Claims:1) A process for preparation of Telmisartan comprising;
a) hydrolyzing ortho tolyl benzonitrile (OTBN) using n-butanol solvent in presence of base to obtain ortho tolyl benzoic acid (OTBA) ) dissolved in n-butanol;
b) esterifying the ortho tolyl benzoic acid dissolved in n-butanol into ortho tolyl benzyl n-butyl ester (OTBBE) in presence of acid;
c) reacting ortho tolyl benzyl n-butyl ester with dibromodimethylhydantoin (DDH) to obtain bromo ortho tolyl benzyl n-butyl ester (Bromo-OTBBE) followed by reacting the bromo ortho tolyl benzyl n-butyl ester with 2n-propyl -4-methyl-6-(1- Methyl benzimidazole-2yl)-Benzimidazole) (BIM) followed by treating with HCl to obtain Telmisartan n-Butyl ester di hydrochloride; and
d) hydrolyzing the Telmisartan n-butyl ester di hydrochloride with a base to obtain Telmisartan.

2) The process according to claim 1, wherein the esterification reaction is conducted in situ.

3) The process according to claim 1, wherein the n-butanol solvent is used in the range of 2 to 6 volumes per gram of ortho tolyl benzonitrile.

4) The process according to claim 1, wherein the base used in step 1a is selected from the group consisting of alkali metal hydrides, alkali metal hydroxide, alkali metal alkoxides and alkali metal carbonates.

5) The process according to claim 1, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.

6) The process according to claim 1, wherein the acid used in step 1b is sulphuric acid, hydrochloric acid or p-toluene sulphonic acid.

7) The process according to claim 1, during the HCl treatment of step 1c, pH of the reaction mass is adjusted to below 5.

8) The process according to claim 1, wherein the base used in step1d is potassium hydroxide.

9) Telmisartan n-butyl ester di hydrochloride of Formula-VIII.

10) The Telmisartan n-butyl ester di hydrochloride according to claim 9, is having characteristic XRPD 2? values at 6.16, 7.41, 8.19, 9.29, 10.86, 12.44, 15.50, 16.59, 20.43, 21.81, 23.11, 23.44, 23.80, 24.78, 27.53, 29.04, 30.50, 31.07 and 32.26 ± 0.2.
, Description:Field of the invention:
The present invention relates to a process for the preparation of angiotensin-II receptor antagonist drug, Telmisartan. The invention particularly relates to process for the preparation of ortho tolyl benzyl n-butyl ester by hydrolysis of ortho tolyl benzonitrile followed by esterification in n-butanol solvent and further conversion to Telmisartan via Telmisartan n-butyl ester di hydrochloride.

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 using 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 hydrolysing the tertiary-butyl ester precursor of Telmisartan with trifluoroacetic acid in dimethylformamide.

Journal of Medicinal Chemistry; vol. 36; nb. 25; (1993); p. 4040 - 4051 discloses preparation of the tertiary-butyl ester precursor. It is prepared by reacting bromo ortho tolyl benzyl t-butyl ester with 2n-propyl -4-methyl-6-(1- Methyl benzimidazole-2yl)-Benzimidazole. Another patent, US 7943781, discloses preparation of the methyl ester precursor by reacting bromo ortho tolyl benzyl methyl ester with 2n-propyl -4-methyl-6-(1- Methyl benzimidazole-2yl)-Benzimidazole.

US20020095042 discloses preparation of bromo ortho tolyl benzyl alkyl ester by bromination of ortho tolyl benzyl alkyl ester with dibromodimethylhydantoin in the presence of chemical initiator 2,2'-azobisisobutyronitrile.

It was reported in the literature that ortho tolyl benzyl alkyl esters are commonly employed as raw materials for preparation of Telmisartan. US6369266 disclosed preparation of ortho tolyl benzyl tertiary butyl ester by hydrolyzing ortho tolyl benzonitrile with sodium hydroxide in ethylene glycol solvent at 170°C for 8 hrs. After completion of reaction, water was added, neutralized with HCl and then extracted product, ortho tolyl benzoic acid with toluene solvent. Crystallized the product and then reacted with isobutene in toluene solvent to obtain ortho tolyl benzyl tertiary butyl ester.

WO2010018441 patent application reported preparation of ortho tolyl benzyl ethyl ester by hydrolyzing ortho tolyl benzonitrile with aqueous potassium hydroxide in ethylene glycol at 155-160°C over a period of 12-13 hrs. Then the product is isolated by filtration after neutralization and further reacted with ethyl alcohol in presence of sulfuric acid to obtain ortho tolyl benzyl ethyl ester.

Another patent application, US20080269305, reported preparation of ortho tolyl benzyl t-butyl ester by reacting with thionyl chloride, distilling excess thionyl chloride, followed by reacting with potassium t-butoxide.

The process to prepare ortho tolyl benzyl t-butyl/ethyl esters as mentioned in above publications, ‘266 and ‘441, involves use of different solvents for hydrolysis and esterification. The other publication ‘305 also involves additional steps of conversion into acid chloride and use of expensive base. Moreover, the reported processes involve isolation of intermediate, ortho tolyl benzoic acid, involving cumbersome work up, increasing time cycle and causing less productivity.
Therefore, the object of the present invention is to provide an economical and industrially applicable improved process for the preparation of ortho tolyl benzyl n-butyl ester (OTBBE) which ameliorates most of the problems associated with the use of different/multiple solvents and less productivity due to isolation of intermediate, ortho tolyl benzoic acid. Further objective of the invention is to provide process for the preparation of Telmisartan.

While screening methods for preparation of ortho tolyl benzyl n-butyl ester and Telmisartan, unexpectedly, the present inventors found an effective process for which protection is sought.

Summary of Invention:
According to one aspect, the present invention provides a process for preparation of Telmisartan which comprises;
a) hydrolyzing ortho tolyl benzonitrile (OTBN) using n-butanol solvent in presence of base to obtain ortho tolyl benzoic acid (OTBA) dissolved in n-butanol;
b) converting the ortho tolyl benzoic acid dissolved in n-butanol into ortho tolyl benzyl n-butyl ester (OTBBE) in presence of acid;
c) reacting ortho tolyl benzyl n-butyl ester with dibromodimethylhydantoin (DDH) to obtain bromo ortho tolyl benzyl n-butyl ester (Bromo OTBBE) followed by reacting the bromo ortho tolyl benzyl n-butyl ester with 2n-propyl -4-methyl-6-(1- Methyl benzimidazole-2yl)-Benzimidazole) (BIM) followed by treating with HCl to obtain Telmisartan n-Butyl ester di hydrochloride; and
d) hydrolyzing the Telmisartan n-butyl ester di hydrochloride with a base to obtain telmisartan.

Another aspect of the invention provides novel Telmisartan n-Butyl ester di hydrochloride.

In a preferred embodiment, present invention provides hydrolyzing ortho tolyl benzonitrile (OTBN) using n-butanol solvent in presence of base to obtain ortho tolyl benzoic acid (OTBA) in n-butanol solvent and without isolation of the product, OTBA, the reaction mass is further subjected to acid treatment in situ to obtain ortho tolyl benzyl n-butyl ester (OTBBE). The process of the invention is simple and cost-effective as it proceeds insitu without isolating the product OTBA, thereby eliminating change of reactors, cumbersome work up, use of multiple solvents for hydrolysis and esterification reactions, in addition to elimination of hazardous chemicals such as thionyl chloride etc. The process of the present invention further results in Telmisartan with good yields and purity.

Brief description of diagrams:
Figure-1 shows X-Ray Powder Diffractogram of Telmisartan n-butyl ester di hydrochloride.
Figure-2 shows Differential Scanning Calorimetry graph of Telmisartan n-butyl ester di hydrochloride.

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 hydrolysis of ortho tolyl benzonitrile (OTBN) with a base using n-butanol solvent to obtain ortho tolyl benzoic acid (OTBA).

Preferably inorganic base is used for accomplishing hydrolysis. The inorganic base is selected from the group consisting of alkali metal hydrides, alkali metal hydroxide, alkali metal alkoxides and alkali metal carbonates. However, more preferred base is sodium hydroxide or potassium hydroxide from alkali metal hydroxides.

Typically the hydrolysis reaction is conducted at above 100°C temperature to reflux temperature of the solvent used. Preferably, the reaction is performed at reflux temperature at 117-122°C. Usually the reaction completes in 20 hours.
n-butanol solvent may be used for the reaction in 2 to 6 volumes per gram of OTBN used. However, preferably n-butanol solvent may be used in the range of 3.5 to 4.5 volumes per gram of OTBN used.

After completion of reaction, water is added and layers separated, pH of the n-butanol layer is adjusted between 3-4 with an acid and then the product, ortho tolyl benzoic acid, dissolved in the n-butanol is directly taken for esterification step without isolation.

To the obtained ortho tolyl benzoic acid dissolved in the n-butanol, a strong acid such as sulphuric acid, hydrochloric acid or p-toluene sulphonic acid is added and refluxed for about 6 hours to complete the esterification. After completion of reaction, the product may be isolated by the procedures known in the art such as washing the organic layer with water and isolation of the ortho tolyl benzyl n-butyl ester by concentration.

The ortho tolyl benzyl n-butyl ester is further reacted with dibromo dimethyl hydantoin (DDH) and azobis-isobutyronitrile (AIBN) in a solvent to obtain bromo-ortho tolyl benzyl n-butyl ester. The bromo-ortho tolyl benzyl n-butyl ester is further reacted with 2n-propyl -4-methyl-6-(1- Methyl benzimidazole-2yl)-Benzimidazole in presence of sodium hydroxide in methyl isobutyl ketone solvent in presence of tetra butyl ammonium bromide catalyst to obtain Telmisartan n-butyl ester. The product, Telmisartan n-butyl ester, present in the reaction mass may be directly taken for further reaction without isolation of product.
In another aspect, the present invention provides a novel compound of Telmisartan n-butyl ester di hydrochloride.

The Telmisartan n-butyl ester present in methyl isobutyl ketone solvent is reacted with HCl. The HCl may be used in dry gas form by purging into the solution directly or dilute HCl may be mixed with isopropanol and the IPA-HCl solution may be added to form Telmisartan n-butyl ester di hydrochloride. The HCl is added to adjust the pH of reaction mass to below 5. Usually the dihydrochloride salt formation is completed at 60-65°C temperature. After completion of reaction the product, Telmisartan n-butyl ester di hydrochloride, is filtered and washed with methyl isobutyl ketone.

The Telmisartan n-butyl ester di hydrochloride is a novel compound having following formula.

It is obtained in crystalline form and characterized by a powder X-ray diffraction pattern with peaks at about 6.16, 7.41, 8.19, 9.29, 10.86, 12.44, 15.50, 16.59, 20.43, 21.81, 23.11, 23.44, 24.78, 27.53, 29.04, 30.49, 31.10 and 32.26 ± 0.2 degrees 2? values. The crystalline form is also characterized by a Differential Scanning Calorimeter (DSC) thermogram having endotherm at Peak 1 at 97.3°C, Peak 2 at 233.6°C and Peak 3 at 236.5°C. The Telmisartan n-butyl ester di hydrochloride is also characterized by NMR, Mass and IR.

The Telmisartan n-butyl ester di hydrochloride obtained as per the present invention is hydrolysed with a base such as sodium hydroxide or potassium hydroxide in suitable solvent such as alcohols, for example methanol, either alone or in combination with water. Usually the hydrolysis reaction is completed in the range of 65-75°C temperature and in about 12 hours time. After completion of reaction, the product, Telmisartan, is isolated by standard methods such as filtration followed by washing with the solvent.

The Telmisartan obtained by the process of the present invention, may be formulated into a suitable dosage form such as tablets, capsules, etc., by combining with one or more pharmaceutically acceptable excipients using known techniques. The dosage form may include a suitable amount of the active ingredient and other pharmaceutical agents. The dosage forms prepared may be administered to a mammal in need, for treatment of hypertensive diseases, heart diseases and heart strokes.

The present invention is depicted in scheme-1.

Scheme-1:


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 Bromo-Ortho tolyl benzyl butyl ester (V) from Ortho-Tolyl benzonitrile (I)
Ortho-tolyl benzonitrile (I) (150g, 0.77moles) was taken in n-butanol (600ml) and heated to 40-50° C after which sodium hydroxide (93.14g, 2.0moles) followed by water (7.5ml, 0.416moles) was added. The temperature of the reaction mass was further increased to 117-122° C where the reaction mass was maintained for 22 hours. The reaction mass was then cooled to 70-80° C wherein water (750ml) was added and the pH adjusted between 3-4 with concentrated hydrochloric acid (250ml). After stirring the obtained biphasic mixture for 15 minutes at 70-80° C the upper organic layer was separated and washed with water (300ml). The separated organic layer was then dried azeotropically with continuous removal of water at 100-117° C and cooled to 25-30° C to provide a dried solution of ortho tolyl benzoic acid (III). To the obtained dried organic layer concentrated Sulphuric acid (57g, 0.58moles) was added and the temperature raised to 117-122° C. After maintaining the reaction mass at 117-122° C for 6 hours it was cooled to 25-30° C, washed sequentially with water (300ml), saturated sodium bicarbonate solution (300ml) and water (150ml). The separated organic layer was then concentrated under vacuum at 60° C to an oily residue. Traces of 1-butanol was removed by its co-distillation with dichloromethane (75ml) under vacuum at 60° C which provides crude Ortho tolyl benzyl butyl ester (IV) as an brown colored viscous oil. The obtained crude Ortho tolyl benzyl butyl ester (IV) oil was then treated with dibromo dimethyl hydantoin (133.3g, 0.47moles) and azobis-isobutyronitrile (8.96g, 0.05moles) in dichloromethane (200ml) for 17 hours at 42-43° C. The reaction mass was then cooled to 25-30° C and washed sequentially with water (416ml), 10% Sodium metabisulphite solution (416ml) and water (416ml). The lower organic layer was then separated and concentrated under vacuum at 45-50° C to provide Bromo-Ortho tolyl benzyl butyl ester (V) as an Orange oil.
Yield: Quantitative
1H-NMR in CDCl3 at 300MHz (ppm): 0.84-0.86 (t, 3H), 0.98-1.17 (m, 2H), 1.30-1.46 (m, 2H), 4.03-4.07 (m, 2H), 4.57 (s, 2H), 7.28-7.63 (m, 7H), 7.86-7.91 (m, 1H).
13C-NMR in CDCl3 at 75MHz (ppm): 13.76, 49.0, 30.10, 33.41, 65.10, 126.29, 127.46, 128.64, 128.84, 129.96, 130.61, 131.27, 131.36, 136.74, 140.85, 168.79.
FT-IR as such (cm-1): 2958, 1716, 1280
Mass Analysis (ESI, +ve mode): Molecular ion peak observed at 347.5 a.m.u which corresponds to M+ peak of title compound.

Example 2: Preparation of Telmisartan n-butylester dihydrochloride (VIII)
Bibenzimidazole (VI) (50g, 0.16 moles), bromo-ortho tolyl benzyl butyl ester (V) (74.2g, 0.21moles) and tetra butyl ammonium bromide (TBAB) catalyst (1g, 0.003moles) were taken in methyl isobutyl ketone (200ml) at 25-30° C. To this obtained reaction mass a solution of sodium hydroxide (13.1g, 0.33 moles) in water (30ml) was added and the reaction mass was maintained 10-12 hours at 25-30° C. After maintaining was over the reaction mass was washed with water (250ml) and the upper organic layer was separated after which its pH was adjusted to below 5 with a solution of 12% hydrochloric acid in isopropyl alcohol (115ml) at 25-30° C. The temperature of this obtained reaction mass was then increased to 60-65°C and further maintained at this temperature for 1 hour whereupon it was cooled to 0-5°C. The precipitated solid was then filtered, washed with methyl isobutyl ketone (25 ml) and dried under vacuum at 65-75° C to afford Telmisartan n-butyl ester dihydrochloride as an off-white crystalline solid.
Yield: 85g (85 % by Theory).
1H-NMR in DMSO-d6 at 300MHz (ppm): 0.68 (t, 3H), 0.99-1.06 (m, 5H), 1.23-1.28 (m, 3H), 1.79-1.89 (sextet, 2H), 2.76 (s, 3H), 3.21 (t, 2H), 3.93 (2H), 4.02 (s, 3H), 5.85 (s, 2H), 7.28 (s, 1H), 7.31 (s, 1H), 7.34 (d, 1H), 7.37 (bs, 1H), 7.39 (bs, 1H), 7.48 (sextet, 1H), 7.58-7.66 (m, 3H), 7.71-7.73 (dd, 1H), 7.84-7.90 (m, 2H), 8.32 (bs, 1H).
FT-IR as such (cm-1): 3380, 2960, 2351, 1777, 1695
Mass Analysis(ESI, +ve mode): Molecular ion peak observed at 571.50 a.m.u which corresponds to (M-2HCl)+ peak of title compound.
XRPD Analysis (Observed 2? values): 6.16, 7.41, 8.19, 9.29, 10.86, 12.44, 15.50, 16.59, 20.43, 21.81, 23.11, 23.44, 23.80, 24.78, 27.53, 29.04, 30.50, 31.07, 32.26.
DSC: Differential Scanning Calorimeter (DSC) thermogram exhibits three characteristic endotherms at 97.3°C (Peak 1); at 233.6°C (Peak 2) and at 236.5°C (Peak 3).

Example 3: Preparation of Telmisartan n-butylester dihydrochloride (VIII)
Bibenzimidazole (VI) (25g, 0.08 moles), bromo-Ortho tolyl benzyl butyl ester (V) (35.6g, 0.0.102moles) and tetra butyl ammonium bromide (TBAB) catalyst (0.5g, 0.0015moles) were taken in methyl isobutyl ketone (100ml) at 25-30° C. To this obtained reaction mass a solution of sodium hydroxide (6.6g, 0.165 moles) in water (15ml) was added and the reaction mass was maintained 10-12 hours at 29-32° C. After maintaining was over the reaction mass was washed with water (125ml) and the upper organic layer was separated after which its pH was adjusted below 3 by purging gaseous hydrochloric acid at 0-5° C. The temperature of this obtained reaction mass was then increased to 60-65°C and further maintained at this temperature for 1 hour whereupon it was further cooled to 0-5°C. The precipitated solid was then filtered, washed with methyl isobutyl ketone (25 ml) and dried under vacuum at 70-75° C to afford Telmisartan n-butyl ester dihydrochloride as an off-white crystalline solid.
Yield: 45.6g (91 % by Theory).

Example 4: Preparation of Telmisartan (IX) from Telmisartan butyl ester dihydrochloride (VIII).
To a well stirred mixture of potassium hydroxide (22g, 0.33moles) in 85% aqueous methanol (250ml) at 25-30° C, Telmisartan butyl ester hydrochloride (VIII) (50g, 0.082moles) was added in a single lot. The temperature of the obtained reaction mass was increased to 70-72° C wherein the reaction mass was maintained for 12 hours. After maintaining was over the reaction mass was cooled to 25-30° C wherein activated charcoal (2.5g) was added and the reaction mass was further heated and maintained at 70-72° C for 30 minutes. The reaction mass was then cooled to 25-30° C whereupon activated charcoal was filtered off through a celite bed and the celite bed washed with 85% aqueous methanol (200ml). The combined filtrate was then heated to 60-65° C at which acetic acid (57.2ml) was added slowly. After addition of acetic acid was complete the obtained reaction mass was maintained further at 60-65° C for 1 hour. The precipitated solid was then filtered, washed with 85% aqueous methanol (100ml), water (150ml), suck dried for 30 minutes and finally dried under vacuum at 65-75° C to afford Telmisartan as off-white to white solid.
Yield: 38g (90 % by Theory)

1H-NMR in DMSO-d6 at 300MHz (ppm): 1.0 (t, 3H), 1.76-1.86 (sextet, 2H), 2.63 (s, 3H), 2.93 (t, 2H), 5.63 (s, 2H), 7.17 (m, 7H), 7.41-7.46 (sextet, 1H), 7.48 (bs, 1H), 7.51-7.60 (m, 2H), 7.67-7.70 (dd, 2H), 7.73 (bs, 1H), 12.90 (bs, 1H)
13C-NMR in DMSO-d6 at 75MHz (ppm): 14.33, 16.95, 21.23, 29.20, 32.23, 46.56, 109.80, 110.89, 119.12, 122.31, 122.55, 123.60, 123.68, 126.87, 127.79, 128.69, 129.17, 129.59, 130.82, 131.33, 132.74, 135.16, 136.42, 137.04, 140.61, 140.95, 142.80, 143.15, 154.47, 156.67, 170.03
FT-IR as such (cm-1): 3060, 2955, 2460, 1695
Mass Analysis(ESI, +ve mode): Molecular ion peak observed at 515.43 a.m.u which corresponds to (M+ H)+ peak of title compound.
DSC Analysis: Endotherm peaks observed at 269.56°C
XRPD Analysis (Observed 2? values): 4.79, 6.87, 9.54, 9.82, 10.72, 12.56, 13.64, 14.18, 14.28, 15.16, 16.28, 16.90, 17.32, 17.56, 18.42, 19.10, 19.41, 19.66, 20.24, 21.45, 22.39, 23.25, 23.92, 24.23, 25.09, 25.43, 26.43, 26.92, 27.62, 28.10, 28.55, 29.20, 29.84, 30.69, 31.10, 31.86, 32.35, 34.16, 35.03, 37.30, 38.90, 39.28, 39.90, 40.96
Purity by HPLC : 99.82%