get 6.5 g of title compound. Purity by HPLC: 98.1%.

Example-19
Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[[2'-(1H-tetrazol-5-yl)[l,l'-biphcnyI]-4-yl]methyI]-1H-imidazole-5-carboxylic acid (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester 5 g of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate was added in 25 ml of acetonitrile, contents were cooled to 0-5°C. 45 ml 1.4% HCI solution was added slowly and maintained at same temperature for 2 hours. Reaction completion was confirmed using thin layer chromatography. pH was adjusted to 4.5 by using 7% sodium bicarbonate solution. Charged 25 ml of water and 25 ml of ethyl acetate. Separated organic layer and extracted aqueous layer with 25 ml of ethyl acetate. Combined organic layers washed with 25 ml 10% sodium chloride solution. The solvent was distilled off at 50°C under vacuum. 80 ml of Toluene and 20 ml of n-heptane was added to the residue and stirred at reflux for 30 min. Filter the solid obtained and was recrystallised from ethyl acetate to give 2.0 g of title compound.

Example-20

Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid (5-methyl-2-oxo-l,3-dioxol-4-yI)methyl ester 5 g of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate was added in 39 ml of acetic acid and 13 ml of water, contents were heated to 55°C and maintained at same temperature for 2 hours. Reaction completion was confirmed using thin layer chromatography. 50 ml of 5% NaC1 solution was charged and by¬product filtered and washed with a mixture of 10 ml of acetic acid in 15 ml of water. The filtrate was extracted with 3x15 ml of methylenedichloride. Combined organic layer washed with 3x25 ml 5% sodium chloride solution. The solvent was distilled off at 50°C under vacuum. 20 ml of hcxane was added to the residue and stirred at room temperature for 2 hours. The solid was filtered and washed with 5 ml hexane. The solid was dried at 50°C to get 3.0 g of title compound

CLAIMS:

1) A process for the preparation of olmesartan medoxomil which comprises:

a) reacting diethyl 2-propyl-1H-imidazole-4,5-dicarboxylate with 5-(4'-(bromomethyl)biphenyl-2-yl)-l-trityl-1H-tetrazole to give diethyl 2-propyl-1 -((2'-( 1 -trityl-1 H-tetrazol-5-yI) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxylate in presence of base and catalyst,

b) reacting the obtained diethyl 2-propyl-l-((2'-(l -trityl- 1H-tetrazol-5-yl) biphenyl-4-yl) methyl)-1H-imidazole-4,5-dicarboxylate with methylmagnesium halide to yield ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylate,

c) hydrolyzing the ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazolc-5-carboxylate to obtain trityl olmesartan salt,

d) esterifying the salt of trityl olmesartan with 4-halomethyl-5-methyl-2-oxo-1,3-dioxolene in an organic solvent in the presence of catalyst and optionally in the presence of additional base to obtain tirtyl olmesartan medoxomil followed by.

e) deprotection of the trityl olmesartan medoxomil to give olmesartan medoxomil.

2) The process according to claim 1 step (a and d), wherein the catalyst employed is polyethylene glycol 400.

3) The process according to claim 1 step (a), wherein the bases employed are selected from alkali metal carbonates, alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal hydrides, alkali metal alkoxides, and organic amines.

4) The process according to claim (1) step (d), wherein the bases employed are selected from alkali metal carbonates, alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal hydrides, alkali metal alkoxides, and organic amines.

5) The process according to claim 1, wherein the organic solvents used are selected from aromatic hydrocarbons, ethers, alcohols, amides, ketones, nitriles, sulfoxides, and halogenated aliphatic hydrocarbons.

6) The process for preparing Olmesartan medoximil comprises of:

a) deprotecting trityl olmesartan medoximil in presence of acid and water mixture in water miscible solvent,

b) adjusting the pH from 4.0 to 4.5,

c) extracting the residue with ethylacetate or methylene dichloride,

d) evaporating the organic layer to give residue containing triphenyl carbinol and olmesartan medoximil,

e) refluxing the residue in a mixture of water immiscible solvents,

f) isolating the olmesartan medoximil by filtration.

7) The process as per claim 5(e), wherein water immiscible solvents mixture is toluene and heptane or hexane.

8) The process as per claim 6, wherein water miscible solvent is toluene and hexane/heptane.