FIELD OF THE INVENTION
The present invention relates to a process for preparing olmesartan medoxamil of formula I,
(Formula Removed)
More particularly, the present invention relates to process for preparing olmesartan medoxomil of formula I via detritylation of trityl olmesartan medoxomil.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any art widely known or forms part of common general knowledge in the field.
Olmesartan medoxomil of formula I, is a known antihypertensive drug and is chemically known as 4-( 1-hydroxy-l-methylethyl)-2-propyl-l-[[2'-(1H-tetrazol-5-yl)[ 1,1 "-bipheny l]-4-yl]methyl]-1H-imidazole-5-carboxylicacid(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester.
(Formula Removed)
Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kinase II). Angiotensin II is the principal 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 blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Olmesartan medoxomil is a prodrug that is hydrolyzed during absorption and converted into olmesartan acid.
Olmesartan and pharmaceutically acceptable salts thereof have been first disclosed in U.S. patent 5,616,599. The method disclosed therein comprises the condensation of 5-(l-hydroxy-1-methyl-ethyl)-2-propyl-3H-imidazole-4-carboxylic acid ethyl ester with 4-[2-(trityl tetrazol-5-yl) benzyl bromide in the presence of sodium hydride and dimethyl formamide to obtain 5-(l-hydroxy-1-methyl-ethyl)-2-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-3H-imidazole-4-carboxylic acid ethyl ester, which is then reacted with lithium hydroxide in dioxane to obtain corresponding lithium carboxylate, which is further reacted with 4-chIoromethyl-5-oxo-l,3-dioxolene in the presence of potassium carbonate and dimethyl acetamide and obtained residue is subsequently recrystallized from isopropyl ether to obtain trityl olmesartan medoxomil, which is then deprotected in the presence of acetic acid and water to obtain olmesartan medoxomil.
Particularly the deprotection of trityl olmesartan medoxomil is exemplified in Examples 61(b) and 78 of the above patent. The patent exemplified a process for preparing olmesartan medoxomil from trityl olmesartan medoxomil using aqueous acetic acid followed by purification using column. In another exemplified process, triphenyl carbinol is removed, and olmesartan medoxomil is isolated by evaporation. Precipitated triphenyl carbinol is removed by the filtration and treatment by toluene is
given to the residues and further recrystallization by ethyl acetate to give pure product.
The process is a described by the following scheme:
(Scheme Removed)
Due to the acidic condition and the presence of water during deprotection of trityl olmesartan medoxomil, the impurity OLM-acid is also generated. The given process resulted in crude olmesartan medoxomil containing 2.2% OLM-acid per area percent HPLC as reported in US patent 7,528,258. Besides this, the patent discloses the use of time-consuming purification techniques like column chromatography which is not preferable for large scale synthesis.
Further more synthetic methods for olmesartan medoxomil intermediates are described by: JP 11302260, JP 11292851, JP 07053489, JP 06298683, US Patent 5,621,134,, US patent 6,111,114, and EP 838458.
US patent 7,528,258 discloses process for the preparation of olmesartan medoxomil by 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, the precipitate of triphenyl carbinol is separated from the solution of olmesartan medoxomil and contacting the solution of olmesartan medoxomil with a base to obtain a precipitate of olmesartan medoxomil. Although the said process is an improvement over prior art, but olmesartan medoxomil prepared through deprotection of trityl olmesartan medoxomil still contains 0.89% of OLM-acid impurity per area percent HPLC as disclosed in best mode of the patent and require additional recrystallization step to prepare olmesartan medoxomil of acceptable quality.
PCT publication WO 2007/148344 discloses a process of detritylation of trityl olmesartan medoxomil in which trityl olmesartan medoxomil is reacted with acid in water and water immiscible organic solvent followed by layer separation to remove triphenyl carbinol. The pH of aqueous layer containing olmesartan medoxomil is adjusted to 5-6 with base, thereafter olmesartan medoxomil is extracted using water immiscible organic solvent. However, the patent is silent about the amount of OLM-acid impurity which may be present in the final compound i.e. olmesartan medoxamil and thus needs further re-crystallization, which is not amenable on commercial point of view.
PCT publication WO 2007/017135 discloses a method of making olmesartan medoxomil. In this method, the tritylated intermediate is detritylated in ethylacetate followed by neutralization using inorganic base to a pH value up to 6.
In view of the above, as most of the prior art processes yield olmesartan medoxomil having OLM-acid impurity in unacceptable limits and need further tedious purification method to remove this impurity, therefore there is an urgent need to develop a process for the preparation of olmesartan medoxomil, which can provide pure olmesartan medoxomil and should be industrially applicable. Thus, the present
invention aims to provide an industrially advantageous, process for the preparation of olmesartan medoxamil having reduced amount of OLM-acid impurity.
wherein OLM-acid impurity is reduced to less than 0.5% area by HPLC, preferably 0.2% area by HPLC, more preferably 0.1% area by HPLC.
The process of the present invention is cost effective, eco-friendly, commercially viable as well as reproducible on industrial scale and meets the needs of regulatory agencies.
OBJECT OF THE INVENTION
It is a principal object of the invention to provide a process for preparing pure olmesartan medoxomil of formula I.
It is an object of the present invention to overcome or substantially ameliorate one or more of the disadvantages of the prior art or at least to provide useful alternative.
Another object of the present invention to provide a process for the preparation of the olmesartan medoxomil by detritylation of trityl olmesartan medoxomil.
Further an object of the invention to provide a process for the preparation of the olmesartan medoxomil of formula I having minimum amount of OLM-acid impurity, preferably less than 0.15% area by HPLC.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparing olmesartan medoxomil of formula I;

(Formula Removed)
comprises the steps of:
a) contacting trityl olmesartan medoxomil of formula II;
(Formula Removed)
with an acid in a water miscible solvent to obtain a mixture of olmesartan medoxomil and triphenyl carbinol of formula III;
(Formula Removed)
b) adding a water immiscible solvent to the reaction mixture;
c) adjusting the pH of reaction mixture to 7-8 using a suitable base;
d) separating the layers;
e) distilling the organic layer containing the mixture of olmesartan medoxomil and triphenyl carbinol of formula III;
f) dissolving the resulting residue in an ester solvent; and
g) isolating pure olmesartan medoxomil of formula 1.
In another aspect, the present invention provides a process for preparing the olmesartan medoxomil of formula I, which comprises the steps of:
a) treating 2-propyl-1H-imidazole-4,5-dicaboxylic acid diethyl ester of formula IV
(Formula Removed)
with methyl magnesium halide in an organic solvent to obtain compound of formula V;
(Formula Removed)
b) optionally purifying compound of formula V using a mixture of ether and hydrocarbon;
c) condensing compound of formula V with 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl-1 H-tetrazole of formula VI;
(Formula Removed)
in the presence of base in an organic solvent, optionally in the presence of phase transfer catalyst, to obtain compound of formula VII;
(Formula Removed)
d) hydrolyzing the compound of formula VII followed by condensing in situ with 4-
chloromethyI-5-methyl[l,3]dioxol-2-one in the presence of base in an organic
solvent to obtain trityl olmesartan medoxomil formula II;
(Formula Removed)
e) optionally purifying compound of formula II using an ether, an alcohol or mixture thereof; and
f) converting trityl olmesartan medoxomil of formula II into olmesartan medoxomil of formula I.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: Powder X-ray diffraction pattern of trityl olmesartan medoxomil prepared as per Example 3
Figure 2: Powder X-ray diffraction pattern of trityl olmesartan medoxomil prepared as per Example 4
DETAILED DESCRIPTION OF THE INVENTION
According to one embodiment, the present invention provides a process for preparing pure olmesartan medoxomil of formula I by detritylation of trityl olmesartan medoxomil of formula II. The process comprises contacting trityl olmesartan medoxomil of formula II with an suitable acid in water miscible solvent to obtain a mixture of olmesartan medoxomil of formula I and triphenyl carbinol of formula III and thereafter adding a water immiscible solvent to the reaction mixture and adjusting the pH of reaction mixture to 8 using a base. It is advantageous to add water immiscible solvent to the reaction mass before adjusting the pH of reaction mass to extract pure olmesartan medoxomil of formula I into organic layer leaving OLM-acid impurity in aqueous layer as its alkali or alkaline metal salt depending upon the base employed for the reaction.
Generally, the suitable acids include, but not limited to, organic acids such as formic acid, acetic acid, benzoic acid, and oxalic acid; inorganic acids are sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid. Preferably, hydrochloric acid can be used for the reaction.
Herein above, the acid is used for the deprotection purpose of tritylated olmesartan medoxomil and water miscible solvent which include C3-6 ketones, more preferably acetone is used as reaction media.
The reaction of trityl olmesartan medoxomil of formula II with a suitable acid can be carried out at temperature of about 25°C to 40°C, preferably about 30°C to 40°C, more preferably till the completion of the reaction. The reaction mixture containing trityl olmesartan medoxomil of formula II, a suitable acid and water miscible solvent can be stirred for about 2 to 4 hours, preferably at the temperature of about 30°C to 40°C.
Thereafter, water immiscible solvent is added to the reaction mixture. The water immiscible solvent, added into the reaction mixture includes halogenated solvent;
aliphatic or aromatic hydrocarbon or esters and mixture thereof. Preferably halogenated solvent includes dichloromethane, chloroform, carbon tetrachloride and the like, aliphatic or aromatic hydrocarbon includes toluene, benzene, cyclohexane, ethyl benzene and the like, esters include ethyl acetate, butyl acetate, isomyl acetate, isopropyl acetate; ethers such as isopropyl ether and the like or mixture thereof, more preferably toluene, dichloromethane, ethyl acetate are used.
Triphenyl carbinol of formula III and olmesartan medoxomil of formula I are having the enhanced solubility in the water immiscible organic solvent, which are given above. Upon addition of water immiscible organic solvent, the triphenyl carbinol of formula III and olmesartan medoxomil of formula I will be dissolved in the same.
Thereafter the reaction mass containing olmesartan medoxomil of formula I and triphenyl carbinol of formula III in dissolved condition is contacted with a suitable base to adjust the pH of about 7-8. Suitable base includes, but is not limited to, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal hydroxides, alkaline earth metal hydroxide and the like. Specifically base can be selected among sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and calcium carbonate, sodium hydroxide, potassium hydroxide. Preferably, potassium bicarbonate is preferred.
After pH adjustment, the layers are separated. The organic layer contains olmesartan medoxomil of formula I and triphenyl carbinol of formula III whereas aqueous layer contains OLM-acid in the form of its alkali or alkaline metal salts along with other impurities. The aqueous layer is discarded and the organic layer is washed with brine to remove undesired aqueous traces from the organic layer. The desired compound olmesartan medoxamil of formula 1 can be isolated from the resulting organic layer by the suitable techniques known in the art.
Specifically, if water immiscible solvent is an ester solvent, then organic layer can be distilled out partially or completely. Whenever organic layer is distilled partially, pure olmesartan medoxomil can be isolated by cooling the rest of the ester solvent followed by filtration. It is advantageous to distill out ethyl acetate completely from the reaction mass, and thereafter again, ethyl acetate can be added to the reaction mixture. The resulting reaction mixture can be stirred at a temperature of 25 to 45°C and then cooled to give desired product. Pure Olmesartan medoxamil can be isolated from the reaction mixture using a suitable technique such as filtration, centrifugation and the like.
In an alternate way, if water immiscible solvent is other than ester solvent, pure olmesartan medoxamil can be isolated from the reaction mixture by complete distillation of the solvent followed by addition of ester solvent to the resulting residue. The reaction mixture can be optionally stirred at a temperature of 25 to 45 °C and then cooled to give desired product. Pure olmesartan medoxamil can be isolated from the reaction mixture using a suitable technique such as filtration, centrifugation and the like.
Most preferably ester solvent such as ethyl acetate is being added and reaction mass is stirred at the temperature of about 30°C to 40°C for about 0.5 to 2 hours. The reaction mixture is thereafter cooled at about 15°C to 20°C and the pure product is obtained via filtration.
Triphenyl carbinol of formula III is highly soluble in ethyl acetate, hence triphenyl carbinol remains dissolved into the ethyl acetate and desired compound olmesartan medoxomil is crystallized from solution. Olmesartan medoxomil, isolated here may contain OLM-acid impurity less than 0.1% area by HPLC.
Olmesartan medoxomil thus prepared by the process of the present invention can be purified by using any purification methods known in the art or as described herein below. Olmesartan medoxomil can be optionally purified by washing with a suitable
solvent selected from ether such as isopropyl ether; ketone such as acetone and the like or mixture thereof; or can be slurried in ketonic solvent more preferably acetone or combination thereof can be employed to prepare highly pure olmesartan medoxomil. Slurry of olmesartan medoxomil in acetone can be stirred at temperature of about 40°C to 70°C, more preferably about 60°C. The slurry is then cooled at about 0°C to 10°C. For preparing a slurry of olmesartan medoxomil in ketonic solvent, it is desirable that preferable amount of ketonic solvent should not be more than 3 volumes ketone to I gram of solid olmesartan medoxomil, more preferably amount of ketonic solvent should not be more than 1-1.5 volumes ketone to 1 gram of solid olmesartan medoxomil. Isolation of highly pure olmesartan medoxomil can be performed by any means known in the prior art such as filtration or centrifugation. The process may further include the step of drying which can be carried out at 30-60°C, preferably at about 40-50°C.
Further the trityl olmesartan medoxomil of formula II can be prepared by conventional procedures reported in prior art such as U.S. patent no. 5,616,599, JP 11292851, J.Med.Chem vol-39, pp332 (1996), WO2007/148344 Al. However some improvements are made in the prior process to make it efficient, industrially applicable, environment friendly and commercially viable.
In another important embodiment, the present invention provides a process for preparing the olmesartan medoxomil of formula I, which comprises, condensation of 2-propyl-1H-imidazole-4,5-dicaboxylic acid diethyl ester of formula IV with methyl magnesium halide in an organic solvent to obtain a compound of formula V. Organic solvent include halogenated solvent which can be selected from dichloromethane, chloroform, carbon tetrachloride and the like, more preferably dichloromethane. The methyl magnesium halide employed for the reaction can be used as such or in solution with ether solvent such as tetrahydrofuran and the like. The condensation can be accomplished at temperature of about -60°C to 20°C, more preferably -40°C to 10°C, and stirred. It takes about 3-4 hours for completion of reaction. After

completion of the reaction, the reaction mass is quenched with aqueous hydrochloric acid. The layers are separated out and the aqueous layer is further extracted with halogenated solvent to extract the desired compound. The combined organic layer is distilled out to isolate desired compound.
Further to enhance the purity and quality of compound of formula V, the next step includes the treatment with ethers such as isopropyl ether and hydrocarbons such as n-heptane to give pure 5-(1-hydroxy-l-methyl-ethyl)-2-propyl-3H-imidazole-4-carboxylic acid ethyl ester compound of formula V as a light yellow solid, which is reported in the US' 599 as an oil.
Thereafter compound of formula V is condensed with 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl-1H-tetrazole of formula VI in presence of a base and optionally in presence of a phase transfer catalyst, in an organic solvent to obtain formula VII .
Generally, the condensation reaction can be carried out using a suitable base in organic solvent at a temperature of 50°C to 60°C, preferably till the completion of the reaction. Suitable base can be selected from alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal hydroxides, alkaline earth metal hydroxide, preferably sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and calcium carbonate, sodium hydroxide, potassium hydroxide, more preferably potassium carbonate can be used for the reaction.
The organic solvent includes but not limited to C3-6 ketones, nitriles, alcohols and the like, preferably acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, methanol, ethanol, propanol, isopropanol, more preferably acetone. It is optional to add phase transfer catalyst to the reaction mixture which can be selected from benzyl Irimethylammonium bromide or chloride; cetyl trimethylammonium bromide; phosphonium compounds; synthetic resins; tetra-n-butylammonium bromide; methyltrioctylammonium chloride or bromide; benzyltriethyl ammonium chloride;
tetrabutylammonium hydroxide; tricapryl methylammonium hydrogensulfate; dodecyl sulfate; sodium salt, such as sodium bromide; hexadecyltrimethyl ammonium bromide; PEG 300; PEG 600 and the like, more preferably tetra-n-butylammonium bromide. The reaction can be carried out for few minutes to few hours, preferably 2 to 14 hours or more preferably till the completion of the reaction. Completion of the reaction can be monitored by suitable chromatographic method such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). The compound of formula VII can be isolated from the reaction mixture using a suitable technique known in the art. Preferably, after completion of reaction the reaction mass is cooled to about 25°C-30°C, diluted with the water and stirred for about 4 to 5 hours to precipitate the compound. The resulting precipitated compound is isolated from the reaction mixture by filtration and then washed with aqueous acetone. Optionally the compound of formula VII thus prepared can be purified using alcohols, water and mixture thereof.
Specifically the compound of formula V is condensed with compound of formula VI in presence of potassium carbonate and optionally in presence of tetra-n-butyl ammonium bromide in acetone for about 8 to 10 hours to give compound of formula VII.
The process can further include the step of hydrolyzing the compound of formula VII using a base in a suitable solvent. It is found by the present inventor that during hydrolysis of ester functionality of compound of formula VII, trityl group can be removed that results in the formation of olmesartan acid as an impurity. To overcome this problem, different experiments with the different solvents had been conducted and the best method, which had been adopted, is hydrolysis using potassium hydroxide in a mixture of suitable organic solvent. Suitable organic solvent can be selected from C3-6 ketones, nitriles, alcohols, ethers and the like or mixture thereof, preferably acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, methanol, ethanol, propanol, isopropanol, tetrahydrofuran and mixture thereof,
preferably mixture of tetrahydrofuran and isopropyl alcohol is used. It is advantageous to use a mixture of tetrahydrofuran and isopropyl alcohol during hydrolysis, as complete dissolution of reaction mixture occurs, the reaction proceeded faster because the base used for the reaction consumed completely, generation of impurities is very less and hence the desired compound is obtained in better yields.
After complete hydrolysis, the reaction mass is quenched with water followed by layer separation.. The aqueous layer is then optionally washed with isopropyl ether to remove the undesired impurities and product is extracted with ethyl acetate. Ethyl acetate layer is distilled off.
The process can further include the step of treating the reaction mixture, obtained above, in situ with 4-chloromethyl-5-methyl[l,3]dioxol-2-one in presence of a base, in an above said organic solvent to obtain trityl olmesartan medoxomil formula II. Base can be selected from inorganic weak base such as alkali or alkaline metal carbonate, bicarbonate and the like. Preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like, more preferably potassium carbonate can be used for the reaction at temperature of about 30-70°C. Organic solvent can be selected from C3-6 ketones, nitriles, alcohols, ethers and the like or mixture thereof, preferably acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, methanol, ethanol, propanol, isopropanol, tetrahydrofuran and mixture thereof, preferably ketones and ether or mixture of these is used.
Specifically the reaction is conducted in the presence of potassium carbonate in acetone or mixture of acetone with suitable ether such as tetrahydrofuran at temperature of about 50°C to 60°C till the completion of reaction. After completion of reaction, reaction mass is quenched with water and product is extracted with ethyl acetate. The process can further include the step of distilling the solvent which can be conducted under reduced pressure to isolate trityl olmesartan medoxomil formula II. Optionally trityl olmesartan medoxomil formula II may be purified in mixture of ethers such as isopropyl ether and alcohols such as methanol to enhance the purity.
The major advantage of the present invention is to provide an efficient and industrially advantageous process for preparation of olmesartan medoxomil with enhanced purity. Further, the present invention also provides a process of isolation of olmesartan medoxomil containing OLM-acid impurity less than 0.15% area by HPLC from the reaction mixture itself without isolating crude olmesartan medoxomil.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
Example 1: Preparation of 5-(l-hydroxy-l-methyl-ethyl)-2-propyl-3H-imidazole-4-carboxylic acid ethyl ester
A solution of 2-propyl-lH-imidazole-4,5-dicarboxylic acid diethyl ester (500g, 1.97 mol) in dichloromethane (5.0L) was cooled to -40°C in an atmosphere of nitrogen and a 3 M solution of methyl magnesium chloride in tetrahydrofuran (2.7 L, 7.99 mol) was slowly added at -40°C to -20°C. After addition, the reaction mixture was stirred at -10 to -15 °C for 2 hours. The progress of the reaction was checked using thin layer chromatography. After the completion of reaction, the reaction mass was cooled to -25°C and quenched with 5N aqueous hydrochloric acid (2 L) at -25 to 10°C, followed by dilution of reaction mass with demineralized water (1.8L). The layers were separated and the aqueous layer was extracted with dichloromethane (2.5 L). The aqueous layer was then saturated with sodium chloride (560 g) and then extracted with dichloromethane (2.5L). The combined organic layer was washed with 10% aqueous potassium bicarbonate solution (1.5L) and with brine solution. After the carbon (25g) treatment, the solvent was removed by distillation under reduced pressure at 55-60°C to give residue. Isopropyl ether (1.0L) and n-heptane (1 .0L) was added to the resulting residue and solvents were distilled off. A mixture of
isopropyl ether (2.0L) and n-heptane (1.0L) was added to the residue and stirred for 1 hour to give the crystalline product which was filtered and slurry washed with a mixture of isopropyl ether and n-heptane (1.0L) to give 380g of the title compound having purity of 98.20% by HPLC.
Example 2: Preparation of 5-(l-hydroxy-l-methyl-ethyl)-2-propyl-3-[2'-(l-trityl-1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-3H-imidazole-4-carboxylic acid ethyl ester
A suspension of 5-(l-hydroxy-l-methyl-ethyl)-2-propyl-3H-imidazole-4-carboxylic acid ethyl ester (90 g, 0.38 mol), potassium carbonate (104 g, 0.75 mol), 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl-IH-tetrazole (192g, 0.35mol) and tetra butyl ammonium bromide (18g) in acetone (810ml) was refluxed for 8-10 hours. The progress of the reaction was monitored by HPLC. After the completion of the reaction, reaction mass was cooled to 25-30°C and diluted with demineralized water (900 ml). The reaction mass was stirred at 25-30°C for 4 hours, filtered and washed with aqueous acetone (270ml). The resulting product was purified in water/isopropyl alcohol to give 106 g of the title compound having purity 97.61% by HPLC.
Example 3: Preparation of trityl olmesartan medoxomil
5-( 1 -Hydroxy-1 -methyl-ethyl)-2-propyl-3-[2'-( 1 -trityl-1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid ethyl ester (90g, 0.126mol) and powdered potassium hydroxide (14.6g, 0.26mol) in a mixture of tetrahydrofuran (270ml) and isopropyl alcohol (90ml) was stirred at 25-30°C for 2 hours. The progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was quenched by addition of water (900ml) and aqueous layer was washed with isopropyl ether (2x180ml). The aqueous layer was saturated with sodium chloride (180g) and extracted with cthyi acetate (1x900ml + 1x450ml). The combined organic
layer was washed with brine and the solvent was removed by distillation under reduced pressure at 50-60°C. Acetone (540ml) was added and reaction mass was stirred for 10 minutes at 25-30°C. To the above stirred solution, potassium carbonate (36g, 0.26mol) and 5-methyl-2-oxo-l,3-dioxane-4-yl) methyl chloride (22.4g, 0.15mol) were added at 25-30°C. The reaction mass was stirred at 50-60°C till completion of reaction. After the completion of reaction, the reaction mass was quenched in water and extracted with ethyl acetate (1x900ml + 1x450ml). The combined organic layer was washed with brine solution and distilled under reduced pressure to give title product which was purified in a mixture of isopropyl ether (270ml) and methanol (90ml) to give 5-( 1-hydroxy-1-methyl-ethyl)-2-propyl-3-[2'-(l-trityl-lH-tetrazol-5-yl)-biphenyl-4-yl-methyl]-3H-imidazole-4-carboxylic acid 5-methyl-2-oxo-[l,3] dioxol-4ylmethyl ester as a white solid (80g) with HPLC purity of 99.61%.
Example 4: Preparation of trityl olmesartan medoxomil
5-( 1 -Hydroxy-1 -methy l-ethyl)-2-propyl-3-[2'-( 1 -trityl-1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid ethyl ester (90g, 0.126mol) and powdered potassium hydroxide (14.6g, 0.26mol) in a mixture of tetrahydrofuran (270ml) and isopropyl alcohol (90ml) was stirred at 25-30°C for 2 hours. The progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was quenched by addition of water (900ml) and aqueous layer was washed with isopropyl ether (2x180ml). The aqueous layer was saturated with sodium chloride (180g) and extracted with ethyl acetate (1x900ml + 1x450ml). The combined organic layer was washed with brine and the solvent was removed by distillation under reduced pressure at 50-60°C. A mixture of tetrahydrofuran (270ml) and acetone (270ml) was added and the reaction mass was stirred for 10 minutes at 25-30°C. To the above stirred solution, potassium carbonate (36g, 0.26mol) and 5-methyl-2-oxo-l,3-dioxane-4-yl) methyl chloride (22.4g, 0.15mol) were added at 25-30°C. The
reaction mass was stirred at 50-60°C till completion of reaction. After the completion of reaction, the reaction mass was quenched in water and extracted with ethyl acetate (1x900ml + 1x400ml). The combined organic layer was washed with brine solution and distilled under reduced pressure to give title product which was purified in a mixture of isopropyl ether (270ml) and methanol (90ml) to give 79g of the title compound having purity 99.5% by HPLC
Example 5: Preparation of olmesartan medoxomil
A mixture of trityl olmesartan medoxomil (20g) in acetone (100ml) and 0.5N hydrochloric acid solution (200ml) was stirred for 2 hours at about 30°C to 40°C. After completion of the reaction, dichloromethane (200ml) was added into the reaction mass followed by the adjustment of pH to about 7-8 by using potassium bicarbonate solution. The organic layer was separated and further the aqueous layer was extracted by dichloromethane (100ml) and combined the both organic layer. The combined organic layer was washed with brine solution then dichloromethane was distilled out completely. After distillation of dichloromethane, ethyl acetate was added to the resulting residue and stirred for half an hour at about 30°C to 40°C. The reaction mass was cooled to 15°C to 20°C and product was filtered off. Acetone (20 ml) was added into the resulting product and stirred for half an hour at about 50°C. The reaction mixture was cooled at about 0 °C to 10°C, filtered, slurry washed with acetone and dried to give title compound in 71 % yield having purity 99.8% by HPLC and individual OLM-acid impurity 0.09%.
Example 6: Preparation olmesartan medoxomil
A mixture of trityl olmesartan medoxomil (100gm) in acetone (500ml) and aqueous hydrochloric acid solution (1000ml) was stirred for 2 hours at about 30°C to 40°C. After completion of the reaction the reaction mass was diluted with demineralized
water (500ml) and ethyl acetate (1000ml) followed by the adjustment of pH to about 7-8 by using aqueous potassium bicarbonate solution. The combined organic layer was separated and further the aqueous layer was extracted with ethyl acetate (500ml). The combined organic layer was washed brine solution then ethyl acetate was distilled out completely. After distillation of ethyl acetate(300ml) was added into the residue and stirred for half an hour at about 30°C to 40°C, then cooled to 15°C to 20°C and product was filtered off. The resulting product was washed with isopropyl ether (300ml), taken into acetone (200ml) and stirred for half an hour at about 50°C. The reaction mixture was cooled to about 0°C to 10°C, filtered, slurry washed with chilled acetone to give title compound in 70% yield and having purity 99.7% by HPLC and individual OLM-acid impurity 0.08%.

WE CLAIM
1. A process for preparing olmesartan medoxomil of formula I;
(Formula Removed)
comprises the steps of:
a) contacting trityl olmesartan medoxomil of formula II
(Formula Removed)
with an acid in a water miscible solvent to obtain a mixture of olmesartan medoxomil and triphenyl carbinol of formula III;
(Formula Removed)
b) adding a water immiscible solvent to the reaction mixture;
c) adjusting the pH of reaction mixture to 7-8 using a suitable base;
d) • separating the layers;
e) distilling the organic layer containing the mixture of olmesartan medoxomil and triphenyl carbinol of formula III;
f) dissolving the resulting residue in an ester solvent; and
g) isolating pure olmesartan medoxomil of formula I.
2. The process according to claim 1, wherein in step a) acid is selected from organic
acids like formic acid, acetic acid, benzoic acid, and oxalic acid; inorganic acids like sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like; and water miscible solvent is selected from C3-6 ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; nitriles such as acetonitrile; alcohols such as methanol, ethanol, propanol, isopropanol and the like.
3. The process according to claim 1, wherein in step b) water immiscible solvent is selected from halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride; aliphatic or aromatic hydrocarbons such as toluene, benzene, cyclohexane, ethyl benzene; esters such as ethyl acetate, butyl acetate, isomyl acetate, isopropyl acetate; ethers such as isopropyl ether and the like.
4. The process according to claim 1, wherein in step c) base is selected from alkali carbonates, alkaline earth metal carbonates, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal hydroxides, alkaline earth metal hydroxide and the like such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and calcium carbonate, sodium hydroxide, potassium hydroxide.
5. The process according to 1, wherein in step f) ester is selected from ethyl acetate, butyl acetate, isomyl acetate, isopropyl acetate.
6. The process according to claim 1, wherein olmesartan medoxomil of formula I is optionally washed with a suitable solvent selected from ether or ketone or mixture thereof.
7. A process for preparing the olmesartan medoxomil of formula I, which comprises the steps:
a) treating 2-propyl-1H-imidazole-4,5-dicaboxylic acid diethyl ester of formula
IV
(Formula Removed)
with methyl magnesium halide in an organic solvent to obtain compound of formula V;
(Formula Removed)
b) optionally purifying compound of formula V using a mixture of ether and hydrocarbon;
c) condensing compound of formula V with 5-(4'-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole of formula VI;
(Formula Removed)
in the presence of base in an organic solvent, optionally in the presence of phase transfer catalyst, to obtain compound of formula VII;
(Formula Removed)
d) hydrolyzing the compound of formula VII followed by condensing in situ
with 4-chloromethyl-5-methyl[l,3]dioxol-2-one in the presence of base in an
organic solvent to obtain trityl olmesartan medoxomil of formula II;
(Formula Removed)
e) optionally purifying compound of formula II using an ether, an alcohol or mixture thereof; and
f) converting trityl olmesartan medoxomil of formula II into olmesartan medoxomil of formula I as disclosed in claim 1.
8. The process according to claim 7, wherein in step a), organic solvent is selected from halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like; in steps c) and d) organic solvent is selected from C3-6 ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; nitrites such as acetonitrile; alcohols such as methanol, ethanol, propanol, isopropanol, ethers such as tetrahydrofuran and the like and mixture thereof
9. The process according to claim 7, wherein in steps c) and d) base is selected from alkali carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal hydroxides, alkaline earth metal hydroxide such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and calcium carbonate, sodium hydroxide, potassium hydroxide and the like; in step c) phase transfer catalyst is selected from benzyl trimethylammonium bromide or chloride; cetyl trimethylammonium bromide; tetra-n-butylammonium bromide; methyltrioctylammonium chloride or bromide; benzyltriethyl ammonium chloride; tetrabutylammonium hydroxide; sodium salt, such as sodium bromide; hexadecyltrimethyl ammonium bromide; and the like.
10. The process according to claim 7, wherein in step a) organic solvent is preferably dichloromethane; in step c) base is preferably alkali carbonates, alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, organic solvent is preferably ketone, phase transfer catalyst is preferably tetra-n-butylammonium bromide, benzyl trimethylammonium bromide or chloride; in step d) during hydrolysis, base is preferably alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, organic solvent is preferably ether or alcohol or mixture thereof; in step d) during condensation base is preferably alkali carbonates, alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, organic solvent is preferably ketone or ether or mixture thereof