FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
PROCESS FOR THE PREPARATION OF POTASSIUM SALT OF 4-(1-
HYDROXYMETHYLETHYL)-2-PROPYL-1-[2'-(N-TRIPHENYLMETHYLTETRAZOL-
5-YL)-4-BIPHENYLMETHYLlIMIDAZOL-5-YL CARBOXYLIC ACID


Applicant
Name:
Nationality:
Address:

Torrent Pharmaceuticals Limited
Indian
Torrent House, Off Ashram Road,
Near Dinesh Hall,
Ahmadabad 380 009.
Gujarat, India

The following specification describes the invention:


FIELD OF THE INVENTION
The invention relates to a new crystalline form of ethyl 4-(1-hydroxymethylethyl)-2-
propyl-1-[2'-(N-tri-phenylmethyltetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl
carboxylate and its use for the preparation of olmesartan medoxomil. The invention also relates to crystalline potassium salt of 4-{1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyl-tetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl carboxylic acid, its preparation and use for the preparation of olmesartan medoxomil.
BACKGROUND OF THE INVENTION
Olmesartan medoxomil (I) is a powerful angiotensin II receptor antagonist and widely used for the treatment of hypertension and related diseases and conditions.

(I) US 5,616,599 (the '599 patent) discloses a process for the preparation of olmesartan medoxomil comprising:
• condensing ethyl 4-(1-hydroxymethylethyl)-2-propylimidazole-5-carboxylate (II) with 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) in presence of sodium hydride and dimethyl formamide to obtain amorphous ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylme-thyl]imidazol-5-yl carboxylate (IV);
• hydrolyzing ethyl 4-{1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyl-tetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) in presence of

lithium hydroxide in dioxane to obtain corresponding lithium salt of the acid, which is then reacted with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene in presence of potassium carbonate and dimethyl acetamide to get trityl olmesartan (V) and
deprotecting trityl olmesartan (V) in presence of acetic acid and water followed by recrystallization in ethyl acetate.



C(Ph)3

In J. Med. Chem., 39 (1996), 323-338, the alkylation step between ethyl 4-(1-hydroxymethylethyl)-2-propylirriidazole-5-carboxylate (II) and 4-[2-(trityltetrazol-5-yl)phe-nyl]benzyl bromide (III) is described to have been performed in presence of potassium tert-butoxide as base and dimethyl acetamide as solvent. The product obtained was purified first by column chromatography and then recrystallized from a mixture of hexane and isopropyl ether.
WO 07/048361 A1 (the '361 application) discloses a process for the preparation of trityl olmesartan (V) comprising preparation of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenyl-methyl]imidazol-5-yl carboxylate (IV) from ethyl 4-(1-hydroxymethylethyl)-2-propylimidazole-5-carboxylate (II) and 4-[2-(trityl-tetrazol-5-yl)phenyl]benzyl bromide (III) in presence of acetone/potash/polyethylene glycol; recrystallization of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenyl-methyl]imidazol-5-yl carboxylate (IV) from ethanol; hydrolyzing ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenyl-methyl]imidazol-5-yl carboxylate (IV) in presence of potassium hydroxide in tetrahydrofuran to obtain in situ potassium salt of


4-(1-hydroxymethylethyl)-2-propyl-1-[2'-{N-triphenylmethyltetrazol-5-yl)-4-biphenylme-thyl]imidazol-5-yl carboxylic acid (VI), reaction of potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yi)-4-biphenylmethyl]imi-dazol-5-yl carboxylic acid (VI) with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene in presence of potassium iodide to obtain the desired trityl olmesartan (V).
The process for the preparation of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethy!tetrazol-5-yl)-4-biphenyl-methyl]imidazol-5-yl carboxylate (IV) according to the '599 patent produces the amorphous form of the compound; whereas the process as described in the '361 application as well as J. Med. Chem., 39 (1996), 323-338 involves recrystallization of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) from hexane-isopropyl ether mixture, respectively. Crystalline forms are advantageous over amorphous form. The crystalline forms are easy to handle in bulk manufacturing and can easily be dried. The '361 Application and J. Med. Chem., 39 (1996), 323-338 are silent about the polymorphic forms of compound of formula (IV). We have surprisingly produced a crystalline form of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV).

The advantage of preparing the potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylic acid (VI) over lithium salt as described in the '361 application is that the next step of the reaction i.e. its reaction with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene does not require the presence of a base. But, the '361 application does not isolate potassium salt of 4-{1 -hydroxymethylethyl)-2-propyl-1 -[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylic acid (VI). We have surprisingly found that when ethyl 4-(1 -hydroxymethy!ethyl)-2-propyl-1 -[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylate (IV) is hydrolyzed by a potassium source in alcoholic solvent, potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylic acid (VI) could easily be isolated from the reaction mixture and recrystallized from an ester solvent.
SUMMARY OF THE INVENTION
In one embodiment, the specification discloses a crystalline form of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylate (IV).
In another embodiment, the specification discloses a process for the preparation of crystalline ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) comprising:
i) reacting ethyl 4-(1 -hydroxymethylethyl)-2-propylimidazole-5-
carboxylate (II) and 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III)
in presence of a base and a polar solvent for 4 to 15 hours at 20-80
°C;
ii) quenching the reaction mixture by water;
iii) filtering the solid obtained in step (ii); and iv) recrystallizing the solid in a solvent.

In yet another embodiment, the specification discloses potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylic acid (VI).
In still another embodiment, the specification discloses a process for the preparation
of potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-
triphenylmethyltetrazol-5-yl)-4-biphenyl-methyl]imidazol-5-yl carboxylic acid (VI) comprising:
i) reacting crystalline ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-
triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) with a potassium source in alcoholic solvent for 1 to 10 hours at 20-60 °C; jj) removing the solvent from the reaction mixture; and iii) recrystallizing the residue obtained in step (ii) in an ester solvent.
In another embodiment, the specification discloses the potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylic acid (VI) as an intermediate for the preparation of olmesartan medoxomil.
DESCRIPTION OF THE DRAWINGS
Pig. 1: X-ray diffraction (XRD) of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-
triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl carboxylate (IV)
recrystallized from methanol. Pig. 2: XRD of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-
methyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV)
recrystallized from acetone. Pig. 3: XRD of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-
methyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV)
recrystallized from isopropanol.

Fig. 4: XRD of ethyl 4-(1 -hydroxymethylethyl)-2-propyl-1 -[2'-(N-triphenyl-
methyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV)
recrystallized from ethyl acetate.
Fig. 5: XRD of potassium salt of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (VI).
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the specification discloses a process for the preparation of crystalline ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) comprising:
i) reacting ethyl 4-(1-hydroxymethylethyl)-2-propylimidazole-5-
carboxylate (II) and 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III)
in presence of a base and a polar solvent for 4 to 15 hours at 20-80
°C;
ii) quenching the reaction mixture by water;
iii) filtering the solid obtained in step (ii); and iv) recrystallizing the solid in a solvent.
Ethyl 4-(1-hydroxymethylethyl)-2-propylimidazole-5-carboxylate (II) and 4-[2-(trityl-tetrazol-5-yl) phenyl] benzyl bromide (III) are dissolved together at 20-25 °C in a polar solvent, wherein polar solvent is selected from dimethyl formamide, dimethyl sulphoxide and dimethyl acetamide. Metal carbonate, like potassium carbonate, sodium carbonate, cesium carbonate or lithium carbonate, is added to the reaction mixture and heated to 20-80 °C, preferably to 30-60 °C, more preferably to 40-50 °C for 4-15 hours, preferably for 10-12 hours. The reaction is quenched with chilled water and the resulting solid is filtered and washed again with water. The solid is dissolved in dichloromethane, washed with water and the organic layer is removed to obtain ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylate (IV). Ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylate (IV), obtained thus is dissolved in a suitable solvent and heated to 40-60

°C, preferably to 40-45 °C and stirred at this temperature for 10-30 minutes,
preferably for 15-20 minutes. It is cooled to 20-35 °C, preferably to 20-25 °C for 30
minutes to 2 hours, preferably for 1 hour. The solid is filtered, washed with solvent
and suck dried to obtain crystalline ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-
(N-triphenylmethyltetrazol-5-yl)-4-biphenyl methyl]imidazol-5-yl carboxylate
(IV). The organic solvent is selected from an alcohol, ketone, ester solvent and the like. The alcohol solvent is selected from a methanol, ethanol, isopropanol, n-butanol, terf-butanol; ketone solvent is selected from acetone, methyl ethyl ketone, diethyl ketone, isobutyl ethyl ketone; and ester solvent is selected from ethyl acetate, ethyl lactate, n-propyl acetate, isopropyl acetate, ethyl formate. More preferably, the solvent is selected from methanol, isopropanol, acetone and ethyl acetate. It is noted that the same polymorph of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]-imidazol-5-yl carboxylate (IV) is obtained when it is recrystallized from a solvent selected from an alcohol, ketone and ester solvent and the like.
Fig. 1-4 show the XRDs of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]-imidazol-5-yl carboxylate (IV) recrystallized from methanol, acetone, isopropanol and ethyl acetate, respectively.
Ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-
biphe-nylmethyl]-imidazol-5-yl carboxylate (IV) is characterized by X-ray powder diffraction peaks at about 4.3, 9.2, 9.8, 10.9, 11.9, 13.8, 14.6, 18.9, 21.4, 22.1, 22.6 and 23.5° ±0.2° 26.
Table 1 depicts the peak position (in °26) of the major peaks of compound (IV) in methanol, acetone, isopropanol and ethyl acetate.

Table 1:

Peak Position [°28]
Methanol Acetone Isopropanol Ethyl acetate
4.361 4.368 4.342 4.374
9.191 9.187 9.210 9.181
9.858 9.849 9.887 9.849
10.988 10.981 11.009 10.985
11.958 11.962 11.956 11.952
13.800 13.798 13.779 13.797
14.625 14.660 14.617 14.621
18.971 18.921 19.099 19.022
21.431 21.413 21.421 21.410
22.152 22.260 22.029 22.073
22.694 22.696 22.727 22.686
23.578 23.547 23.626 23.590
In another embodiment, the specification discloses crystalline potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyljimi- dazol-5-yl carboxylic acid of formula (VI).
The crystalline potassium salt of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl carboxylate (VI) is characterized by X-ray powder diffraction peaks at about 6.2, 7.2, 9.6, 11.0, 12.1, 12.6, 13.2, 14.5, 15.1, 18.9, 19.2, 19.7, 20.3, 20.7, 21.0, 21.8, 22.2, 22.4, 22.8, 23.4, 24.0, 24.2, 25.6, 26.6, 26.8 and 29.1° ± 0.2° 29.
The X-ray diffraction pattern of potassium salt of ethyl 4-(1-hydroxymethylethyl)-2-
propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl
carboxylate (VI) is expressed in Fig. 5 and Table 2.
Table 2:

[°26] d-spacing [° A] Relative Intensity [%]
6.287 14.0468 44.84
7.263 12.1619 87.71
9.614 9.1923 43.44
11.017 8.0243 18.29
12.178 7.2621 27.04

12.606 7.0161 33.55
13.225 6.6895 91.47
14,567 6.0759 22.92
15.110 5.8588 23.16
18.958 4.6773 20.95
19.222 4.6137 14.36
19.711 4.5003 9.93
20.326 3.3656 23.90
20.726 4.2823 11.50
21.053 4.2164 100.00
21.856 4.0632 20.08
22.279 3.9870 36.90
22.470 3.9536 30.21
22.820 3.8937 16.74
23.458 3.7893 9.94
24.018 3.7022 48.66
24.210 3.6731 59.02
25.621 3.4740 10.20
26.625 3.3454 15.75
26.881 3.3140 17.82
29.148 3.0613 11.61
In yet another embodiment, the specification discloses a process for the preparation of potassium salt of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyl-tetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl carboxylate (VI) comprising:
i) reacting ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-
methyl-tetrazol-5-yl)-4-biphenyl-methyl]imidazol-5-yl carboxylate (IV)
with a potassium source in alcoholic solvent for 1 to 10 hours at 20-60
°C;
ii) removing the solvent from the reaction mixture; and
iii) recrystallizing the residue obtained in step (ii) in an ester solvent.
Potassium source includes potassium hydroxide, potassium methoxide, potassium carbonate, potassium terf-butoxide, preferably potassium hydroxide, is dissolved in alcoholic solvent such as methanol, ethanol and isopropanol at 30-40 °C and ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenyl-methyl]imidazol-5-yl carboxylate (IV) is dissolved in the above solution. The reaction

mixture is heated to 20-60 °C, preferably to 30-50 °C, more preferably to 30-35 °C
for 1 to 10 hours, preferably for 4-6 hours. The solvent is removed by evaporation
from the reaction mixture to obtain potassium salt of ethyl 4-(1-hydroxymethylethyl)-
2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl
carboxylate (VI) as residue. An ester solvent selected from a group consisting of ethyl acetate, ethyl lactate, methyl acetate, isobutyl acetate, n-propyl acetate, isopropyl acetate, ethyl formate, terf-butyl acetate, preferably ethyl acetate is added to the obtained residue of potassium salt of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-{N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylate (VI) for recrystallization at 35-60 °C, preferably at 40-45 °C and is then stirred for 5-30 minutes, preferably for 5-10 minutes. The above solid mass is then cooled to 20-30 °C for 15 minutes to 1 hour, preferably for 30 minutes. The solid is filtered, washed with the same solvent used for recrystallization and dried under vacuum to obtain crystalline potassium salt of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylme-thyl]imidazol-5-yl carboxylate (VI). In still another embodiment, the specification discloses the use of crystalline potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-y!)-4-biphe-nylmethyl]imidazol-5-yl carboxylic acid (VI) for the preparation of olmesartan medoxomil.
4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene is dissolved in a ketone solvent, preferably acetone and potassium iodide is added to the solution. Crystalline potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylic acid (VI) is added to the above solution and stirred at 40-55 °C for 30 minutes to 1 hour. The reaction mixture is filtered and the solvent is removed from the reaction mixture. An alcoholic solvent selected from a group consisting of methanol, ethanol, isopropanol, terf-butanol, preferably methanol is added to the residue and stirred at 40-50 °C for 15 minutes to 30 minutes. The reaction mixture is then cooled to 15-30 °C and stirred for 1 hour to 2 hours. The solid obtained is filtered, dried and recrystallized from an ester solvent, preferably ethyl acetate to obtain trityl olmesartan (V).

Trityl olmesartan (V) is dissolved in a mixture of acid and water. The acid is selected from a group consisting of acetic acid, hydrochloric acid, preferably acetic acid. The reaction mixture is first heated to 35-40 °C for 3 to 6 hours and then cooled to 25-30 °C. The cooled reaction mixture is filtered and extracted with a mixture of organic solvents of type ! and type II. Type I solvent includes dichloromethane, chloroform, carbon tetrachloride and type II solvent includes methanol, ethanol, and isopropanol. The organic layer is dried and distilled under vacuum. The solid obtained is crystallized from an ester solvent selected from a group consisting of ethyl acetate, methyl acetate, ethyl lactate, methyl formate, preferably ethyl acetate to obtain olmesartan medoxomil (I).
The preparation of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyl-tetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV), crystalline potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylme-thyl]imidazol-5-yl carboxylic acid (VI) and olmesartan medoxomil (I) as described herein may be illustrated by way of the following examples which are not to be construed as limiting the scope of the invention:
Example 1:
Preparation of ethyl 4-(1 -hydroxymethylethyl)-2-propyl-1 -[2'-{N-triphenyl-methyl-tetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl carboxylate (IV) Ethyl 4-(1-hydroxymethylethyl)-2-propylimidazole-5-carboxylate (II) (50 gm, 0.21 mole) was dissolved in dimethyl acetamide (350 mL) at 25 °C. Potassium carbonate (36 gm, 0.26 mole) was added to the above solution, followed by 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) (110.2 gm, 0.20 mole). The reaction mixture was heated to 40-45 °C for 12 hours and then cooled to 25-30 °C. Chilled water (2.0 L) was added to quench the reaction mixture and the resulting solids were then filtered and washed with water (2x100 mL). The solid was dissolved again in dichloromethane (500 mL) and the organic layer was washed with water (2x500 mL). Dichloromethane was completely evaporated and stripped with methanol (100 mL). The resulting residue was dissolved in methanol (600 mL) and stirred at 40-45 °C for

15-20 mins. The solution was cooled to 25-30 °C and stirred for 1 hour. The obtained solid was filtered, washed with methanol (2x50 mL) and dried under vacuum at 40-45 °C for 8-10 hours to obtain crystalline ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphe-nylmethyl]imidazol-5-yl carboxylate (IV).
Yield; Weight of dried solid is 130.8 gm.
Example 2:
Preparation of ethyl 4-{1 -hydroxymethylethyl)-2-propyl-1 -[2'-(N-triphenyl-methyl-tetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) Ethyl 4-(1-hydroxymethylethyl)-2-propylimidazole-5-carboxylate (II) (50 gm, 0.21 mole) was dissolved in dimethyl acetamide (350 mL) at 25 °C. Potassium carbonate (36 gm, 0.26 mole) was added to the above solution followed by 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) (110.2 gm, 0.20 mole). The reaction mixture was heated to 40-45 °C for 12 hours and then cooled to 25-30 °C. Chilled water (2.0 L) was added to quench the reaction mixture and the resulting solids were then filtered and washed with water (2x100 mL). The solid was dissolved again in dichloromethane (500 mL) and the organic layer was washed with water (2x500 mL). Dichloromethane was completely evaporated and stripped with acetone (100 mL). The resulting residue was dissolved in acetone (500 mL) and stirred at 40-45 °C for 15-20 mins. The solution was cooled to 25-30 °C and stirred for 1 hour. The obtained solid was filtered, washed with acetone (2x50 mL) and dried under vacuum at 40-45 °C for 8-10 hours to obtain crystalline ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imi-dazol-5-yl carboxylate (IV).
Example 3:
Preparation of ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-
methyl-tetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV)
Ethyl 4-(1-hydroxymethylethyl)-2-propylimidazole-5-carboxylate (II) (50 gm, 0.21
mole) was dissolved in dimethyl acetamide (350 mL) at 25 °C. Potassium carbonate

(36 gm, 0.26 mole) was added to the above solution followed by 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) (110.2 gm, 0.20 mole). The reaction mixture was heated'to 40-45 °C for 12 hours and then cooled to 25-30 °C. Chilled water (2.0 L) was added to quench the reaction mixture and the resulting solids were then filtered and washed with water (2x100 mL). The solid was dissolved again in dichloromethane (500 mL) and the organic layer was washed with water (2x500 mL). Dichloromethane was completely evaporated and stripped with ethyl acetate (100 mL). The resulting residue was dissolved in ethyl acetate (500 mL) and stirred at 40-45 °C for 15-20 mins. The solution was cooled to 25-30 °C and stirred for 1 hour. The obtained solid was filtered, washed with ethyl acetate (2x50 mL) and dried under vacuum at 40-45 °C for 8-10 hours to obtain crystalline ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyl-tetrazol-5-yl)-4-biphenylmethylJimidazol-5-yl carboxylate (IV).
Example 4:
Preparation of ethyl 4-{1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyl-tetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) Ethyl 4-(1-hydroxymethylethyl)-2-propylimidazole-5-carboxylate (II) (50 gm, 0.21 mole) was dissolved in dimethyl acetamide (350 mL) at 25 °C. Potassium carbonate (36 gm, 0.26 mole) was added to the above solution followed by 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide (III) (110.2 gm, 0.20 mole). The reaction mixture was heated to 40-45 °C for 12 hours and then cooled to 25-30 °C. Chilled water (2.0 L) was added to quench the reaction mixture and the resulting solids were then filtered and washed with water (2x100 mL). The solid was dissolved again in dichloromethane (500 mL) and the organic layer was washed with water (2x500 mL). Dichloromethane was completely evaporated and stripped with isopropanol (100 mL). The resulting residue was dissolved in isopropanol (500 mL) and stirred at 40-45 °C for 15-20 mins. The solution was cooled to 25-30 °C and stirred for 1 hour. The obtained solid was filtered, washed with isopropanol (2x50 mL) and dried under vacuum at 40-45 °C for 8-10 hours to obtain crystalline ethyl 4-(1-

hydroxymethylethyl)-2-propyl-1-[2l-(N-tri-phenylmethyltetrazol-5-yl)
biphenylmethylJimidazol-5-yl carboxylate (IV).
Example 5:
Preparation of potassium salt of 4-{1-hydroxymethylethyl)-2-propyl-1-[2'-(N-
triphenylmethyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylic acid
(VI)
Potassium hydroxide (5.85 gm, 0.10 mole) was suspended in isopropanol (400 mL) and heated to 30-35 °C. After a clear solution was obtained, ethyl 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyltetrazol-5-yl)-4-biphenylmethyl]imidazol-5-yl carboxylate (IV) (50 gm, 0.07 mole) was added to the solution and the reaction mixture was stirred for 4-5 hours at 30-35 °C. Isopropanol was removed from the reaction mixture under vacuum below 45 °C. Ethyl acetate (400 mL) was added to the residue and stirred for 5-10 mins and then cooled to 25-30 °C and stirred further for 30 mins. The solid was filtered, washed with ethyl acetate and dried under vacuum at 45-50 °C to obtain crystalline potassium salt of 4-(1-hydroxymethylethyl)-2-propyl-1-[2'-(N-triphenyl-methyl-tetrazol-5-yl)-4-biphenylmethyl] imidazol-5-yl carboxylic acid (VI).
Yield: Weight of the dried solid is 55.7 g.
Example 6:
Preparation of trityl olmesartan (V)
4-Chloromethyl-5-methyl-2-oxo-1,3-dioxolene (12.26 gm, 0.08 mole) was dissolved in acetone (60 mL). Potassium iodide (0.9 gm, 0.005 mole) was added to the above solution and heated to 45-50 °C. Compound of formula (VI) (40 gm, 0.055 mole) was added to the above solution and stirred for 1 hour at 45-50 °C. The reaction mixture was filtered and the filtrate was distilled under vacuum below 45 °C. The residue, obtained thus was stripped with methanol (80 mL), Ivlethanol (400 mL) was added to the above residue and stirred for 10-15 mins at 40-45 °C. The reaction mixture was then cooled to 25-30 °C and stirred for 1 hour. Trityl olmesartan (V) was filtered,

washed with methanol (3x40 mL) and dried at 35-40 °C under vacuum for 6-8 hours. The solid trityl olmesartan (V), obtained thus was crystallized from ethyl acetate.
Example 7:
Preparation of olmesartan medoxomil (I)
Trityl olmesartan (V) (100 gm, 0.125 mole) was dissolved in acetic acid (375 mL) and water (125 mL) was added toithe above solution. The reaction mixture was heated to 35-40 °C for 4 hours and then the reaction mixture was cooled to 25-30 °C. Another portion of water (125 mL) was added to the reaction mixture and stirred for 15-20 mins. Reaction mixture was filtered to remove triphenyl carbinol and the solid was washed with water (50 mL). The combined filtrate was quenched in sodium chloride solution (1200 mL; 17 % w/v). The aqueous layer was extracted with dichloromethane:methanol::75:25 (3x500 mL); the combined organic layer was washed with sodium bicarbonate solution (2x500 mL; 8 % w/v) and saturated sodium chloride solution (500 mL). The organic layer, obtained thus was distilled under vacuum at 35-40 °C and stripped with ethyt acetate (200 mL). Ethyl acetate (500 mL) was charged at 35-40 °C and stirred for 15-20 mins. The solution was cooled to 25-30 °C and stirred for 1 hour. Olmesartan medoxomil, precipitated thus was filtered, washed with ethyl acetate (2x50 mL) and dried at 30-40 °C for 15 hours.
Yield: Weight of the dried solid is 59.0 g.

Dated this 8th day of May, 2009