1. TITLE OF THE INVENTION
An improved process for the preparation of substantially pure Teimisartan.

2. APPLICANT(S)
(a) NAME
(b) NATIONALITY
(c) ADDRESS

CADILA PHARMACEUTICALS LTD.
An INDIAN Company
"Cadila Corporate Campus", Sarkhej- Dholka Road, Bhat, Ahmedabad - 382210, Gujarat, India.

Breif description of the invention:
Fig-1. It depicts the X-ray powder diagram of the crystalline form of substantially pure
Telmisartan ethyl ester. Fig-2. It depicts the Differential Scanning Calorimetry examination of the crystalline form of
substantially pure Telmisartan ethyl ester. Fig-3. It depicts IR-spectroscopy of the crystalline form of substantially pure Telmisartan ethyl
ester. Fig-4. It depicts x-ray powder diffraction diagram of the crystalline form of substantially pure
Telmisartan. Fig-5. It depicts Differential Scanning Calorimetry of the crystalline form of substantially pure
Telmisartan. Fig-6. It depitcs IR-spectroscopic of the crystalline form of substantially pure Telmisartan. Fig-7. It depicts HPLC chromatographic purity of 4'-Methyl biphenyl-2-carboxy!ic acid. Fig-8. It depicts HPLC chromatographic purity of Ethyl-4'-[[2-n-propyl-4-methyl-6-{1-
methylbenzimidazol-2-yl)- benzimidazol-1-yl]-methyl] biphenyl carboxylate [Telmisartan
ethyl ester]. Fig-9. It depicts HPLC chromatographic purity of 4'-[[2-n-propyl-4methyl-6-{1-
methylbenzimidazol-2-yl)- Benzimidazol-1-yl]-methyl] bipheny! carboxylic acid
[Telmisartan]. The present invention is further illustrated by following non-limiting examples.
Example-1
Preparation of 4'-Methyl bipheny!-2-carboxylic acid form 2- Cyano-4'- Methyl biphenyl
To ethylene glycol [1250 ml] and 4'-Methyl 2-cyano biphenyl [250.0 gm] mixture potassium hydroxide [255.0 gm] and water [12.5 ml] were added and heated to 155-160°C and stirred at same temperature till 2-Cyano-4'-methyl biphenyl was < 0.1 % [ about for 12-13 hours]. The reaction mass was cooled to 80°C, water [1000 ml] was added, the reaction mass was cooled to 20-25 °C. pH of the reaction mass was adjusted to 2-3 using cone. Hydrochloric acid [- 390 ml]. The reaction mass was stirred for one hour at 20-25°C, filtered, washed with water and dried at temp. 60 -70°C till moisture content remained was < 0.25 %. Dry wt. of the product is 265.0 gm and purity is 99.94 %.
Example-2
Preparation of Ethyl - 4'-methyl biphenyl-2-carboxylate from 4'- methyl biphenyl-2-carboxylic acid.
Sulfuric acid [103.96 gm] was added to the mixture of 4'- methyl biphenyl-2-carboxylic acid [150.0 gm] and ethyl alcohol [300.0 ml] at 25 to 30°C temperature maximum up to 60°C.

The reaction mass was stirred at 80-85°C till 4'- methyl biphenyl-2-carboxylic acid was not more than 5 % [for about 18-20 hours].Ethanol was distilled out to give an oily mass. The reaction mass was cooled to 25-30°C, ethyl acetate [750.0 ml] and water [400.0 ml] were added, the mass was stirred for about 15 minutes and the layers were separated. The organic phase was washed with water [2 x 400.0 ml], aqueous sodium bicarbonate solution [500.0 ml x 3] (120.0 gm sodium bicarbonate dissolved in 1500.0 ml, water)], water [2 x 400ml] and sodium chloride brine [400.0 mi]. The organic layer was dried over anhydrous sodium sulphate (50.0 gm), filtered and washed with fresh ethyl acetate. Ethyl acetate layer was distilled completely to give an oily mass. Hexane [150.0 ml] was added to the oily mass and traces of ethyl acetate were removed by distilling hexane under vacuum, to give Ethyl - 4'-methyl biphenyl-2-carboxylate as an oil. Wt= 157.0 gm, Purity: 99.45 % (By HPLC).
ExampIe-3
Preparation of Ethyl - 4-{bromomethyi) biphenyl-2-carboxylate form Ethyl - 4'-methyl biphenyl-2-carboxylate.
To dichloromethane [750.0 ml] , Ethyl - 4'-methyl bipnenyl-2-carboxylate [150.0 gm] was added and the mass was stirred at 25-30°C for 10-15 minutes. Di bromodimethyl hydantoin [DDH- 98.2 gm] was added to the reaction mass at 25-30°C and stirred for 10-15 minutes. AIBN (Azo bis iso-butonyl nitrile) [15.0 gm] was added, the reaction mass was heated to 40°C, the reaction mass was stirred at 40-42°C for about 5 hours. The reaction mass was cooled to 25-35°C, water [300.0 ml] was added, the mass was stirred for 20-30 min and the layers were separated. The organic layer was washed with water [ 2x 300.0 ml], 5% aqueous sodium bisulphite solution [300.0 ml] , water [2 X 300.0 ml], NaCI brine [300.0 ml]. The organic layer was separated and dried over anhydrous sodium sulphate 50.0 gm, filtered and washed with fresh DCM (Dichloro methane), DCM was distilled under vacuum at 30-35°C. Hexane [150.0 ml] was added, and distilled under vacuum at 50-55°C.The reaction mass was cooled to 25-35°C. Hexane [300.0 ml] was added to the mass, cooled to about 5°C and stirred for 30 minutes, the solid material was separated by filtration, washed with chilled hexane [75.0 ml]. The oily mass and n-Hexane layer were transferred to a distillation flask from which hexane was recovered by vacuum distillation. Weight of the oily product is 177.0 gm and purity is 85.17% (by HPLC).
ExampIe-4
Preparation of Ethy!-4'-[[2-n-propyl-4-methyl-6-(1 -methylbenzimidazol-2-yl)-benzimidazol-1 -yl]-methyl] biphenyl carboxylate [Telmisartan ethyl ester]
9

To a solution of BIM [90.0 gm], DMF [500.0 ml] was added at about 15° C. Potassium tertiary butoxide [41.4 gm] was added and stirred for about 15-20 minutes at 15-20°C.
Ethyl - 4-(bromomethyl) biphenyl-2-carboxylate [138.7 gm] in DMF [250.0 ml ] was added slowly to the mixture of 1,7'-dimethyl-2'-propyl-2,5"-bi-1H-benzimidazole [BIM] and potassium tertiary butoxide in DMF at temperature 15-20°C over 45 to 60 minutes. The reaction mass was stirred for about 30 minutes at 15-20°C till both the reactants [BIM and Ethyl - 4-(bromomethyl) biphenyl-2-carboxylate] are almost consumed.[BIM present < about 1 % by HPLC]. Ethyl acetate [1500.0 ml] and water [2000 ml] were added to the reaction mass at 20-30° C for 15-20 minutes and the layers were separated. Aqueous layer was extracted with ethyl acetate [1000 ml]. The combined organic layer was washed with water [3 X 1000 ml]. The organic layer was dried over anhydrous sodium sulfate. Dried ethyl acetate solution was filtered and total ethyl acetate was removed by distillation under vacuum at 50-55°C. Ethyl acetate [500 ml] was added to the residue to make a solution at 60-65°C. The reaction mass was cooled to 50-55° C, hexane [200.0 ml] was added and stirred for 30 minutes and cooled up to 10° C. The reaction mass was further stirred for about 1 hour at 5-10° C. The material was filtered and washed with a mixture of ethyl acetate : hexane 200.0 ml (7;3, vol / vol) at 8-12°C. The wet cake was dissolved in ethyl acetate [600.0 ml ] at 60-65°C, cooled to 50 - 55°C, hexane (240.0 ml) was added and cooled to 10°C under sterring, then stirred at 5-10°C for about one hour. The material was filtered and washed with a mixture of ethyl acetate and hexane (7:3 vol/vol) [120.0 ml] at 8-12° C, the material was suck dried and used as such. Obtained product = 108.2 gm, Purity: 99.6 % (By HPLC).
Example-5
Preparation of 4'-[[2-n-propyl-4methyl-6-(1-methyibenzimidazo|-2-yl)-benzimidazol-1-yl]-methyl] biphenyl carboxylic acid [Tetmisartan].
Ethyl-4'-[[2-n-propyl-4-methyi-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl] biphenyl carboxylate [90.0 gm] was stirred with aqueous hydrochloric acid [810.0 ml; 32-35 % wt/vol] at 95± 2°C for about 8-10 hours [till about max 0.5 % of ethyl ester remains in the reaction mass]. The reaction mass was cooled to 25-30°C. Dichloromethane [180.0 ml] and water [1350.0 ml] were added, pH of the reaction mass was adjusted 9.0 to 10.0 using 20 % aqueous NaOH. The reaction mass was stirred for about 30 minutes at 30-35°C and the layers were separated. MDC (Methylene Dichloride) [1800.0 ml] was added to aqueous phase at 25-30°C pH of the solution was adjusted to 3.0 to 3.5 with acetic acid [~315.0 ml]. The mass was stirred for about 20 minutes and the layers were separated. Aqueous layer was extracted with DCM [900.0 ml], organic phase was separated. The organic layers were combined and washed with water [2 x 900.0 ml]. The organic phase was dried over anhydrous sodium sulfate and


charcoalized, organic phase was distilled to recover about 8O-85 % 0f total vol. of DCM at 40-42 C. The reaction mass was slowly cooled to 8°C and stirred at 8-12°C for about 60 minutes. Acetone [2700 ml] was slowly added at temperature 8-12°C. The reaction mass was stirred for 2 hours with slow RPM [Revolution per minute] at 8-12°C. The mass was filtered at 8-12DC and washed with acetone [2 X 180.0 mfl.The product was sucked dry for 30-45 minutes, and dried under vacuum 720 - 740 mmHg at 85-90°C till OVI (organic Volatile impurity) complies [35-40 hours].
The weight of the Telmisartan is 70.0 gm and purity is 99.84%.
It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. Therefore, this invention is not limited to the particular embodiment disclosed, but it is intended to cover modifications that are within the spirit and scope of the invention.
Dated this on 1st day of August, 2008.
For, CADILA PHARMACEUTICALS LTD.