A NEW PROCESS FOR THE PREPARATION OF PURE TELMISARTAN
Field of the Invention The present invention relates to a new process for preparing 4'-[2-n-propyl-4-methyl-6-(1 -niethylbenzimidazol-2-yl)benzimidazol-1 -ylmethyl]biphenyl-2-carboxylic acid (INN: telmisartan). More particularly, process for preparing pure 4'-[2-n-propyl-4'-methyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l -ylmethyl]biphenyl-2-carboxylic acid (INN: telmisartan).
Background of the Invention Telmisartan (brand name- Micardis) exhibits antihypertensive activity is an angiotensin II receptor antagonist used in the management of hypertension, heart strokes and bladder diseases as described in EP 502314 Bl. It is chemical known as 4'-((l,7'-dimethyl-2'-propyl-lH,3'H-2,5'-bibenzo[d]imidazol-3'-yl)methyl)biphenyl-2-carboxylic acid with following structure:

Various process for the preparation of telmisartan has been reported in the prior art. The
patent EP 502314 Bl describe the preparation of telmisartan by condensation of -n-
propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl)benzimidazole with alkyl 4'-
(bromomethyl) biphenyl-2-carboxylate and subsequent hydrolysis yield the title product. The main limitation of the process is the formation of several impurities more particularly is the impurity B (I) as per European Pharmacopeia which results to poor yield.

us 7193089 B2 discloses the preparation of telmisartan by reacting 2-n-propyl-4-methyl-
6-(r-methylbenzimidazol-2'-yl)benzimidazole with 4'-Bromomethyl-2-cyanobiphenyl to
obtain 2-cyano-4'-[2"-n-propyl-4"-methyl-6"- (1 •"-methylbenzimidazol-2"'-yl)
benzimidazole -l"-ylmethyl] biphenyl, subsequent hydrolyzing the nitrile function of compound obtained from step (a) into the acid function to obtain telmisartan. This process involves use of tert-butylmethylether for isolation of telmisartan nitrile, high temperature distillation and workups at 80°C in the preparation of telmisartan hydrochloride which is very unsafe; and product obtained resuUs of poor yield.
WO 2006103068 Al (examples 10 & 11) covers the process for preparation of telmisartan where use of chemicals like DIBAL-H, sodium perborate and Kmno4 is not convenient to handle for large scale production because of the corrosive problems and environmental problems associated by using them, and very low yield of the product is reported.
US 20060264491 Al (example 1 & 2) discloses a process for the preparation of telmisartan by reacting 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-r-yl)methyl]-[l,r- biphenyl]-2-carboxamide with potassium hydroxide powder, and propylene glycol. This process involves high temperature distillation and work up and also the product obtained by this method doesn't meet the requirements of European pharmacopoeia.
All the reported process does not describe, how to control impurity B, which is the regioismer generate during condensation step, to the desired pharmacopeial limit <0.15% either at condensation or at hydrolysis step. We found that all the processes suffer with the formation of impurity 2 (Table-1). So in order to meet the desired quality requirement, it always needs exhaustive purification operations. This resulted more processing time, huge waste generation, poor productivity, less yield and finally high cost. Therefore this is always required for efficient cost effective process of telmisartan which meets pharmacopoeia and ICH quality requirements.
Table 1: Preparation of Telmisartan and 2 with reported synthetic schemes

Condensation* Hydrolysis*
P Process Yield**
reference N-3 Ip Impurity I p (%)
isomer ^ B -^
EP
1 502314 0.5 93.3 0.30 98.1 67
Bl
US ^ ^ ^ ~
2 2006026 1.3 94.7 0.63 97.2 65
4491 Al
US '
3 7193089 0.8 93.2 0.45 97.6 70
B2
♦HPLC reaction monitoring data, *♦ Isolated yield for hydrolysis step of pure product
The aim of the present invention is therefore to provide an alternative method of preparing telmisartan, which can be used on a large scale and allows telmisartan to be easily worked up, purified, and isolated without the disadvantages mentioned above.
Object and Summary of the Invention It is a principal object of the present invention to provide a process for the production of telmisartan.
It is a further object of the present invention to provide a pure process for producing telmisartan.
It is another object of the present invention to provide a process for producing telmisartan by condensation of N-methyl dibenzimidazole with 4'-Bromomethyl-2-cyanobiphenyl to obtain telmisartan nitrile.
It is yet another object of the present invention to provide a process for producing telmisartan, wherein the process requires low boiling distillation, as well as minimized isolation procedure in. This provides for better control for the process related impurities also.
According to the first aspect, the present invention provides a process for the preparation of telmisartan, comprising: condensation of -n-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl)benzimidazole(I)


Detailed description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can

be more readily understood through reading the following detailed description of the invention and study of the included examples.
According to the present invention, condensation of -n-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl)benzimidazole (I) with a compound of general formula (II) in wherein Z preferably denotes a halogen atom, particularly the bromine atom, is conveniently carried out in a ketonic solvent such as acetone, MIBK (methyl isobutyl ketone, ethyl isopropyl ketone, methyl isopropyl ketone, methylethyl ketone, terbutyl methyl ketone, in the presence of base such as sodium hydroxide or potassium hydroxide at a temperature between 10[deg.] C. and 40[deg.] C.
Preferably, the reaction of the compound (I) with a compound of general formula (II) in wherein Z preferably denotes a halogen atom, particularly the bromine atom, is conveniently carried out in a ketonic solvent such as acetone, MIBK (methyl isobutyl ketone, ethyl isopropyl ketone, methyl isopropyl ketone, methylethyl ketone, terbutyl methyl ketone, in the presence of base such as potassium hydroxide at a temperature between 15[deg.] C. and 30[deg.] C.
Particularly preferably, the condensation of the compound (I) with a compound of general formula (II) in wherein Z preferably denotes a halogen atom, particularly the bromine atom, is conveniently carried out in a ketonic solvent such as acetone in the presence of base such as potassium hydroxide at a temperature between 20 [deg.] C. and 25 [deg.] C. to obtain compound 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(l"'-methylbenzimidazol-2"'-yl)benzimidazol-l"-ylmethyl]biphenyl (III). After the completion of the reaction the material is filtered, washed with chilled acetone, followed by washings with water, and then dried in a air dryer to get the telmisartan Nitrile.
Hydrolysis of the isolated compound (III) in excess amount of base in the presence of solvent to obtain telmisartan at a temperature ranging from 120 [deg.] C. and 180 [deg.] C.

Preferably, hydrolysis of the compound (III) is carried out in the presence of excess base such as sodium hydroxide or potassium hydroxide in the presence of solvents such as ethylene glycol, DMSO, DMF, Dimethyl acetamide at a temperature ranging from 140 [deg.]C.andl70[deg.]C.
More preferably, hydrolysis of the compound (III) is carried out in the presence of excess base such as potassium hydroxide in the presence of solvents such as ethylene glycol, at a temperature ranging from from 150 [deg.] C. and 160 [deg.] C. The reaction is show below in Scheme I.

After the completion of the reaction the reaction mass is cooled to 20-25 [deg.] C. and dilute by adding alcohols such as methanol, ethanol and butanol, more preferably methanol, precipitate the material v^th acid such as acetic acid by adjusting the pH 5.7 -6.0 at 20-25 [deg.] C and dilute fiirther by adding de-mineralized water. Stir the precipitate for 60 mns in the same temperature, and then the crystals are suction filtered. The wet material dissolve in alcohol such as methanol, ethanol and butanol, more

preferably methanol with non aqueous organic base or inorganic base such as triethyl amine, diisoprolyl ethyl amine, potassium hydroxide or sodium hydroxide preferably potassium hydroxide, followed by treatment of charcoal crystallize the telmisartan by adding acetic acid. Isolation with filtration and washing with water, then dried in a tray drier to obtain pure telmisartan.
Alternatively, invention also describes the single pot process for preparation of
telmisartan without isolating 2-cyano-4'-[2"-n-propyl-4"-methyl-6"-(r"-
methylbenzimidazol-2"'-yl)benzimidazol-r'-ylmethyl]biphenyl (III) and subsequently hydrolyzing to form telmisartan.
The invention is further explained in detail in the following examples which is provided by way of illustrations only and should not be construed to limit the scope of the invention.
EXAMPLES;
Experiment-l: Preparation of 2-cyano-4-[2-n-propyl-4-methyl-6-(l-
methyIbenzimidazoI-2-yl)bnzimidazoI-l-ylmethyl] biphenyl.
Add 2-n-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl) benzimidazole 100 g in 1000ml of acetone and of potassium hydroxide 22.0 g with stirring at 20-25°C. Then of 4-bromomethyl-2'-cyanobiphenyI 92g is added at 20-25°C. Monitor the reaction on thin layer chromatography, after compilation reaction, the crystals are suction filtered, washed with chilled acetone, water, and then dried in a air drying cupboard at 80° C. Yield: 135.0 g (82.82% of theory); melting point: 196° C.-197° C; HPLC: 99.30%. N-3 isomer: 0.08%.
Experiment-2: Preparation of 2-cyano-4-[2-n-propyl-4-methyl-6-(l-
niethylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl.
Add 2-n-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl) benzimidazole 100 g in 1000ml of acetone and of potassium hydroxide 22.0 g with stirring at 20-25°C. Then of 4-bromomethyl-2'-cyanobiphenyl 92g is added at 20-25°C. Monitor the reaction on thin layer chromatography, after the reaction is completed, cooled to 0 to 5.0° C. and stirred

for another hour at this temperature. The material is filtered, washed with chilled acetone, then wash with water, and then dried in a air drying cupboard at 80° C. Yield: 141.50 g (87.73% of theory); melting point: 196° C.-197° C; HPLC: 99.50%. N-3 isomer: 0.16%
Experiment-3: Preparation of Telmisartan.
Add potassium hydroxide 80g in 500ml of ethylene glycol then add 2-cyano-4'-[2-n-propyl-4-methyl-6-(l-methyl benzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl lOOgm at room temperature. Stir the reaction mixture and raise temperature to 150- 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800 ml methanol then telmisartan precipitates by adding of acetic acid at 25 to 30°C and further diluted with water. Then stirred for further 90min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in 500ml methanol with 12gm potassium hydroxide then after treatment of charcoal crystallize the telmisartan to adjusting of pH 6.0 to 6.4 by acetic acid then dilute with 400ml water. Filtered and then dried in a vacuum tray drier at 85°C. Yield: 90g (87.37% of theory); HPLC: 99.91%.
Experiment-4: Preparation of Telmisartan.
Add potassium hydroxide lOOg in 500ml of ethylene glycol then add 2-cyano-4'-[2-n-propyl-4-methyl-6-(l-methyl benzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl lOOgm at room temperature. Stir the reaction mixture and raise temperature to 150-155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C then diluted with 800ml methanol then telmisartan crystallize by adding of acetic acid at 25 to 30°C then dilute with 300ml water. Stir for fiirther 90min at 25 to 30°C. Filter and then dried in a vacuum drying cupboard at 85°C. Yield: lOlg (1.03% of theory); HPLC: 99.90%.
Experiment-5: Preparation of pure Telmisartan.
Crude telmisartan 101 g (fi-om example 4) & activated carbon lOg is added in methanol 100ml, dichloromethane 500ml at 25 to 30°C. Stir the reaction mixture then the brown

solution is filtered through hyflow bed, Completely distilled out filtrate below 50°C then add 800ml water at that temperature and stir for Ihr. The telmisartan is hot filtered and washed with water. The telmisartan is dried at 80° C. in a vacuum drying cupboard. Yield: 90 g (87.37% of theory); HPLC: >99.95%.
Experimeiit-6: Preparation of Telmisartan.
2-cyano-4'-[2-n-propyl-4-methyl-6-(l-methyl benzimidazoI-2-yl) benzimidazol-1-ylmethyl] biphenyl lOOgm is added in 500ml of ethylene glycol with lOOg of potassium hydroxide powder at 20-25°C. Stir and raise temperature to 160° C. to 165° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 70 to 75°C then diluted with methanol and water then telmisartan crystallize by adding of acetic acid to adjust the pH 5.5 to 6.0 at 25 to 30°C. Stir for further 60min at 25 to 30°C. After the crystals have been suction filtered. The wet material dissolve in methanol with potassium hydroxide 12gm then after treatment of charcoal crystallize the telmisartan by adding of acetic acid by adjusting of pH 6.0 to 6.4 then stir for fiirther 60min. The material is filtered and dried in a vacuum drying cupboard at 85°C. Yield: 86.56g (84.03% of theory); HPLC: >99.96%.
Experiment-?: Preparation of Telmisartan.
of 2-n-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl) benzimidazole 100 g is add in 1000 ml of acetone, and of potassium hydroxide 22 gm with stirring at 20-25° C and then 90.0 g of 4-bromomethyl-2'-cyanobiphenyl is added at 20-25°C. The temperature of the reaction mixture is maintained at 20 to 25° C. Stir for a fiirther 6.0 to 8.0 hours at 20 to 25° C. Monitor the reaction on thin layer chromatography, after compilation reaction distil out acetone. Add ethylene glycol 500ml and potassium hydroxide lOOgm to residue Stir the reaction mixture and raise temperature to 150° C. to 155° C. The mixture is stirred for 15 to 18 hours at this temperature and monitor reaction mass by HPLC. After compilation of reaction cool to 30 to 35°C. Reaction mass diluted with methanol and stir for 30min then telmisartan precipitated by adding of acetic acid to adjust the pH 6.0 to 6.5 at 25 to 30°C. Then dilute with water and filter, wash with of methanol. Wet telmisartan is dissolved in methanolic potassium hydroxide, filtered to remove un

dissolved material. Acetic acid is added to adjust the pH 6.0 to 6.4 , water added for complete precipitation of material. Finally telmisartan is suction filter and wash with water at 40 to 45°C. The telmisartan is dried at 80° C. in a vacuum drying cupboard. Yield: 130g HPLC: 99.4%.1H NMR (DMS0-d6) 5 1.0 (t,3H), 1.9 (q, 2H), 2.95 (t, 2H), 2.4 (s, 3H), 3.95 (s, 3H), 5.8 (s, 2H), 7.28 (s,lH),7.80 (s,lH), 7.75 (d, 2H), 7.25 (t, 2H), 7.10 (d, 2H), 7.30 (d, 2H), 7.40 (d, IH), 7.40 (t, IH), 7.30 (t, IH), 7.45 (d, IH). 12.9 (s, lH).m/z 514.7 [M + H]+.

We Claim:
1. A process for the preparation of pure telmisartan with hnpurity B <0.05%, comprising:
a. Condensation of -n-propyl-4-methyl-6-(r-methylbenzimidazol-2'-yl)benziniidazole
(I) with a compound of general formula (II) conveniently carried out in a ketonic solvent
in the presence of base to obtain tehnisartan nitrile (III) and followed by isolation.

b. Hydrolysis of isolated compound (III) by using base at a temperature between
120[deg.] C. and 180[deg.] C in second solvent to obtain telmisartan.
c. After completion of hydrolysis third solvent is added and pH adjusted in neutral range
to obtain telmisartan.
d. Product is filter and followed by washing with water.
e. Wet material is further dissolved in third solvent in the presence of base and filtered
to get clear solution.
f. Added acid to crystallize the telmisartan.
g. Filter, wash with water and dry to get the pure telmisartan

2. The process according to claim 1, wherein the ketonic solvents is selected from the group acetone, methyl isobutyl ketone, ethyl isopropyl ketone, methyl isopropyl ketone, methylethyl ketone and terbutyl methyl ketone.
3. The process according to claim 2, wherein said the ketonic solvents is acetone.
4. The process according to claim 1, wherein said the base is selected from
sodium hydroxide, potassium hydroxide and lithium hydroxide.
5. The process according to claim 4, wherein said the base selected is potassiimi hydroxide.
6. The process according to claim 1, wherein isolation of telmisartan nitrile (III) is carried out by filtration.
7. The process according to claim 1, wherein said the second solvent is selected from the group ethylene glycol, DMSO, DMF and dimethyl acetamide.
8. The process according to claim 7, wherein said the second solvent selected is ethylene glycol.
9. The process according to claim 1, wherein said the third solvent is selected from the group of alcohols.
10. The process according to claim 9, wherein said the third solvent selected is methanol, ethanol, propanol, butanol, ethylene glycol and monoglyme.
11. The process according to claim 10, wherein wherein said the third solvent selected is methanol,
12. The process according to claim 1, wherein pure telmisartan is obtained of purity not less than 99.5% and impurity B <0.15%
13. The process according to claim 1, wherein pure telmisartan is obtained of purity not less than 99.8% and impurity B <0.10%
14. The process according to claim 1, wherein pure telmisartan is obtained of purity not less than 99.9% and impurity B <0.05%
15. The process according to claim 1, wherein telmisartan is prepared without isolating telmisartan nitrile and subsequent hydrolysis to obtain pure telmisartan.