FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION: “A NOVEL PROCESS FOR PREPARATION OF TELMISARTAN”
2. APPLICANT(S):
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivali Industrial Estate, Charkop,
Kandivali (West), Mumbai–400067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:

Field of the invention:
The present invention relates to a process for the preparation of angiotensin-II receptor antagonist drug, Telmisartan and its pharmaceutically acceptable salts.
Background of Invention:
Telmisartan is chemically known as 4′-[[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid, and has the following structural formula.

Telmisartan is an angiotensin-II receptor antagonist, useful in the treatment of hypertensive diseases, heart diseases and heart strokes, and is commercially available as tablets sold under the brand name MICARDIS™.
Telmisartan was first reported in U.S. Pat. No. 5,591,762. This patent discloses a process for the preparation of Telmisartan by hydrolyzing the tertiary-butyl ester precursor of Telmisartan with trifluoroacetic acid in dimethylformamide. This process involves expensive reagents and solvents.
A different route is reported in US7193089, which mentioned hydrolysis of 2-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenyl (Cyano Telmisartan) using potassium hydroxide in ethylene glycol and water solvent system to obtain Telmisartan. Another patent application, US 20060264491, also reported hydrolysis of 4′-[(1,4′-dimethyl-2′-propyl [2,6′-bi-1H-benzimidazol]-1′-yl)methyl]-[1,1′-biphenyl]-2-carboxamide with KOH in propylene glycol to obtain Telmisartan. A

later patent application, IN2535MUM2009, reported hydrolysis of Cyano Telmisartan using KOH and glycerol and water solvent system to obtain Telmisartan.
All these three references reported use of expensive and high-boiling solvent systems selected from ethylene glycol/water, glycerol/water and propylene glycol/water and thus more impurities were formed with these processes. Further, use of such high boiling solvents in the preparation of the final product, i.e., Telmisartan is undesirable as the complete removal of these solvents are highly impossible and thus pose residual solvent issues. Additional purification step was also required to get desired quality of Telmisartan. Therefore, these processes were increasing the manufacturing cost of Telmisartan and time cycle for synthesis thereby making these processes undesirable for industrial scale up.
Therefore, the objective of the invention is to provide a novel process for preparation of high purity Telmisartan which is economical and industrially applicable.
Summary of Invention:
Present inventors have, surprisingly, found a novel process to prepare high purity Telmisartan. Accordingly, the present invention provides a process for preparation of Telmisartan which comprises; hydrolyzing Cyano Telmisartan with a base in a solvent under pressure followed by addition of an acid to obtain Telmisartan. The novel process according to the present invention is shown in scheme 1 below.
Scheme 1:


In a preferred embodiment, present invention provides hydrolyzing Cyano Telmisartan with a base in an alcohol-water solvent system under pressure to obtain Telmisartan.
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

Accordingly the present invention provides a process for preparation of Telmisartan comprising hydrolyzing Cyano Telmisartan with a base in a solvent under pressure to obtain Telmisartan.
In accordance with the same, the process for preparation of Telmisartan which comprises;
a) hydrolyzing Cyano Telmisartan with a base in low boiling solvent system under pressure to obtain corresponding salt of Telmisartan; and
b) treating the salt of the Temisartan with an acid to obtain Telmisartan.
Base used in the hydrolysis reaction may be an organic or inorganic base. The bases are preferably selected from the group consisting of a metal carbonate or hydroxides or alkoxides or amines. Exemplary bases are selected from sodium hydroxide, potassium hydroxide, sodium carbonate or bicarbonate, ammonia, Diethylamine, triethyl amine, diisopropyl ethylamine, tetrabutylammonium hydroxide. However, most preferred base is potassium hydroxide or Sodium Hydroxide.
Suitable solvents are selected from the solvents having low boiling points. Low boiling solvents used for hydrolysis reaction includes water, water miscible organic solvents selected from, C1-C6 alcohols (straight chain or branched) such as methanol, ethanol, n-propanol, i-propanol, n-butanol,2-butanol, ethers such as diethyl ether, di-isopropyl ether, ketones such as acetone, methyl isobutyl ketone or mixtures thereof. However, a preferred solvent system is alcohol-water solvent system. Most preferred solvent system is methanol-water, ethanol-water, propanol-water or butanol-water system.
When alcohol-water solvent system is used, about 1 to 30% v/v of water with respect to alcohol is used. Preferably 1 to 15% v/v of water with alcohol is used. According to present invention, hydrolysis reaction is conducted under pressure. Typically, after charging all reactants and solvents into autoclave, the autoclave is

closed and the reaction mass is heated to about 140-150°C, under closed condition resulting in build up pressure in the system. High temperature required for this reaction is achieved by using low boiling solvent due to high vapour load of solvent generated in a closed system. During heating, pressure of the reaction may be increased upto 20 Kg/cm2 depending upon boiling point of the solvent used but preferably in the range of 1 to 10 Kg/cm2Usually reaction is completed in 6 to 30 hours of maintenance at 140-150°C under pressure depending on the alcohol used in the process. After completion of reaction, the mass is diluted with aqueous alcohol to get clear solution. Optionally, charcoal treatment is given and then the mass is acidified with an acid.
The suitable acids includes, but not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. In a preferred embodiment, acetic acid is used.
The acetic acid is added till pH 5-6 to precipitate solids. Further reaction mass is cooled to about 20°C and then filtered to get Telmisartan. The obtained crystalline Telmisartan was found to be matching with FORM-A of Telmisartan.
The starting material, Cyano Telmisartan may be prepared as mentioned in the art by reacting 2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole (BIM) with 4-bromomethyl-2′-cyanobiphenyl (OTBB) in presence of potassium hydroxide in acetone solvent to obtain Cyano Telmisartan as a major product and Regio isomer as a minor product, this isomer ultimately forms impurity B in Telmisartan Drug substance and is controlled at a level of NMT 0.1% in pharmacoepial monograph.
The present invention is represented in following scheme 2.
Scheme 2:


The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.
Example-1: Preparation of 2-cyano-4’-[2-n-propyl- 4-methyl-6-(1-methyl-benz- imidazole-2-yl) benzimidazole-1-ylmethyl]biphenyl (Cyano Telmisartan)
To a stirred solution of 4'-(bromomethyl)-2-cyanobiphenyl (OTBB) (70.41 g, 0.258 mole) in acetone (675 ml), 4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl -1H-benzimidazole (BIM) (75 g, 0.246 mole) was added. The reaction mixture was cooled to 10-15 0C and aqueous solution of potassium hydroxide (29.27g, 0.44 mole) was added dropwise in 25-35 minutes. After addition, the temperature was raised to 25-35°C and the reaction was continued for 4-6 hr. After completion of reaction, 300 ml of water was added dropwise and reaction mass was cooled to 10-15°C, stirred further for 45-60 min. The reaction mass was

filtered and washed with pre-cooled acetone (37.5 ml) followed by 225 ml of water. After suck dried, the material was unloaded and dried in air oven at 70-80°C for 12 hrs to get the Cyano Telmisartan. Yield: 105 g (86% of theory) HPLC Purity: 98.90% Regio Isomer: 0.58%
Example-2 : Preparation of 2-cyano-4’-[2-n-propyl- 4-methyl-6-(1-methyl-benz- imidazole-2-yl) benzimidazole-1-ylmethyl]biphenyl (Cyano Telmisartan)
To a stirred solution of 4'-(bromomethyl)-2-cyanobiphenyl (OTBB) (93.87 g, 0.344 mole) in acetone (900 ml), 4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl -1H-benzimidazole (BIM) (100 g, 0.3285 mole) was added. The reaction mixture was cooled to 0-10 0C and potassium hydroxide powder (39.02g, 0.5913 mole) was added. After addition, the reaction mass was stirred for 5-10 minutes and then the temperature was raised to 25-35°C and reaction continued for 6- 8 h. After completion of reaction, 800 ml of water was added dropwise and reaction was cooled to 10-15°C, and stirred further for 45-60 min. The reaction mass was filtered and washed with pre-cooled acetone (50 ml) followed by 300 ml of water. After suck dried, the material was unloaded and dried in air oven at 70-80°C for 12 hrs to get the Cyano Telmisartan. Yield: 151.6 g (93% of theory). HPLC Purity: 98.93% Regio Isomer: 0.52%
Example-3: Preparation of 2-cyano-4’-[2-n-propyl- 4-methyl-6-(1-methyl-benz- imidazole-2-yl)benzimidazole-1-ylmethyl]biphenyl (Cyano Telmisartan)
To a stirred solution of 4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl -1H-benzimidazole (BIM) (100g, 0.3285 mole) in Acetone (900 ml) and water (14 ml), Potassium hydroxide powder (39.02 g, 0.5913 mole) was added. The

resulting reaction mixture was stirred for 20-30 minutes at temperature 25-35oC. The reaction mixture was cooled to 10-20oC and then 4'-(bromomethyl)-2-cyanobiphenyl (OTBB) (89.40 g, 0.3285 mole) was added. After addition, the temperature of the reaction mass was raised to 20-30°C and continue the reaction for 4-6 hr (monitored by HPLC). After completion of reaction, water (800 ml) was added drop wise and cool to 10-15°C. The reaction mixture was stirred for 45-60 minutes, filtered and washed with pre-cooled acetone water mixture (100 ml:100 ml) followed by water (300 ml). After Suck dry, the material was unloaded and dried it under vacuum at 70-80°C for 12 hrs to get the Cyano Telmisartan. Yield: 151.7 g (93% of theory) HPLC Purity: 99% Regio Isomer: 0.73%
Example-4 : Preparation of Telmisartan API
In 420 ml 15% aqueous methanol, 2-cyano-4’-[2-n-propyl-4-methyl-6-(1-methylbenz- imidazole-2-yl)benzimidazole-1-ylmethyl]biphenyl (Cyano Telmisartan) (60.0 g, 0.121 moles) and potassium hydroxide powder (47.9 g, 0.853 moles) were added and heated to 140-145°C in autoclave with stirring for 22- 26 hrs. The pressure generated during reaction was 7-9 kg/cm2.
After completion of reaction, the reaction mass was diluted with 480 ml 15% aqueous methanol, followed by charcoalization. The solution was acidified with 200 ml acetic acid at 60- 65°C to get the solid at pH 5-6. It was further stirred for 60 min at same temperature. The crystallized solid was cooled to 25- 35°C and stirred for 60 min. Precipitated solid was filtered, washed with 120 ml 15% aqueous methanol, followed by 180 ml water twice and dried in air oven at 75-80°C for 10- 12 hrs to get Telmisartan. Yield: 53.6 g (86.7% of theory) HPLC: 99.78%
Regio isomer (Imp. B as per EP): ND Telmisartan Amide (Imp. F as per EP): 0.05%

Example-5 : Preparation of Telmisartan API
In 420 ml 15% aqueous methanol, 2-cyano-4’-[2-n-propyl-4-methyl-6-(1-methylbenz-imidazole-2-yl)benzimidazole-1-ylmethyl]biphenyl (Cyano Telmisartan) (60.0 g, 0.121 moles) and sodium hydroxide (27.2 g, 0.68 moles) were added and heated to 145-150°C in autoclave with stirring for 18-20 hrs. The pressure generated during reaction was 8- 10 kg/cm2.
After completion of reaction, the reaction mass was diluted with 180 ml 15% aqueous methanol, followed by charcoalization. The solution was acidified with 132 ml acetic acid at 60-65°C to get the solid at pH 5- 6. It was further stirred for 60 min at same temperature. The crystallized solid was cooled to 25- 35°C and stirred for 30 min. Precipitated solid was filtered, washed with 120 ml 15% aqueous methanol, followed by 180 ml water twice and dried in air oven at 75-80°C for 10-12 hrs to get Telmisartan. Yield: 53.5 g (86.5% of theory) HPLC: 99.91%
Regio isomer (Imp. B as per EP): ND Telmisartan Amide (Imp. F as per EP): 0.03%
Example-6 : Preparation of Telmisartan API
In 420 ml 15% aqueous 1-butanol, 2-cyano-4’-[2-n-propyl-4-methyl-6-(1-methyl-benzimidazole-2- yl)benzimidazole-1-ylmethyl]biphenyl (Cyano Telmisartan) (60.0 g, 0.121 moles), water (5 ml) and potassium hydroxide powder (44.74 g, 0.797 moles) were added and heated to 145- 150°C in autoclave with stirring for 12- 14 hrs. The pressure generated during reaction was 2.5- 3.5 kg/cm2. After completion of reaction, solid was observed in the reaction mass. It was further diluted with 120 ml water and 60 ml 1-butanol, followed by charcoalization and the bed was washed with 120 ml 15% aqueous butanol. The solution was acidified with 180 ml acetic acid at 60-65°C to get the solid at pH 5-6. It was further stirred for 60 min at same temperature. The crystallized solid was cooled to 25- 35°C and stirred for 60 min. Precipitated solid was filtered, washed

with 120 ml 15% aqueous butanol, followed by 120 ml water and dried in air oven
at 75-80°C for 10-12 hrs to get Telmisartan.
Yield: 49.5 g (80.0% of theory)
HPLC: 99.89%
Regio isomer (Imp. B as per EP): ND
Telmisartan Amide (Imp. F as per EP): 0.03%
Example-7 : Preparation of Telmisartan API
In 420 ml 15% aqueous 1-butanol, 2-cyano-4’-[2-n-propyl-4-methyl-6- (1-methyl-benzimidazole-2- yl)benzimidazole-1-ylmethyl]biphenyl (Cyano Telmisartan) (60.0 g, 0.121 moles), water (5 ml) and sodium hydroxide (27.2 g, 0.68 moles) were added and heated to 145-150°C in autoclave with stirring for 7-8 hrs. The pressure generated during reaction was 2.5- 3.5 kg/cm2. After completion of reaction, solid was observed in the reaction mass. It was further diluted with 250 ml water to get clear solution, followed by layer separation. The butanol layer was distilled and degassed completely to get residue. 500 ml of 15% aqueous methanol was added to this residue to dissolve it completely, followed by charcoalization. The solution was acidified with 20 ml acetic acid at 60-65°C to get the solid at pH 5-6. It was further stirred for 45 min at same temperature. The crystallized solid was cooled to 25- 35°C and stirred for 30 min. Precipitated solid was filtered, washed with 180 ml 15% aqueous methanol, followed by 180 ml water and dried in air oven at 75- 80°C for 10- 12 hrs to get Telmisartan. Yield: 41.5 g (67.1% of theory) HPLC: 99.95%
Regio isomer (Imp. B as per EP): ND Telmisartan Amide (Imp. F as per EP): ND
Example -8: Preparation of Telmisartan API
In 420 ml 15% aqueous methanol, 2-cyano-4’-[2-n-propyl-4-methyl-6-(1-methylbenz- imidazole-2-yl)benzimidazole-1-ylmethyl]biphenyl (Cyano

Telmisartan) (60.0 g, 0.121 moles) and sodium hydroxide (27.11 g, 0.68 moles) were added and heated to 140-150°C in autoclave with stirring for 20-25 hrs. The pressure generated during reaction was 7- 10 kg/cm2.
After completion of reaction, the reaction mass was diluted with 15% aqueous methanol (180ml), followed by charcoalization. The reaction mass was acidified with Hydrochloric acid (60 ml) at room temperature to achieve pH between 5.5-6.5 and heated to 60-65°C and stirred for 60 minutes. The precipitated solid was cooled to 25-35°C and stirred for 30 minutes and filtered. The obtained wet material was washed with 120 ml 15% aqueous methanol followed by slurry wash with water (540 ml) twice and dried under vacuum at 75-80°C for 10-12 hrs to get Telmisartan.
Yield: 54.6 g (88.35% of theory) HPLC: 99.91%
Regio isomer (Imp. B as per EP): ND Telmisartan Amide (Imp. F as per EP): 0.02%

We claim;
1) A process for preparation of Telmisartan which comprises;
a) hydrolyzing Cyano Telmisartan with a base in a low boiling solvent
system under pressure to obtain corresponding salt of Telmisartan; and
b) treating the salt by the addition of an acid to obtain Telmisartan.

2) The process as claimed in claim 1, wherein the base is selected from the
group consisting of a metal carbonates, or hydroxides or alkoxides or
amines. Exemplary bases are selected from sodium hydroxide, potassium
hydroxide, sodium carbonate or bicarbonate, ammonia, diethylamine,
triethyl amine, diisopropyl ethylamine and tetrabutylammonium
hydroxide.
3) The process as claimed in claim 1 or claim 2, wherein the base is
hydroxide and/or Sodium Hydroxide.
4) The process as claimed in claim 1, wherein the low boiling solvent is
selected from the group consisting of water, C1-C6 alcohols, ethers,
ketones or the combinations thereof.
5) The process as claimed in claim 4, wherein the solvent is selected from the
group consisting of water, methanol, ethanol, n-propanol, i-propanol, n-

butanol, 2-butanol, diethyl ether, di-isopropyl ether, acetone and methyl isobutyl ketone or combinations thereof.
6) The process as claimed in claim 1, wherein the solvent is mixture of water and an alcohol selected from group consisting of methanol, ethanol, n-propanol, i-propanol, n-butanol and 2-butanol.
7) The process as claimed in claim 6, where in the ratio of water to alcohol mixture is 1 to 30% v/v of water with respect to alcohol is used.
8) The process as claimed in claim 1, wherein the reaction is conducted under pressure up to 20 Kg/cm2.
9) The process as claimed in claim 8, wherein the reaction is conducted under pressure in the range of 1 to 10 Kg/cm2 .
10) The process as claimed in claim 1, wherein the acid is selected from the group consisting of formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.