WO2007047838A2

WO2007047838A2 - Process for preparing olmesartan medoxomil

Info

Publication number: WO2007047838A2
Application number: PCT/US2006/040883
Authority: WO
Inventors: Sonny Sebastian; Srinivas Reddy Gade; Srinivasa Reddy Mallepalli; Nageswara Rao Koduri; Ravindranath Tagore Amirisetty; Sri Hari Babu Karrothu
Original assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2005-10-20
Filing date: 2006-10-18
Publication date: 2007-04-26
Anticipated expiration: 2008-04-20
Also published as: WO2007047838A3

Abstract

Olmesartan medoxomil, i.e. 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, is prepared. Precursors of Olmesartan medoxomil are prepared as well. In particular a process for the preparation of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-2-(trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate and its use in the preparation of Olmesartan medoxomil is disclosed. Olmesartan medoxomil is a selective angiotensin Il receptor antagonist, pharmaceutically used as an antihypertensive.

Description

PROCESS FOR PREPARING OLMESARTAN MEDOXOMIL

INTRODUCTION TO THE INVENTION

The present invention relates to a process for the preparation of olmesartan medoxomil and intermediates thereof. In particular, it relates to a process for the preparation of methyl 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1-{4-2-(trityltetrazol-5- yl) phenyl} methyl imidazole-5-carboxylate and its use in the preparation of olmesartan medoxomil.

Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[p-(o-1 H-tetrazol-

5ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate, and is represented by the following structural Formula I.

Formula I Olmesartan is a selective angiotensin Il 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 under 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. The patent also describes a process for the preparation of imidazole derivatives useful for the synthesis of olmesartan. According to the following Scheme 1 , diethyl 2-propylimidazole-4,5-dicarboxylate of Formula A was reacted with the Grignard reagent methyl magnesium bromide to give ethyl 4-(1 -hydroxy-1 -methylethyl)-2-propylimidazole-5-carboxylate of Formula B which on condensation with 4-[2-(trityltetrazole-5-yl)phenyl]benzyl bromide of Formula C gave the compound ethyl 4-(1 -hydroxy-1 -methylethyl)-2- propyl-1-{4-[2-(trityltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate of Formula D.

Formula A

Formula D

Scheme 1 The above-mentioned process results in a low quality of the compound of

Formula B, due to non-selectivity of the Grignard reaction with the intermediate of Formula A. In this reaction, two ester groups with similar chemical environments are exposed to the Grignard reagent and therefore a mixture of products can be expected due to the side reaction of methyl magnesium bromide with the second ester group. This condition leads to a substantial reduction in purity and yield of the compound of Formula B.

The experimental evidence also shows that methyl magnesium bromide is reacting with both ester groups to generate unwanted products along with the intermediate of Formula B and those impurities are inseparable by recrystallization. The quality of the compound of Formula D is also affected by the use of the impure intermediate of Formula B.

Additional synthetic methods for olmesartan medoxomil have been described in U.S. Patent Application Publication Nos. 2006/0148870 and US 2006/0149078, and in International Application Publication No. WO 2006/029057. None of the additional methods has overcome the problems of the prior process described above, hence there remains a need for a process that overcomes the problems, and which is simple, easy to operate and more economical. The present invention provides a process for the preparation of olmesartan medoxomil, which can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield based on the starting materials employed.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of olmesartan medoxomil and intermediates thereof. In particular, it relates to a process involving the preparation of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-2-

(trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate and its use in the preparation of olmesartan medoxomil. One aspect of the present invention provides a process for the preparation of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-2-(trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate of Formula V and its salts.

In an embodiment, a process for the preparation of methyl 4-(1-hydroxy-1- methylethyl)-2-propyl 1-{4-2-(trityltetrazol-5-yl) phenyl} methyl imidazole-5- carboxylate of Formula V and its salts comprises: a) reacting dimethyl-2-propylimidazole-4,5-dicarboxylate compound of

Formula il with 4-[2-(trityltetrazol-5-yl) phenyl] benzyl bromide of Formula III to give dimethyl 2-propyl-1-[4-(2-trityltetrazol-5-yl) phenyl] phenylmethyl imidazole-

4,5-carboxylate of Formula IV;

Formula Il Formula III b) reacting dimethyl 2-propyl-1-[4-(2-trityltetrazol-5-yl) phenyl] phenylmethyl imidazole-4,5-carboxylate of compound Formula IV with methyl magnesium halide to yield methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 -{4-2-(trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate of Formula V; and

Formula IV Formula V c) reacting methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 -{4-2-(trityltetrazol-

5-yl) phenyl} methyl imidazole-5-carboxylate of Formula V with a suitable base in a suitable solvent to obtain its salt.

Suitably, one or more sequential steps a) to c) are carried out in situ. In one embodiment of the invention, step b) is carried out in situ followed by isolation of the salt of the compound of Formula V.

Another aspect of the present invention provides methyl 4-(1 -hydroxy- 1- methylethyl)-2-propyl 1 -{4-2-(trityltetrazol-5-yl) phenyl} methyl imidazole-5- carboxylate of Formula V and its base addition salts.

Formula V

Still another aspect of the present invention provides a process for the conversion of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 -{4-2-(trity ltetrazol-5- yl) phenyl} methyl imidazole-5-carboxylate of Formula V to olmesartan medoxomil of Formula I. An embodiment of the invention includes a process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:

wherein Ph represents a phenyl group, with a compound having a formula CH₃MgX, wherein X is a halogen, to form a compound having a formula:

Another embodiment of the invention includes a process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:

with a compound having a formula:

in the presence of a base, to form an intermediate, and reacting an intermediate with an acid to form olmesartan medoxomil.

A further embodiment of the invention includes a process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:

wherein Ph represents a phenyl group, with a compound having a formula CHsMgX, wherein X is a halogen, to form a compound having a formula:

and further reacting with a base comprising sodium hydroxide, sodium carbonate, or sodium bicarbonate to form a salt, reacting a salt with a compound having a formula:

in the presence of a base to form a compound having a formula:

then reacting with an acid to form olmesartan medoxomil.

An additional embodiment of the invention includes a compound having a formula:

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a differential scanning calorimetry ("DSC") thermogram of the crystalline sodium salt of 4-(1 -hydroxy- 1 -methylethyl)-2-propyl-1 -[4-[2-

(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole-5-carboxylic acid of Formula Vl, prepared according to Example 4.

Fig. 2 is a thermogravimetric analysis ("TGA") thermogram of the crystalline sodium salt of 4-(1 -hydroxy- 1 -methylethyl)-2-propyl-1 -[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl, prepared according to Example 4.

Fig. 3 is an X-ray powder diffraction ("XRPD") pattern of the crystalline sodium salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl, prepared according to Example 4.

Fig. 4 is an infrared ("IR") absorption spectrum of the crystalline sodium salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl, prepared according to Example 4. Fig. 5 is a DSC thermogram of olmesartan medoxomil of Formula I, prepared according to Method 1 of Example 6.

Fig. 6 is an XRPD pattern of olmesartan medoxomil of Formula I, prepared according to Method 1 of Example 6.

Fig. 7 is an IR spectrum of olmesartan medoxomil of Formula I₁ prepared according to Method 1 of Example 6. Fig. 8 is a schematic representation of a process for the preparation of olmesartan medoxomil.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of olmesartan medoxomil and intermediates thereof. In particular, it relates to a process for the preparation of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-2-(trityltetrazol-5- yl) phenyl} methyl imidazole-5-carboxylate and it's use in the preparation of olmesartan medoxomil. One aspect of the present invention provides a process for the preparation of the imidazole derivative, methyl 4-(1~hydroxy-1-methylethyl)-2-propyl 1-{4-2- (trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate of Formula V and its salts.

In an embodiment, the process for preparation of the imidazole derivative, methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-2-(trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate of Formula V and its salts comprises: a) reacting dimethyl-2-propylimidazole-4, 5-dicarboxylate compound of Formula Il with 4-[2-(trityltetrazol-5-yl) phenyl] benzyl bromide of Formula III in the presence of a suitable base and a suitable solvent to give dimethyl 2-propyl-1-[4- (2-trityltetrazol-5-yl) phenyl] phenylmethyl imidazole-4,5-carboxylate of Formula IV;

Formula Il Formula III b) reacting dimethyl 2-propyl-1-[4-(2-trityltetrazol-5-yl) phenyl] phenylmethyl imidazole-4,5-carboxylate of compound Formula IV with methyl magnesium halide to yield methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-2- (trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate of Formula V; and

Formula IV Formula V c) reacting methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-2- (trityltetrazol-5yl) phenyl} methyl imidazole-5-carboxylate of Formula V with a suitable base in a suitable solvent to obtain a salt of 4-(1-hydroxy-1-methylethyl)- 2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid), exemplified by the sodium salt being shown in the compound of Formula Vl.

Formula Vl Suitably, one or more sequential steps a) to c) are carried out in situ. In one embodiment of the invention, step b) is carried out in situ followed by isolation of the salt of the compound of Formula Vl.

Step a) involves reaction of dimethyl-2-propylimidazole-4,5-dicarboxylate of Formula Il with 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide of Formula III in the presence of a suitable base, and a suitable solvent to get the dimethyl 2-propyl-1- [4-(2-trityltetrazol-5-yl)phenyl]phenyl methylimidazole-4,5-carboxylate of Formula IV.

Suitable solvents which can be used include but are not limited to: alcoholic solvents such as Ci to C₄ alcohols; C₂ to C₆ ketone solvents including acetone, ethyl methyl ketone, and diethyl ketone; chlorinated solvents, such as Ci to Ce straight chain or branched chlorohydrocarbons, including dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chloro benzene, dichlorobenzene, and the like; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide and the like; and mixtures thereof.

The temperature for conducting the reaction can range from about 20 to about 130° C, or from about 110 to about 115° C, or at the reflux temperature of the solvent used.

When a mixture of solvents is used, suitably, the lower boiling solvent is distilled off and the product is isolated from the reaction mixture containing the product in the higher boiling solvent by addition of water.

The isolated solid can be optionally purified by recrystallization or slurrying in a suitable solvent.

Suitable solvents which can be used for recrystallization or slurrying include, but are not limited to: hydrocarbons such as toluene, xylene, n-hexane, cyclohexane, n-heptane and the like; ether solvents such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1 ,4- dioxane and the like; and mixtures thereof or their combinations with water in various proportions without limitation. Step b) involves reacting dimethyl 2-propyl-1-[4-(2-trityltetrazol-5-yl)phenyl] phenylmethyl imidazole-4,5-carboxylate of Formula IV with a methyl magnesium halide to give methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-2-(trityltetrazol-5- yl) phenyl}methyl imidazole-5-carboxylate of Formula V.

In the compound dimethyl 2-propyl-1-[4-(2-trityltetrazol-5- yl)phenyl]phenylmethyl imidazole-4,5-carboxylate of Formula IV, one of the ester groups is sterically hindered by a bulky aromatic group, and the other has less steric hindrance. Because of the different environments present for the two ester groups, the Grignard reagent selectively reacts with the ester carbon having less steric hindrance, which is the desired ester carbon. This results in forming a high purity intermediate having Formula V, and a high purity final product.

Grignard reagents that can be used include, but are not limited to, methyl magnesium chloride, methyl magnesium bromide, or methyl magnesium iodide. Suitable solvents that can be used for the reaction include: hydrocarbons, which can be aliphatic or aromatic, such as hexane and toluene; halogenated hydrocarbons, including halogenated aliphatic hydrocarbons such as methylene chloride or 1 ,2-dichloromethane; ethers such as tetrahydrofuran or diethyl ether; and the like.

Since Grignard reagents are senstitive to the presence of moisture, suitably, moisture is removed from the reaction medium containing dimethyl 2- propyl-1-[4-(2-trityltetrazol-5-yl)phenyl] phenylmethyl imidazole-4,5-carboxylate of

Formula IV and the solvent. The moisture can be removed by azeotropic distillation, or by using dehydrating agents like sodium sulphate or magnesium sulphate, or molecular sieves or other suitable methods. Suitable temperatures for conducting the reaction range from about -20 °C to about 70 ⁰C.

Methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 -{4-2-(trity ltetrazol-5-y I) phenyl} methyl imidazole-5-carboxylate of Formula V may or may not be isolated.

The product can be directly progressed to the next stage. Step c) involves reacting methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-

2-(trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate of Formula V with a suitable base to obtain a salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-

(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid). In one embodiment, the salt is the sodium salt of 4-(1 -hydroxy- 1- methylethyl)-2-propyl-1-[4-[2~(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -

5-carboxylic acid having Formula Vl.

Suitable solvents include but are not limited to: alcoholic solvents such as

Ci to C₄ alcohols; C₂-Ce ketone solvents including acetone, ethyl methyl ketone, and diethyl ketone; chlorinated solvents, such as Ci-Cβ straight chain or branched chlorohydrocarbons, including dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, and the like; and mixtures thereof.

Suitable bases that can be used include, but are not limited to, sodium hydroxide, sodium carbonate, sodium bicarbonate, and the like. Suitably, other base addition salts can be prepared by reaction with: organic bases such as triethylamine, trimethylamine, di-isopropylethylamine and the like; and with inorganic bases such as potassium hydroxide, potassium carbonate, potassium bicarbonate and the like. Another aspect of the present invention provides an imidazole derivative, methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1 -{4-2-(trityltetrazol-5-yl) phenyl} methyl imidazole-5-carboxylate of Formula V and its salts.

In one embodiment, the present invention provides a crystalline sodium salt of the compound 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula V, represented by Formula Vl.

The crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1-[4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by its X-ray powder diffraction pattern ("XRPD") pattern. All XRPD data reported herein were obtained using Cu Kα-1 radiation, having the wavelength 1.541 A, and were obtained using a Bruker Axe D8 Advance Powder X-ray Diffractometer.

The crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by its XRPD pattern substantially in accordance with the pattern of Fig. 3. It is also characterized by an XRPD pattern having significant peaks at about 13.2, 21.0, 21.7, 19.0, and 18.2, ± 0.2 degrees two-theta. It is also characterized by the additional XRPD peaks at about 10.5, 9.9, 11.4, 12.2, 14.9, and 16.0, ± 0.2 degrees two-theta.

The crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1-[4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by an infrared absorption spectrum in potassium bromide substantially in accordance with Fig. 4. It is also characterized by an infrared absorption spectrum in potassium bromide comprising peaks at about 3392, 2966, 1586, 1492, 1174, 750, and 759, ± 5 cιτf¹.

The crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1- [4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by a differential scanning calorimetry curve substantially in accordance with Figure 1.

The crystalline sodium salt of 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1- [4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl is characterized by a TGA thermogram curve substantially in accordance with Figure 2. It is desirable to obtain the intermediates in the individual steps in highly purified form for use in the succeeding steps. Crystallinity of intermediates reflects their purity and is highly desirable since unwanted side reactions involving impurities can be avoided in the subsequent steps of the overall process. The crystalline sodium salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1- [4-[2- (trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid of Formula Vl of the present invention has a purity of more than about 95%, or more than about 98%, by high performance liquid chromatography ("HPLC").

Still another aspect of the present invention provides a process for the conversion of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-{4-2-(trityltetrazol-5- yl) phenyl} methyl imidazole-5-carboxylate of Formula V or its salts to olmesartan medoxomil of Formula I.

Optionally, the compound of Formula Vl can be progressed to the next stage without isolation.

An embodiment of a process for the preparation of olmesartan medoxomil of Formula I from 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid) of Formula Vl comprises; a) reacting the sodium salt of 4-(1 -hydroxy- 1 -methylethyl)-2-propyl-1 - [4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid) of Formula Vl with 5-methyl-4-chloromethyl-1 ,3-dioxolen-2-one of Formula VII to give (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl-4 (1 -hydroxy 1-methylethyl) 2-propyl1- {phenyl}4-[2-(trityltetrazol-5-yl) phenyl]methylimidazol-5-carboxylate of Formula VIII; and

Formula VII Formula VIII b) deprotection of (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl-4 (1- hydroxymethylethyl) 2-propyl1 -{phenyl} 4-[2-(trityltetrazol-5-yl) phenyl] methylimidazol-5-carboxylate of Formula VIII to give olmesartan medoxomil of Formula I.

Step a) involves reaction of the sodium salt of 4-(1-hydroxy-1-methylethyl)- 2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid) of Formula Vl with 5-methyl-4-chloromethyl-1 ,3-dioxolen-2-one of Formula VII in the presence of a suitable base to give (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl-4 (1-hydroxy1-methylethyl) 2-propyl 1 -{phenyl}4-[2-(trity ltetrazol-5-yl) phenyl]methylimidazol-5-carboxylate of Formula VIII.

Suitable bases which can be used include, but are not limited to: sodium methoxide, sodium ethoxide or their solutions in alcohol, potassium methoxide, potassium ethoxide or their solutions in alcohol, sodium tertiary butoxide, and potassium tertiary butoxide; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate and the like; alkali metal hydrides such as sodium hydride; and the like.

Suitable solvents which can be used include but are not limited to: hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N, N- dimethylacetamide and the like; and mixtures thereof in various proportions without limitation.

Suitable temperatures for conducting the reaction range from about 35 ⁰C to about 200 ⁰C. The product obtained can be optionally purified by recrystallization or slurrying in a suitable solvent.

Suitable solvents that can be used for recrystallization or slurrying include but are not limited to: hydrocarbon solvents such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like; and nitrile solvents such as acetonitrile, propionitrile and the like.

Step b) involves deprotection of (5-methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl- 4 (1 -hydroxy 1-methylethyl) 2-propyl-1 -{phenyl} 4-[2-(trityltetrazol-5-yl) phenyl] methylimidazol-5-carboxylate of Formula VIII to give olmesartan medoxomil. Deprotection can be suitably carried out in acidic environment.

Suitable acids which can be used for providing the acidic environment include, but are not limited to: inorganic acids such as hydrochloric acid, sulphuric acid, and the like; and organic acids such as oxalic acid, tartaric acid, formic acid, acetic acid, para-toluene sulfonic acid and the like.

Suitable solvents which can be used include but are not limited to: water; alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; hydrocarbon solvents such as toluene, xylene, heptane, hexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof or their combination with water in various proportions without limitation.

An embodiment of an entire process, beginning with the compound having Formula II, is shown schematically in Fig. 5.

Olmesartan medoxomil obtained above can be further purified by recrystallization or slurrying in suitable solvents. Recrystallization involves providing a solution of crude olmesartan medoxomil in a suitable solvent and then crystallizing the solid from the solution.

Suitable solvents which can be used for recrystallization and slurrying include, but are not limited to: halogenated solvents such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbon solvents such as toluene, xylene, heptane, hexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof in various proportions.

The concentration of olmesartan medoxomil in the solvent can range from 40 to 80% or more. The solution can be prepared at an elevated temperature if desired to achieve a desired concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the olmesartan medoxomil is obtained and is not detrimental to the drug substance chemically or physically. The solution may be brought down to room temperature for further processing if required or an elevated temperature may be used. A higher temperature will allow the precipitation from solutions with higher concentrations of Zolpidem resulting in better economy of manufacture.

The compound obtained can be further dried suitably using a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 70° C. The drying can be carried out for any desired time period until the required solvent removal is obtained, times from about 1 to 20 hours frequently being suitable.

The compound 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[4-[2-(trityltetrazol-5- yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid) of Formula V or its salts obtained above can also be converted to olmesartan medoxomil by processes known in the art, for example one being given in U.S. Patent No. 5,616,599.

Olmesartan medoxomil prepared according to the process of the present invention has a low level of impurities as determined by HPLC. For example, it contains less than about 0.15%, or less than about 0.05%, of 4-(1 -hydroxy-1 - methylethyl)-2-propyl-1- [4-[2-(tetrazol-5-yl) phenyl] phenyl] methylimidazole-5- carboxylic acid of Formula Il A, hereinafter referred to as "olmesartan acid impurity";

Formula MA less than about 0.15%, or less than about 0.03%, of (5-Methyl-2-oxo-1 ,3-dioxolen- 4-yl)methyl 4-isopropenyl-2-butyl-1-[4-[2-(tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxylate of Formula HB, hereinafter referred to as "olmesartan dehydro impurity";

Formula HB less than about 0.15% of 5-Acetyl-4-(1~hydroxy1-methylethyl)-2-propyl1-1-[4-[2- tetrazol-5-yl)phenyl]phenyl]methyl imidazole of Formula HC, hereinafter referred to as "5-acetyl olmesartan"; and

Formula IIC less than about 0.15% of (5- methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl4 -(1-hydroxy- 1 -methyl ethyl)-2-propyl-1-[4- [2-((5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyltetrazol- 5-yl)phenyl]phenyl]methylimidazole-5-carboxylate derivative of Formula HD, hereinafter referred to as "bis dioxolene impurity."

Formula HD The above impurity contents are expressed as weight percentages.

Olmesartan medoxomil prepared according to the process of the present invention contains less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of methanol, and less than about 200 ppm, or less than about 100 ppm, of individual residual organic solvents like hexane, acetone, tetrahydrofuran, ethyl acetate, methanol, dichloromethane, acetonitrile, toluene, ortho-xylene, N,N-dimethylformamide, N,N-dimethylacetamide, and acetic acid. It contains less than about 1000 ppm, or less than about 500 ppm, of acetone, less than about 1000 ppm, or less than about 500 ppm, of methanol, and less than 1000 ppm, or less than 500 ppm, of acetonitrile. Olmesartan medoxomil prepared according to the process of the present invention has particle sizes less than about 500 μm and a bulk density of about 0.5 to about 1 g/ml.

The Dm, D₅₀ and D₉₀ values are useful ways for indicating a particle size distribution. D₉₀ refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D50 and D₁₀ refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining Di₀, D₅₀ and D₉₀ include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern, Worcestershire, United Kingdom) equipment.

Olmesartan medoxomil prepared according to the process of the present invention has D₁₀ less than about 50 μm, or less than about 30 μm, D₅₀ less than about 150 μm, or less than about 100 μm, and D₉₀ less than about 250 μm, or less than about 200 μm. There is no specific lower limit for any of the D values. Olmesartan medoxomil prepared according to the process of the present invention has a bulk density of less than 0.5 g/ml or less than 1 g/ml before tapping, and bulk density of less than 0.5 g/ml, or less than 1 g/ml after tapping. The bulk densities are determined using Test 616 "Bulk Density and Tapped Density," United States Pharmacopeia 24, pages 1913-4 (United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999).

Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are not intended to limit the scope of the appended claims in any manner.

EXAMPLE 1

PREPARATION OF DIMETHYL-2-PROPYLIMIDAZOLE- 4,5-DICARBOXYLATE (FORMULA II)

150 g of thionyl chloride was added slowly to a solution of 100 g of 2- propylimidazole-4, 5- dicarboxylic acid in 300 ml of methanol at 43 ⁰C over about one hour. The reaction mixture was stirred at 43 °C for 10 hours. The reaction completion was confirmed using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 2 ⁰C and added slowly to 300 ml of chilled water. The reaction mixture was neutralized by the addition of 700 ml of 10% sodium hydroxide solution in water. Precipitated product was filtered, washed with 200 ml of water and dried at 70 ⁰C for 10 hours to get 98 g of the title compound.

EXAMPLE 2

PREPARATION OF DIMETHYL 2-PROPYL-1-f4-(2-TRITYLTETRAZOL-5-YL) PHENYL1PHENYLMETHYL IMIDAZOLE - 4,5-CARBOXYLATE (FORMULA IV)

100 g of dimethyl-2-propylimidazole-4,5-dicarboxylate was dissolved in 500 ml of acetone. 100 ml of N,N-dimethylacetamide, 258.8 g of 4-[2-(trityltetrazole-5- yl)phenyl]-benzyl bromide and 122.1 g of potassium carbonate were added with stirring at 30 °C to the solution. The reaction mass was heated to 60 ⁰C and maintained for 5 hours. Reaction completion was confirmed using thin layer chromatography. After the reaction was completed, 60% of the initial volume of acetone was distilled off atmospherically from the reaction mass and cooled to 30 ⁰C. 1000 ml of water was added to the reaction mass and stirred for one hour. The solid was filtered and washed with 500 ml water. The solid was dried at 78 ⁰C for 10 hours to get 308 g of the title compound. Purity by HPLC: 95.54%.

EXAMPLE 3

PREPARATION OF METHYL 4-(1 -HYDROXY-1-METHYLETHYL)-2~PROPYL 1- {4-[2-(TRITYLTETRAZOL-5-YL) PHENYL! PHENYL) METHYL IMIDAZOLE -5- CARBOXYLATE (FORMULA V)

20 g of dimethyl 2-propyl-1-[4-(2-trityltetrazol-5-yl) phenyl]phenylmethyl imidazole-4,5-carboxylate was added to 60 ml of toluene and then was added 25 ml of a 25.5% solution of methyl magnesium chloride in tetrahydrofuran at 30 ⁰C. The contents were stirred for the completion of the reaction. Reaction completion was checked using thin layer chromatography. After the reaction completion, the reaction mass was quenched with 61 ml of 10% aqueous acetic acid and extracted with 20 ml of toluene. The solvent was distilled off at a temperature of 50 °C under a pressure of 400 mm Hg to obtain 20.5 g of the title compound. Purity by HPLC: 94%. EXAMPLE 4

PREPARATION OF 4-(1-HYDROXY-1-METHYLETHYL)-2-PROPYL-1-f4-r2- (TRITYLTETRAZOL-5-YL) PHENYL! PHENYL! METHYL IMIDAZOLE -5- CARBOXYLIC ACID SODIUM SALT (FORMULA Vl) To a solution of 100 g of methyl 4-(1-hydroxy-1-methylethyl)-2-propyl 1-[4-

[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylate of Formula Il in 700 ml of acetone was added a solution of 5.7 g of sodium hydroxide in 500 ml water and the reaction mixture was stirred at 28 ⁰C for 5 hours. After completion of reaction, the reaction mixture was diluted with 300 ml of 25% sodium chloride solution and extracted first with 600 ml ethyl acetate, followed by extraction with 100 ml of ethyl acetate. The ethyl acetate layer was washed twice with 400 ml of a 25% aqueous sodium chloride solution. The solvent was distilled from the organic layer at a temperature of 43 ⁰C and a pressure of 300-400 mm Hg, and the residue co-distilled with 200 ml toluene twice. To the resultant residue, 270 ml heptane was added and stirred for solid separation for 30 minutes. Solvent was removed by decantation and the product was again washed with 100 ml of heptane. The product was dried under a vacuum of 300 mm Hg at 29 ⁰C to yield 112 g of the title compound. Purity by HPLC: 98.89%.

EXAMPLE 5

PREPARATION OF (5-METHYL-2-OXO-1 , 3-DIOXOLEN-4-YL) METHYL-4 (1- HYDROXY1 -METHYLETHYL) 2-PROPYL1 -(PHENYL)4-r2-(TRITYLTETRAZOL- 5-YL) PHENYLIMETHYLIMIDAZOL-δ-CARBOXYLATE (FORMULA VIII) 100 g of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl] methyl imidazole -5-carboxylic acid sodium salt of Formula Vl was added to 300 ml of N,N-dimethylacetamide. 23.3 g of potassium carbonate and 27.2 g of 4-chloromethyl-5-methyl-1 ,3-dioxolen-2-one were added to the above reaction mass and heated to 50° C for 5 hours. 1000 ml of 10% aqueous sodium chloride solution and 500 ml of toluene were added to the reaction mixture and pH was adjusted to 7.6 with 10% aqueous hydrochloric acid. The aqueous layer was separated and extracted with 200 ml toluene. The combined organic layers were washed with 400 ml of 10% sodium chloride solution twice. The solvent was evaporated under a pressure of 300 mm Hg and the residue was recrystallized from acetonitrile to get 60.8 g of the title compound.

EXAMPLE 6 PREPARATION QF (5-METHYL-2-OXO-1 ,3-DIOXOLEN-4-YL)METHYL 4-(1- HYDROXY-1-METHYLETHYL)-2-PROPYL-1-r4-f2-(TETRAZOL-5-YL)PHENYL1 PHENYL1METHYL -IMIDAZOLE-δ-CARBOXYLATE (OLMESARTAN MEDOXOMIL-FORMULA I)

METHOD 1 : 50 g of (5-Methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl-4 (1 -hydroxy 1- methylethyl) 2-propyl1-{phenyl}4-[2-(trityltetrazol-5-yl)phenyl]methylimidazol-5- carboxylate of Formula VII was taken into 1500 ml of 40% aqueous acetic acid and heated at 55 to 60° C for 3 hours. The reaction mass was cooled to 28° C and diluted with 750 ml of water. The precipitated solid was removed by filtration and the filtrate was extracted with 1250 ml methylene chloride. The organic layer was washed with a mixture of 5% aqueous sodium bicarbonate solution (450 ml) and aqueous 5% sodium chloride solution (450 ml) three times. The solvent was distilled from the organic layer under a pressure of 300-400 mm Hg and the residue was co-distilled with 50 ml toluene. The crude product was finally recrystallized from acetone to get 26.5 g of the title compound. METHOD 2:

10 g of (5-Methyl-2-oxo-1 , 3-dioxolen-4-yl) methyl-4 (1-hydroxy1- methylethyl) 2-propyl1-{phenyl}4-[2-(trityltetrazol-5-yl)phenyl]methylimidazol-5- carboxylate of Formula VII was added to a mixture of 20 ml methanol and 5 ml methylene chloride. 7.6 ml of a methanolic solution of hydrochloric acid (9% w/v) was added at 3° C to the above reaction mass. The reaction mixture was stirred at 0-5° C for 1 to 2 hours. The reaction mixture was diluted with water, neutralized with sodium hydroxide solution and stirred with a mixture of 250 ml toluene and 10 ml ethyl acetate. The precipitated product was filtered, and washed with water. The compound was dried at 70 to 80° C for 2 to 3 hours to get 5.2 g of the title compound.

METHOD 3:

110 g of (5-Methyl-2-oxo-1 , 3-dioxolen-4~yl)-methyl-4(1 -hydroxy 1- methylethyl)2-propyl1- {phenyl} 4-[2-(trityltetrazol-5-y I) phenyl] methylimidazol-5- carboxylate of Formula VII was added to 2200 ml of 50% aqueous acetic acid, and the reaction mass was heated at 60° C for 2 hours. After completion of reaction, the reaction mass was diluted with 1100 ml of water and cooled to -5° C. The precipitated solid was removed by filtration and the filtrate was extracted with 3300 ml of methylene chloride. The organic layer was washed with 1320 ml of aqueous 5% sodium chloride solution three times. After concentration of solvent, the residue was co-distilled with 660 ml toluene three times. The crude product was finally recrystallized from acetonitrile to get 56 g of the title compound.

EXAMPLE 7

24 liters of dimethylacetamide, 110 liters of acetone, and 24 kg of dimethyl- 2-propylimidazole-4,5-dicarboxylate were taken into a reactor and stirred for 45 minutes. 29.2 kg of potassium carbonate, and 62 kg of 5-[4-(bromomethyl)-[1 ,1- biphenyl]-2-yl]-2H-tetrazole were then added. Another 20 liters of acetone was used to rinse the walls of the reactor. The reaction mass was heated to 61 ⁰C and maintained for 6 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, about 70 % of the acetone was distilled off atmospherically from the reaction mass at 61 ⁰C. The reaction mass was then cooled to 36 ⁰C and 240 liters of water was added, and a vacuum of 680 mm Hg was applied to distill off the remaining acetone. The remaining reaction mass was filtered and the solid was washed with 60 liters of water. 152 liters of toluene was taken into a reactor and the wet solid obtained after filtration was added to it. The mixture was heated to 84 ⁰C to get clear dissolution. After clear dissolution was obtained, the solution was cooled to 34 ⁰C. The solution was maintained at that temperature for 1 hour for complete isolation of the solid. It was then filtered and the wet solid was washed with 38 liters of toluene. The wet material was dried under a vacuum of 600 mm Hg and a temperature of 70 °C for 5 hours. The dry material was milled and again dried at 77 ⁰C under a vacuum of 600 mm Hg for 3 hours to yield 61.8 kg of the title compound. (Yield 82.8%). Purity by HPLC: 99.4%. EXAMPLE 8

PREPARATION OF (5-METHYL-2-OXO-1 , 3-DIOXOLEN-4-YL) METHYL-4 (1- HYDROXY1 -METHYLETHYU 2-PRQPYL1-(PHENYL)4-r2-(TRlTYLTETRAZOL- 5-YL) PHENYLIMETHYLIMIDAZOL-δ-CARBOXYLATE (VIII) 190 liters of toluene was taken into a reactor and heated to 110 ⁰C. The solvent was distilled to azeotropically remove water. The solvent was then cooled to 28 ⁰C and 55 kg of dimethyl-2-propyl-1-{4-2-(trityltetrazole-5-yI)phenyl}methyl imidazole-4,5 dicarboxylate was added to it. 62 liters of a 3 Molar solution of methyl magnesium chloride in tetrahydrofuran was added slowly at 49 ⁰C to the above reaction mass. The reaction mass was maintained at 49 °C for one hour. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 24 ⁰C. A solution of 20 liters of acetic acid in 180 liters of water was prepared and added to the reaction mass until the pH of the reaction mass was 4.05. The reaction mass was stirred for another 10 minutes. The organic layer was separated and the aqueous layer was extracted with 55 liters of toluene. The combined organic layer was washed with 345 liters of water in three equal lots. The organic layer was distilled at 35 °C under a vacuum of 700 mm Hg. The residue was cooled to 40 ⁰C and 190 liters of acetone was added to it. The reaction mass was stirred at 43 ⁰C for clear dissolution. The reaction mass was then cooled to 36 ⁰C and 200 liters of acetone was added to it. A solution of 3.1 kg of sodium hydroxide flakes in 275 liters of water was prepared and added to the above reaction mass at 29 ⁰C. The reaction mass was maintained at this temperature for 1 hour. Reaction completion was checked using thin layer chromatography. After the reaction was completed, a solution of 0.9 liters of acetic acid in 8.5 liters of water was prepared and the pH of the reaction mass was adjusted to 8.7 using this solution. 330 liters of ethyl acetate was added, followed by a solution of 42.7 kg of sodium chloride in 170 liters of water. The reaction mass was stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with 55 liters of ethyl acetate. The combined organic layer was washed with a solution of 56.9 kg of sodium chloride in 230 liters of water in two equal lots. The organic layer was distilled completely at a temperature of 23 ⁰C and a vacuum of 700 mm Hg. To the residue obtained, 55 liters of toluene was added to dissolve the residue. The toluene was distilled completely under a vacuum of 700 mm Hg and a temperature of 40 ⁰C. 170 liters of dimethylacetamide was added and the reaction mass was heated to 49 ⁰C and stirred for 20 minutes. 5 kg of sodium carbonate, and 15.2 kg of 4-ch!oromethyl-5~methyl-1 ,3-dioxolene-2-one were added. The reaction mass was maintained at 44 ⁰C for 5 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 33 °C. 275 liters of toluene was added to the reaction mass. A solution of 142.2 kg of sodium chloride in 570 liters of water was added to the reaction mass. pH of the reaction mass was adjusted to 6.6 using a solution of 6.6 liters of hydrochloric acid in 55 liters of water. The reaction mass was stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with 110 liters of toluene. The combined organic layer was distilled completely at a temperature of 33 °C and a vacuum of 650 mm Hg. The residue was co-distilled with 30 liters of acetonitrile under a vacuum of 650 mm Hg and a temperature of 33 °C. 110 liters of acetonitrile was then added to the residue and the mixture was cooled first to 28 ⁰C and maintained for 2.5 hours, then it was cooled to 5 ⁰C and maintained for one hour. The reaction mass was then filtered and the solid was washed with 55 liters of acetonitrile. The wet material was taken into another 110 liters of acetonitrile and heated to 80 ⁰C and maintained for 30 minutes. The reaction mass was then cooled to 29 ⁰C and maintained for 2 hours. The separated solid was filtered and washed with 55 liters of acetonitrile. The wet material was dried under a vacuum of 660 mm Hg at a temperature of 75 ⁰C for 2 hours. The dry material obtained was taken into another reactor and 173 liters of acetonitrile was added to it. The mixture was heated to 81 ⁰C to obtain clear dissolution and maintained for 15 minutes. Then the mixture was cooled to 29 ⁰C and maintained for 1.5 hours. The separated solid was filtered and washed with 35 liters of acetonitrile. The wet compound was taken into another reactor and another 173 liters of acetonitrile was added to it. The mixture was heated to 81 ⁰C to obtain clear dissolution and maintained for 45 minutes. Then the mixture was cooled to 29 ⁰C and maintained for 1.5 hours. The separated solid was filtered and washed with 35 liters of acetonitrile. The wet material was dried at 71 ⁰C and a vacuum of 660 mm Hg for 3 hours to yield 25.7 kg of the title compound. (Yield 41.1 %).

EXAMPLE 9 PREPARATION OF (5-METHYL-2-OXO-1 ,3-DIOXOLEN-4-YL)METHYL 4-(1- HYDROXY-1-METHYLETHYL)-2-PROPYL-1-f4-r2-(TETRAZOL-5-YL)PHENYLl PHENYL1METHYL -IMIDAZOLE-δ-CARBOXYLATE (OLM ESARTAN MEDOXOMIL. FORMULA I)

300 liters of acetic acid was taken into a reactor and 418 liters of water was added to it. The reaction mass was stirred for 10 minutes and 25 kg of (5-methyl- 2-0X0-1 , 3-dioxolen-4-yl) methyl-4 (1-hydroxy1-methylethyl) 2-propyl-1-{phenyl}4- [2-(trityltetrazol-5-yl) phenyl]methylimidazol-5-carboxylate obtained above was added. 35 liters of water was added. The reaction mass was then heated to 58 ⁰C and maintained for 2 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 33 ⁰C and a solution of 18.9 kg of sodium chloride in 375 liters of water was added. The reaction mass was maintained at 33 ⁰C for 30 minutes. The reaction mass was filtered and the filter bed was washed with a solution of 10 liters of acetic acid in 15 liters of water. The filtrate was taken into another reactor and 250 liters of dichloromethane was added. The reaction mass was stirred for 10 minutes and the organic layer was separated. The aqueous layer was extracted with 375 liters of dichloromethane in 3 equal lots. The combined organic layer was washed with a solution of 15 kg of sodium chloride, and 15 kg of sodium bicarbonate in 598 liters of water in two equal lots. The organic layer was again washed with a solution of 5 kg of sodium chloride in 100 liters of water in two equal lots. The organic layer was distilled off atmospherically and then under a vacuum of 650 mm Hg at a temperature of 40 ⁰C to distill dichloromethane completely. The residue was then co-distilled with 50 liters of toluene in two equal lots. To the residue 242 liters of acetone was added . The reaction mass was heated to 55 ⁰C and 140 liters of acetone was distilled from the reaction mass. The remaining reaction mass was cooled to 39 ⁰C and 25 liters of acetone was distilled atmospherically. The reaction mass was then cooled to 35 ⁰C and maintained for 1.5 hours. The reaction mass was filtered and the wet material was washed with 13 liters of acetone. The wet compound was taken into another reactor and 158 liters of acetone was added. The mixture was heated to 57 ⁰C and maintained for 10 minutes. The reaction mass was filtered through a candy filter and 50 liters of solvent was distilled from it atmospherically. Another 25 liters of solvent was distilled from the reaction mass and it was cooled to 30 °C and maintained for 1.5 hours. The separated solid was filtered and washed with 5 liters of acetone. The wet material was dried at a temperature of 80 ⁰C for 3 hours to yield 9 kg of the title compound. (Yield 51.4%).

Purity by HPLC: 99.72%. Olmesartan acid impurity: 0.05%.

Olmesartan acetyl impurity: below LOD.

Olmesartan dehydro impurity: 0.06%.

Bis dioxolene impurity: less than 0.1 %.

EXAMPLE 10

PURIFICATION OF (5-METHYL-2-OXO-1 ,3-DIOXOLEN-4-YL)METHYL 4-(1- HYDROXY-1-METHYLETHYL)-2-PROPYL-1-r4-r2-(TETRAZOL-5-YϋPHENYL1 PHENYL1METHYL -IMIDAZOLE-5-CARBOXYLATE (OLMESARTAN MEDOXOMIL, FORMULA I) 9 kg of the crude olmesartan medoxomil obtained above was taken into a reactor and 122 liters of acetone was added. The mixture was heated to 57 °C and maintained for 15 minutes. The solution was filtered through a candy filter in the hot condition. 96 liters of the solvent was distilled atmospherically and the remaining mass was cooled to 29 °C and maintained for 1.5 hours. The mass was filtered and the solid was washed with 9 liters of acetone. The wet compound was dried at 71 ⁰C under a vacuum of 700 mm Hg for 3 hours to yield 7.4 kg of the title compound. The dry compound was then sifted through a 30 micron mesh sieve. Purity by HPLC: 99.8%. Olmesartan dehydro impurity: 0.03%. Olmesartan acid impurity: 0.03%.

Olmesartan acetyl impurity: below LOD. Bis dioxolene impurity: below 0.1 %. Residual solvents: acetone 585 ppm, methanol 50 ppm. Other solvents not detected.

Particle size distribution: D₁₀ 25 μm, D₅₀ 80 μm, Dg₀ 178 μm. Bulk Density: 0.5 g/ml.

EXAMPLE 11

DETERMINATION OF IMPURITIES IN OLMESARTAN MEDOXOMIL USING HPLC

The HPLC analysis conditions for impurities reported in the examples are described in Table 1.

Table 1

* RRT is relative retention time. ** LOD is limit of detection.

EXAMPLE 12

DETERMINATION OF RESIDUAL SOLVENTS IN OLMESARTAN MEDOXOMIL Gas chromatography conditions for residual solvent analyses of the examples are in Table 2. Samples for analysis were prepared by dissolving 200 mg in 10 ml of dimethylsulfoxide, and 1 μl of the solution was injected into the instrument.

Table 2

LOQ is limit of quantitation.

Claims

CLAIMS:

1. A process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:

2. The process of claim 1 , wherein a halogen comprises chlorine.

3. The process of claim 1 , wherein a compound having a formula:

is prepared by reacting a compound having a formula:

with a compound having a formula:

4. The process of claim 1 , further comprising reacting a compound having a formula:

with a base to form a salt, reacting a salt with a compound having a formula:

to form a compound having a formula:

and further reacting with an acid to form olmesartan medoxomil.

5. The process of claim 4, wherein a base comprises sodium hydroxide, sodium carbonate, or sodium bicarbonate.

6. The process of claim 4, wherein one or both of a compound having a formula:

and a product of its reaction to form a salt are not isolated before further reaction.

7. The process of claim 4, wherein a compound having a formula:

is not isolated before further reaction.

8. A compound having a formula:

wherein Ph is a phenyl group, or a salt thereof from reaction with a base.

9. A compound having a formula:

10. A process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:

with a compound having a formula:

11. The process of claim 10, wherein an acid comprises acetic acid.

12. A compound having a formula:

13. A process for preparing olmesartan medoxomil, comprising reacting a compound having a formula:

in the presence of a base to form a compound having a formula:

then reacting with an acid to form olmesartan medoxomil.

14. The process of claim 13, wherein a halogen comprises chlorine.

15. The process of claim 13, wherein an acid comprises acetic acid.

16. The process of claim 13, wherein one or both of a compound having a formula:

17. Olmesartan medoxomil having a particle size distribution comprising D-io less than about 50 μm, D₅₀ less than about 150 μm, and D₉₀ less than about 250 μm.

18. Olmesartan medoxomil having a particle size distribution comprising D₁₀ less than about 30 μm, D₅₀ less than about 100 μm, and D9₀ less than about 200 μm.