FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "Process for the preparation of Telmisartan"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered
Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR THE PREPARATION OF TELMISARTAN
FIELD OF THE INVENTION
The present invention relates to a process of preparing pure Telmisartan of structural formula I comprising the steps of: a) condensing 2-M-propyl-4-methyl-6-(l'-methylbenzimidazol-2'-yl)benzimidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V without employing acid binding agent in jV-methyl-2-pyrrolidone (NMP) or iV-ethyl-2-pyrrolidone (NEP) as a reaction medium to get Telmisartan ester of structural formula VI and b) hydrolysing Telmisartan ester of structural formula VI into pure Telmisartan of structural formula I,
BACKGROUND OF THE INVENTION
Telmisartan is chemically described as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-l'-yl)methyl]-[l,r-biphenyl]-2-carboxylic acid and is represented by structural formula I.

The Proprietary name of Telmisartan is Micardis®. Micardis® is an angiotensin II receptor blocker (ARB) and is indicated for the treatment of hypertension and cardiovascular (CV) risk reduction in patients unable to take ACE inhibitors.

Telmisartan and a process for its preparation are disclosed in U.S. Patent. No. 5,591,762. The process disclosed therein involves condensing 2-«-propyl-4-methyl-6-(r-raethylbenzimidazol-2'-yl)benzimidazole of structural formula II with tert-butyl 4'-bromomethylbiphenyl-2-carboxylate of structural formula III in the presence of acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butoxide, triethylamine or pyridine in a solvent or mixtures of solvents such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethyl formamide or benzene and subsequently saponification of the tert-butyl ester group in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10°C to 120°C. This process is not commercially viable as the use of acid binding agent such as potassium tert-butoxide in the condensation reaction leads to the decomposition of the product and therefore final compound required to be purified by column chromatography technique.


US Patent Publication no. 2006/0094883 describes a process for the preparation of Telmisartan alkyl ester intermediate of structural formula VI by reacting 2-«-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl)benzimidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V in the presence of inorganic base and phase transfer catalyst (PTC) in low boiling point organic solvents such as toluene, methylethylketone, methylisobutylketone, acetone or isobutylacetate. This process involves the use of expensive phase transfer catalyst reagent and therefore not suitable for the production of Telmisartan at commercial scale production.

Where R is a straight or branched chain C|-C4 alkyl.
US Patent Publication no. 2008/0015359 describes a process for the preparation of Telmisartan characterized in that l#-benzimidazole-2-n-propyl-4-methyl-6-(r-methyl benzimidazole-2'-yl) and methyl-4-(bromomethyl)biphenyl-2-carboxylate are subjected to condensation and hydrolysis in a single steps in polar aprotic solvents such as dimethyl formamide or dimethyl sulphoxide in the presence of base such as alkali metal hydroxide, followed by pH adjustment using an aqueous acid. This process suffers from disadvantages such as use of dimethylsulfoxide or dimethylformamide in the penultimate stage of synthesis resulted in high OVI content in final product.

Accordingly there is a need in the art to develop a process for preparing Telmisartan, which obviates the problems, associated with prior art processes of preparing Telmisartan.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a process for preparing pure Telmisartan of structural formula I, without using column chromatographic purification step.
A second aspect of the present invention is to provide a process for preparing pure Telmisartan of structural formula I without using expensive phase transfer catalyst in the condensation of 2-n-propyl-4-methyl-6-(l'-tnetl\ylbenzimidazol-2'-yl) benzimidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxyIic acid alkyl ester of structural formula V.
A third aspect of the present invention is to provide a commercially viable process for the preparation of pure Telmisartan of structural formula I.
A fourth aspect of the present invention is to provide a process of preparing pure Telmisartan of structural formula I comprising the steps of:
a) Condensing 2-«-propyl-4-methyl-6-(l'-methylbenzimidazol-2'-yl)benzimidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V without employing acid binding agent in 7V-methyl-2-pyrrolidone (NMP) or Af-ethyl-2-pyrrolidone (NEP) as a reaction medium to get Telmisartan ester of structural formula VI and


b) Hydrolysing Telmisartan ester of structural formula VI into pure Telmisartan of structural formula I.

Where R is a straight or branched chain C1-C4 alkyl. DETAILED DESCRIPTION OF THE INVENTION
2-«-Propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl)benzimidazole of structural formula II used for the condensation may be dissolved in JV-methyl-2-pyrrolidone (NMP) or N-ethyl-2-pyrrolidone (NEP) solvents.
4'-Bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V used for the condensation may be dissolved in jV-methyI-2-pyrrolidone (NMP) or 7V-ethyl-2-pyrrolidone (NEP) solvents.

Condensation of 2-«-propyl-4-methyI-6-(r-niethylbenzimidazol-2'-yl) benzimidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxyHc acid alkyl ester of structural formula V may be carried out in jV-methyl-2-pyrrolidone (NMP) or iV-ethyl-2-pyrrolidone (NEP) solvents to get Telmisartan ester of structural formula VI
Condensation of 2-«-propyl-4-methyl-6-(l '-methylbenzimidazol-2'-yl)benzimidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V is carried out without employing acid binding agent to get Telmisartan ester of structural formula VI
Examples of acid binding agents include sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, triethylamine, pyridine or mixture(s) thereof.
Condensation of 2-n-propyl-4-methyl-6-(r-methyIbenzimidazol-2'-yl)benzirnidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V may be carried out at a temperature in the range of 25°C to 35°C to get Telmisartan ester of structural formula VI
Condensation of 2-«-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl) benzimidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxyIic acid alkyl ester of structural formula V may be carried out for 16 hours to 24 hours to get Telmisartan ester of structural formula VI
Telmisartan ester of structural formula VI obtained from present invention may be further crystallized from acetone / toluene mixture.
Telmisartan ester of structural formula VI may be hydrolyzed into pure Telmisartan of structural formula I by inorganic base in an organic solvent.

Examples of inorganic base include alkali metal hydroxides.
Examples of alkali metal hydroxides include sodium hydroxide or potassium hydroxide.
Examples of organic solvent include alcholic solvents.
Examples of alcoholic solvents include methanol, ethanol, rc-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
Pure Telmisartan of structural formula I may be isolated by the further steps including cooling, adjusting pH to 3-4 using aqueous acetic acid, filtering, washing and drying.
Pure Telmisartan of structural formula I may be washed with ketonic solvents such as acetone, methyl ethyl ketone or methyl isobutyl ketone.
Pure Telmisartan of structural formula I may be dried at a temperature in the range of 50°C to 55°C under reduced pressure.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
EXAMPLE 1: PREPARATION OF TELMISARTAN
STEP 1: PREPARATION OF 4*-[(l, 4'-DIMETHYL-2'-PROPYL-t2, 6'-BI-lff-BENZIMIDA20L]-1'-YL) METHYL]-[1, l'BffHENYLl-2-CARBOXYLIC ACID METHYL ESTER (TELMISARTAN METHYL ESTER)
A solution of l,4'-dimethyl-2'-propyl-l//,3'//-2,5'-benzimidazole (5gm, 16,42 mmole) in Af-methyl-2-pyrrolidone (NMP, 30ml) was added into a solution of 4'-bromomethyIbiphenyl-2-carboxylic acid methyl ester (5.05gm, 16.42 mmole) in N-methyl-2-pyrrolidone (20 ml, NMP) at an ambient temperature (25-35°C) and stirred for 20 hours at 25° to 30°C. The reaction mass was poured in the water (300 ml) and extracted with ethyl acetate (2x100ml). Combined extract were washed with saturated sodium chloride solution (1x50ml) and evaporated to get crude telmisertan methyl ester (8.5 gm). Crude product was crystallized from acetone-toluene mixture to afford pure Telmisartan methyl ester. Yield: 6.5 gm Purity: 99.5 % (By HPLC)
STEP 2: PREPARATION OF 4'-[(l, 4'-DIMETHYL-2'-PROPYL-[2, 6'-BI-U7-BENZCVHDAZOL]-l'-YL) METHYL]-[1, l'-BIPHENYL]-2-CARBOXYLIC ACID (TELMISARTAN)
Telmisartan methyl ester obtained from step 1 (5.0gm, 9.5 mmole) was suspended in methanol (50 ml), aqueous sodium hydroxide solution (1.6 gm, 40.0 mmol, dissolved in 7.0 ml of water) was added and resulting reaction mass was refluxed for 4 hours. After completion of reaction (monitored thin layer chromatography), reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 using dilute acetic acid.

The resulting product was filtered, washed with water (10ml) and dried at 50-55°C
under reduced pressure to afford crude Telmisartan. The crude Telmisartan was
crystallized in acetone to obtain pure Telmisartan.
Yield: 3.8 gm
Purity: 99.86% (By HPLC)
EXAMPLE 2: PREPARATION OF 4'-[(l,4,-DIMETHYL-2'-PROPYL-[2,6,-BI-lJff-BENZIMIDAZOLl-l'-Y^METHYLj-Il^'-BIPHENYLl-l-CARBOXYUC ACID METHYL ESTER (TELMISARTAN METHYL ESTER)
A solution of l,4'-dimethyI-2'-propyH//,3'//-2,5'-benzimidazole (5gm, 16.42 mmole) in iV-ethyl-2-pyrrolidone (NEP, 30 ml) was stirred at ambient temperature and 4'-bromomethylbiphenyl-2-carboxylic acid methyl ester (5.05gm, 16.42 mmole) in N-ethyl-2-pyrrolidone (NEP, 20 ml) was added to the above reaction mass over 10-15 minutes and maintained at 25-35°C for 15-20 hours. After completion of reaction (monitored thin layer chromatography), reaction mass was poured into water (300 ml) and extracted with ethyl acetate (2x100ml). Combined extract were washed with saturated sodium chloride solution (1x50ml) and evaporated to get crude Telmisartan methyl ester (8.0 gm). Crude Telmisartan methyl ester was crystallized from acetone-toluene mixture to afford pure Telmisartan methyl ester. Yield: 6.2 gm Purity: 98% (By HPLC)

WE CLAIM
1. A process of preparing pure Telmisartan of structural formula I comprising the steps of:
a) Condensing 2-«-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl) benzimidazole of structural formula II with a 4'bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V without employing acid binding agent in jV-methyl-2-pyrrolidone (NMP) or 7vF-ethyl-2-pyrrolidone (NEP) as a reaction medium to get Telmisartan ester of structural formula VI and

b) Hydrolysing Telmisartan ester of structural formula VI into pure Telmisartan of structural formula I.

Where R is a straight or branched chain C1-C4 alkyl.
2. The process according to claim 1, wherein 2-rc-Propyl-4-methyl-6-(l '-mefhylbenzirnidazol-2'-yl)benzimidazole of structural formula II used for the

condensation is dissolved in jV-methyl-2-pyrrolidone (NMP) or ./V-ethyl-2-pyrrolidone (NEP) solvents.
3. The process according to claim 1, wherein 4'-Bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V used for the condensation is dissolved in N-methyl-2-pyrrolidone (NMP) or iV-ethyl-2-pyrrolidone (NEP) solvents.
4. The process according to claim 1, wherein acid binding agents is selected from the group comprising of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, triethylamine, pyridine or mixture(s) thereof.
5. The process according to claim 1, wherein condensation of 2-/?-propyl-4-methyl-6-(r-methylberizimidazol-2'-yl)benzimidazole of structural formula II with a 4'-bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V is carried out at a temperature in the range of 25°C to 35°C to get Telmisartan ester of structural formula VI.
6. The process according to claim 5, wherein condensation of 2-n-propyl-4-methyl-6-(r-methylbenzirmdazol-2'-yl)benzimidazole of structural formula II with a 4'bromomethyl-biphenyl-2-carboxylic acid alkyl ester of structural formula V is carried out for 16 hours to 24 hours to get Telmisartan ester of structural formula VI
7. The process according to claim 1, wherein Telmisartan ester of structural formula VI is hydrolyzed into pure Telmisartan of structural formula I by inorganic base in an organic solvent.

8. The process according to claim 7, wherein inorganic base is alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.
9. The process according to claim 7, wherein organic solvent is alcoholic solvents such as methanol, ethanol, o-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof,
10. A process for preparing pure Telmisartan of structural formula I as herein described in specification and example.