INTRODUCTION
Aspects of the invention relate to the preparation of telmisartan having a purity acceptable for use in pharmaceutical products.
The drug compound having an adopted name “telmisartan” is structurally represented by formula (I).

(I)
Telmisartan has a chemical name 4''-[(1,4''-dimethyl-2''-propyl[2,6''-bi-1H-benzimidazol]-1''-yl)methyl]-[1,1''-biphenyl]-2-carboxylic acid. Telmisartan is a nonpeptide angiotensin II receptor (type AT1) antagonist. MICARDIS® tablets from Boehringer Ingelheim contain 40 mg and 80 mg telmisartan, and are available commercially. MICARDIS tablets are indicated for the treatment of hypertension, and may be used alone or in combination with other antihypertensive agents such as hydrochlorothiazide.
U.S. Patent No. 5,591,762 describes the production of telmisartan from telmisartan t-butyl ester. The hydrolysis of telmisartan t-butyl ester is carried out using trifluoroacetic acid in N,N-dimethylformamide, to produce telmisartan as shown in Scheme 1.

Scheme 1
U.S. Patent No. 6,358,986 discloses crystalline polymorphic Form A and Form B of telmisartan, processes for their preparation, their mixtures, and their pharmaceutical compositions.
Chinese Patent Application 1344712 discloses a process to prepare telmisartan by reacting 1,7''-dimethyl-2''-propyl-2,5''-bi-1H-benzoimidazol with 4''-bromomethyl-biphenyl-2-carboxylic acid methyl or ethyl ester, to form a telmisartan methyl or ethyl ester intermediate, which is then converted to telmisartan by acid or base hydrolysis.
International Application Publication No. WO 2005/10837 discloses a one pot synthesis of telmisartan, in which 1,7''-dimethyl-2''-propyl-2,5''-bi-1H-benzoimidazol and 4''-bromomethyl-biphenyl-2-carboxylic acid methyl ester are condensed and hydrolyzed in situ to produce telmisartan.
International Application Publication No. WO 2006/044754 discloses a process for the preparation of telmisartan. The process involves the hydrolysis of telmisartan methyl ester hydrochloride with potassium hydroxide, to produce a potassium salt of telmisartan, which is then isolated and acidified with acetic acid to produce telmisartan. Purification of telmisartan is done using charcoal and crystallization from a mixture of dichloromethane and methanol. Recrystalization of telmisartan is done with methanol.
International Application Publication No. WO 2006/044648 discloses a process for the preparation of telmisartan, in which 1,7''-dimethyl-2''-propyl-2,5''-bi-1H-benzoimidazol and 4''-bromomethyl-biphenyl-2-carboxylic acid alkyl ester are reacted in the presence of an inorganic base at 55-120°C and maintained for 1-8 hours, to form telmisartan alkyl ester which is then isolated and hydrolyzed under acidic or basic conditions to produce telmisartan. This publication also discloses a process for the preparation of telmisartan in which the condensation and subsequent hydrolysis steps are carried out in a single reaction vessel at 55-120°C and maintained for 6-24 hours, without isolation of telmisartan alkyl ester or telmisartan salt formed with the base.
International Application Publication No. WO 2007/010558 discloses a process for the preparation of telmisartan involving preparation of acid addition salts of telmisartan methyl ester (specifically a hydrochloride salt), which are isolated and treated with aqueous hydrochloric acid to form telmisartan dihydrochloride, which is subsequently converted to telmisartan.
The known processes for the preparation of telmisartan either involve technically difficult steps of intermediate isolation, or are economically not feasible, as they involve the use of a large number of solvents during the process stages and also involve the use of large quantities of solvent for the purification of telmisartan.

SUMMARY
In an aspect, the invention provides simple, industrially scalable and cost-effective processes for the preparation of telmisartan which has purity acceptable for its use in the preparation of pharmaceutical compositions.
In embodiments of the invention, a process for preparation of telmisartan comprises:
(a) reacting 1,7''-dimethyl-2''-propyl-2,5''-bi-1H-benzoimidazol or its hydrate and 4''-bromomethyl-biphenyl-2-carboxylic acid methyl ester;
(b) removing impurities from reaction mass obtained in step (a) by washing an aqueous layer containing telmisartan methyl ester with a water immiscible organic solvent, under acidic pH conditions;
(c) isolating an acid addition salt of telmisartan methyl ester;
(d) converting an acid addition salt of telmisartan methyl ester to produce telmisartan; and
(e) optionally, purifying telmisartan obtained in step (d).
In embodiments of the invention, telmisartan produced according to a process of the invention has crystalline polymorphic Form A and contains less than about 0.1% by weight of total impurities.
In embodiments of the invention, telmisartan produced according to a process of the invention has crystalline polymorphic Form A and contains less than about 0.1% by weight of any individual impurity.

DETAILED DESCRIPTION
In an aspect, the invention provides processes for preparing telmisartan, an embodiment comprising:
(a) reacting 1,7''-dimethyl-2''-propyl-2,5''-bi-1H-benzoimidazol or its hydrate and 4''-bromomethyl-biphenyl-2-carboxylic acid methyl ester;
(b) removing impurities from reaction mass obtained in step (a) by washing the aqueous layer containing telmisartan methyl ester with a water immiscible organic solvent under acidic pH conditions;
(c) isolating an acid addition salt of telmisartan methyl ester;
(d) converting an acid addition salt of telmisartan methyl ester to produce telmisartan; and
(e) optionally, purifying telmisartan obtained in step (d).
In embodiments, step (a) comprises reacting 1,7''-dimethyl-2''-propyl-2,5''-bi-1H-benzoimidazol or its hydrate thereof and 4''-bromomethyl-biphenyl-2-carboxylic acid methyl ester in a low boiling organic solvent, in the presence of an inorganic base, at 15-45°C for about 1-8 hours.
In step (a), an organic solvent can be a C3-C6 ketone, C1-C4 alcohol, C2-C4 nitrile, C2-C4 ether, or C3-C5 ester, having a boiling temperature less than about 120°C. Suitable solvents include acetone and methanol.
In step (a), an inorganic base can be a metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, or strontium hydroxide, or a metal carbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate. Mixtures of bases are useful.
In step (a), the temperatures at which the reaction is carried out are generally about 15-45°C, or about 25-35°C, or about preferably 30°C.
In step (a), the times required for reaction completion are about 1-8 hours, or about 1-3 hours, or about 2 hours. Longer times also can be used.
In embodiments, step (b) comprises removing impurities from the reaction mass obtained in step (a), by:
(i) adding water, followed by a water immiscible organic solvent, to the reaction mass;
(ii) adjusting pH of the reaction mass to about 1.5-3 with an inorganic mineral acid;
(iii) separating the aqueous layer from the organic layer and washing the aqueous layer with an additional quantity of the water immiscible organic solvent;
(iv) separating the aqueous layer from the organic layer; and
(v) adjusting pH of the aqueous layer to 0.5-2 with an inorganic mineral acid at 15-45°C.
In step (b), a water immiscible organic solvent can be a C6-C10 substituted or unsubstituted aliphatic or aromatic hydrocarbon, such as n-heptane, cyclohexane, n-hexane, benzene, toluene, xylene, chlorobenzene, and methoxybenzene.
In step (b), an inorganic mineral acid can be hydrochloric acid, hydrobromic acid, sulphuric acid, etc.
In embodiments, step (c) comprises isolating an acid addition salt of telmisartan methyl ester of formula (III),

(III)
by removal of the solvent using a suitable technique.
In step (c), an acid addition salt of telmisartan methyl ester can be dihydrochloride monohydrate of telmisartan methyl ester of formula (II).

(II)
In step (c), a suitable technique for removal of the solvent can be evaporation, atmospheric distillation, or distillation under vacuum. The product is subsequently filtered. The product isolated in step (c) may be dried by any methods known in the art or it may be used in the wet condition for step (d).
In embodiments, the process of step (d) comprises:
(i) reacting an acid addition salt of telmisartan methyl ester of formula (III) with an inorganic base in a mixture of low boiling organic solvent and water at a temperature from 30°C to the reflux temperature of the solvents, for about 1-8 hours;
(ii) optionally, treating the reaction mass with activated carbon at a temperature from 30°C to the reflux temperature, followed by filtration of the carbon;
(iii) adjusting pH of the filtrate to about 5-6.5 with an acid; and
(iv) isolating telmisartan.
In step (d), an acid addition salt of telmisartan methyl ester can be a dihydrochloride monohydrate of telmisartan methyl ester of formula (II).
In step (d), an inorganic base can be a metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, or strontium hydroxide, or a metal carbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate. Mixtures of bases can be used.
In step (d), an organic solvent can be a C3-C6 ketone, C1-C4 alcohol, C2-C4 nitrile, C2-C4 ether, or C3-C5 ester, having a boiling temperature less than about 120°C. Useful solvents include acetone and methanol.
In step (d), the temperature at which the reaction of an acid addition salt of telmisartan methyl ester of formula (III) with an inorganic base is carried out can be the reflux temperature of the solvents, such as about 60-100°C, or about 70-90°C.
In step (d), the times required for completion of reaction of an acid addition salt of telmisartan methyl ester of formula (III) with an inorganic base typically is about 1-8 hours, or about 2-4 hours, or about 3 hours. Longer times can be used.
In step (d), the reaction mass is optionally treated with activated carbon. The temperatures at which activated carbon is added to the reaction mass can be below the reflux temperature, such as about 40-90°C. The reaction mass may be maintained at the same temperature for a brief time, such as about 5-30 minutes, after which the carbon is removed by filtration, centrifugation, decantation, or any other means.
In step (d), an acid for adjusting pH can be an inorganic mineral acid or an organic acid, such as hydrochloric acid and acetic acid.
In step (d), isolation of the product can be done by cooling the reaction mass to lower temperatures, such as about 0-10°C, followed by collection of the precipitate by any techniques, such as, for example, decantation, filtration by gravity or suction, centrifugation, and the like. The product isolated in step (d) can be dried using methods known in the art.
In step (d), telmisartan obtained can have a purity at least about 99.5%, or at least about 99.7%, by weight as determined using high performance liquid chromatography (HPLC) methods.
In embodiments of the invention, the process of step (e) optionally comprises purifying telmisartan obtained in step (d) by recrystallization or slurrying in a low boiling organic solvent, water, or mixtures thereof, followed by drying.
In step (e), a low boiling organic solvent can be a C3-C6 ketone, C1-C4 alcohol, C2-C4 nitrile, C2-C4 ether, or C3-C5 ester, having a boiling temperature less than about 120°C. Suitable solvents include acetone and methanol.
In steps (a-e) of the invention:
(i) The reaction may be carried out for any desired time periods to achieve the desired product yield and purity.
(ii) It may be advantageous to conduct a reaction under an inert atmosphere, such as, for example, oxygen-free argon or nitrogen gas.
(iii) Isolation of the product obtained includes collection of the material by any techniques, such as, for example, decantation, filtration by gravity or suction, centrifugation, and the like, and optional washing with solvent.
(iv) The solid material obtained by any of the techniques described above may be further dried. Drying may be suitably carried out using any equipment, such as, for example, a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out under reduced pressures and at various temperatures, for a time period that produces the desired purity.
(v) The solid material obtained by any of the techniques described above may be further milled and/or sifted, to achieve desired particle sizes and surface areas.
Processes for the preparation of telmisartan of formula (I) according to embodiments of the present invention are as shown in Scheme 2.

Scheme 2
In embodiments, telmisartan produced according to a process of the invention has crystalline polymorphic Form A and contains less than 0.1% by weight of total impurities, as determined using HPLC.
In embodiments, telmisartan produced according to a process of the invention has crystalline polymorphic Form A and contains less than 0.1% by weight of any individual impurity, as determined using HPLC.
In embodiments of the invention, telmisartan obtained by a process of the invention:
(a) When isolated, the polymorphic form consistently is crystalline Form A as analyzed by powder X-ray diffraction (XRD) and/or differential scanning calorimetry (DSC) methods.
(b) Impurities A to H disclosed in the European Pharmacopoeia 2009 for telmisartan are less than about 0.1%, or less than about 0.05%, by weight as determined using a HPLC method. The other impurities, i.e. the dimer acid impurity of formula (IV) detected at RRT 1.38 (telmisartan=1) by the HPLC method described below,

(IV)
and the chloro analogue impurity of formula (V) detected at RRT 1.45 (telmisartan=1) by the HPLC method below,

(V)
are present in amounts less than about 0.1%, or less than about 0.05%, by weight.
(c) Any single highest known or unknown impurity is present in amounts less than about 0.1%, or less than about 0.05%, by weight as determined using a HPLC method.
(d) Total impurities are present in amounts less than about 0.1%, or less than about 0.05%, by weight using a HPLC method.
In embodiments, telmisartan having crystalline polymorphic Form A obtained by a process of the invention,
(a) has needle shaped particles;
(b) has a particle size distribution wherein d(0.5) is less than about 25 µm, or less than about 15 µm, or less than about 10 µm, and d(0.9) is less than about 50 µm, or less than about 35 µm, or less than about 25 µm, as determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, United Kingdom;
(c) has a moisture content less than about 1%, or less than about 0.4%, by weight;
(d) has a sulphated ash content less than about 0.1%, or less than about 0.05%, by weight; and
(e) contains residual solvents within the limits set by ICH guidelines, e.g., less than 500 ppm, or less than 50 ppm, determined using a gas chromatography (GC) method.
An example of a HPLC method that can be used for the analysis of telmisartan and related substances or impurities includes a Kromasil C18, 125 mm×4.0 mm, 5 µm or equivalent column. Additional method parameters are given in Table I.
Table I
Flow rate 1.0 mL/minute
Elution Gradient
Wavelength 230 nm
Injection volume 10 µL
Column Oven temperature 40°C
Run time 45 minutes
Diluent Methanol
Mobile phase Mobile phase A: 2.0 g potassium dihydrogen phosphate and 3.8 g of sodium pentane sulphonate monohydrate are dissolved in water and pH is adjusted to 3.0 with dilute phosphoric acid and then diluted to 1000 ml with water.
Mobile phase B: A mixture of methanol and acetonitrile in the volume ratio of 20:80.
Gradient program Minutes Mobile Phase A Mobile Phase B
0.01 70 30
3.00 70 30
35.00 20 80
40.00 70 30
45.00 70 30
Telmisartan obtained by a process of the invention can be converted into its pharmaceutical compositions, wherein the term "pharmaceutical compositions" includes tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations. Pharmaceutical compositions containing telmisartan of the present invention may be prepared with pharmaceutical excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of telmisartan of the present invention can be used depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Certain specific aspects and embodiments of the invention are further explained by the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention, and the scope of the invention is not to be limited by the examples.

Examples
Example 1: Preparation of methyl-4''-[(2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate dihydrochloride monohydrate of formula (II).
Acetone (210 mL), 1,7''-dimethyl-2''-propyl-2,5''-bi-1H-benzoimidazol hydrate (30.0 g), potassium hydroxide flakes (11.2 g) and 4''-bromomethyl-biphenyl-2-carboxylic acid methyl ester (39.0 g) are charged into a round bottom flask and stirred for 90 minutes at 30°C. Water (360 mL) and toluene (75 mL) are added with stirring. pH of the mass is adjusted 2.2 with hydrochloric acid. The mass is then allowed to settle and the aqueous layer is separated. The aqueous layer is washed with toluene (75 mL). pH of the aqueous layer is adjusted to 0.75 with hydrochloric acid. The solvent is distilled under vacuum less than 650 mm Hg till the temperature reaches 55°C and then the solvent is distilled without vacuum till the temperature reaches 90oC. The mass is then cooled to 28°C and filtered. The solid is washed with water (60 mL). The wet solid is dried at 75°C in an oven to produce the title compound (50.0 g; yield: 87.0%; HPLC purity: 99.11%).

Example 2: Preparation of methyl-4''-[(2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate dihydrochloride monohydrate of formula (II).
Acetone (105 L), 4''-bromomethyl-biphenyl-2-carboxylic acid methyl ester (19.5 kg), 1,7''-dimethyl-2''-propyl-2,5''-bi-1H-benzoimidazol hydrate (15.0 kg) and potassium hydroxide flakes (5.55 kg) are charged into a reactor and the mass is maintained at 30°C for 2 hours. Water (180 L) is added, followed by adding toluene (37.5 L). pH of the mass is adjusted 2.4 with hydrochloric acid. The mass is allowed to settle for 30 minutes and the bottom aqueous layer is separated from the organic layer and transferred to another reactor. Toluene (37.5 L) is added to the aqueous layer and pH of is adjusted 2.4 with hydrochloric acid. The mass is allowed to settle for 30 minutes and the aqueous layer is separated from the organic layer and transferred to another reactor. pH of the aqueous layer is adjusted to 0.8 with hydrochloric acid. The solvent is distilled under vacuum less than 650 mm Hg till the temperature is 55°C and then without vacuum the solvent is distilled till the temperature reaches 90oC. The mass is then cooled to 28°C and filtered. The mass is cooled to 30°C and maintained at that temperature for 2 hours. The mass is then filtered and the solid is washed with water (30 L). The wet solid is spin dried followed by oven drying at 73°C to produce the title compound (23.85 g; yield: 91.4%).

Example 3: Preparation of telmisartan.
Methanol (500 mL) and methyl-4''-[(2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate dihydrochloride monohydrate of formula (II) (100.0 g) are charged into a round bottom flask with stirring at 30°C. Potassium hydroxide flakes (63.0 g) and water (100 mL) are added with stirring at the same temperature. The mass is heated to 70°C for 3 hours and then activated carbon is added at the same temperature. The mass is filtered through a Hyflow (flux-calcined diatomaceous earth) bed at 70°C and the filter cake is washed with methanol (200 mL) at the same temperature. The filtrate and methanol (1 L) are charged into a round bottom flask and heated to 65°C. pH of the mass is adjusted 5.8 with acetic acid (120 mL) at 65°C with stirring. The mass is cooled to 2oC and the precipitated solid is filtered. The solid is washed twice with methanol (200 mL). The wet solid is spin dried and then charged into a round bottom flask with water (1 L). The mass is heated to 92°C and maintained for 1 hour. The mass is cooled to 30°C and then filtered, followed by washing the solid with chilled methanol (200 mL). The compound is suction dried and then charged into a round bottom flask with methanol (1 L) and heated to 65°C. The mass is cooled to 30°C and then filtered, followed by washing the solid with methanol (200 mL). The wet compound is dried at 65°C to afford telmisartan, which is milled and sifted as required (63.5 g; yield: 76.5%; HPLC purity: 99.96%).
The crystalline polymorphic Form A is characterized by the XRD peaks (using copper K? radiation) at 6.7, 14.2, 15, and 19, ±0.2 degrees 2?, and a DSC endothermic peak at 270°C. The particle size distribution has values of d(0.5) of 3.3 µm and d(0.9) of 14.6 µm, by the Malvern method. The specific surface area is 4.86 m2/g from BET analysis. Dimer impurity is not detected and chloro analogue impurity is 0.04%.

Example 4: Preparation of telmisartan.
Potassium hydroxide flakes (13.9 kg) and water (22 L) are placed in a reactor and stirred for dissolution. The solution is charged into another reactor followed by charging of methanol (110 L) and methyl-4''-[(2-n-propyl-4-methyl-6-(1-methyl benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate dihydrochloride monohydrate of formula (II) (22.0 kg) at 30°C. The mass is heated to reflux (70°C) and maintained for 3 hours for completion of the reaction. Activated carbon (1.1 kg) in methanol (11 L) is added at the same temperature. The mass is filtered at 70°C and the filter cake is washed with methanol (33 L) at the same temperature. Methanol (220 L) and acetic acid (28.6 L) are charged into the reactor and heated to 65°C and pH of the mass is adjusted 5.8-5.9. The mass is maintained at this temperature for 75 minutes; cooled to 2°C and then maintained at this temperature for 100 minutes. The mass is filtered and the solid is washed twice with methanol (20 L). The wet solid is spin dried and charged into a reactor with water (226 L). The mass is heated to reflux and maintained for 1 hour. The mass is cooled to 30°C, filtered and then washed with methanol (42 L). The solid is spin dried and the wet solid is dried at 70°C to afford telmisartan, which is milled and sifted as required (14.4 kg; yield: 78.7%).