Field of the Invention:

The present invention relates to an improved method to (INN, USAN and BAN)
manufacture 4'-[(4-methyl-6-(l-methyl-1H-benzimidazole-2-yl)-2-propyl-lH-
benzimidazole-1-yl] methyl] biphenyl-2-carboxylic acid [(Telmisartan) (I)].

Description of the Related Art:

The compound Telmisartan is known from European Patent EP502314B1 and has the following chemical structure Telmisartan and the physiologically acceptable salts thereof have valuable pharmacological properties. Telmisartan is an angiotensin antagonist, particularly an angiotensin- II- antagonist which by virtue of its pharmacological properties may be used for example to treat hypertension and cardiac insufficiency, to treat ischaemia peripheral circulatory disorders, myocardial ischaemia (angina), to prevent the progression of cardiac insufficiency after myocardial infarct, to treat diabetic neuropathy , glaucoma, gastrointestinal diseases and bladder diseases. Other possible therapeutic applications can be found in EP 502314B1, the contents of which are here by referred to and US Patent No.5,591,762.

US Patent No.5,591,762 or EP 0502314 and Jour. Med. Chem, 1993, 36, 25 discloses telmisartan, methods for its preparation and methods of pharmaceutical formulations using Telmisartan.

The process disclosed in US'762 involves, Reaction of 4-methyl-6(1-methylbenzimidazol-2-yl)-2-n-propyl-1H-benzimidazole witht-Butyl-4’-(bromomethyl)-biphenyl-2-carboxylate in the presence of potassium tertiary butoxide by using dimethyl formamide (DMF) or dimethyl sulfoxide as solvents.

It further discloses the formation of a mixture of the 1 and 3 isomers and their separation by chromatography using a substrate such as silica gel or aluminum oxide to obtain t-Butyl-4'-[4-Methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-n-propyl-lH-benzimidazol-lyl-methyl]biphenyl-2-carboxylate. Hydrolysis of the t-Butyl 4'-[4-Methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-n-propyl-lH-benzimidazol-l-yl-methyl]biphenyl-2-carboxyate with trifluro acetic acid in dimethyl formamide followed by purification with silica gel column and crystallization to yield telmisartan.

In US 2004/0236113, 4-bromomethyl, 2-cyano biphenyl was used in place of methyl- 4'-(bromomethyl)-biphenyl-2-carboxylate and subsequently hydrolysed the nitride group in ethylene glycol at 185°C to yield telmisartan.

US Patent application No. 2003/139608 discloses a process for the preparation of pure 4-methyl-6(l -methyl benzimidazole-2-yl)-2-n-propyl-lH-benzimidazole by purifying the crude product obtained by reaction of 2-n-propy 1-4-methyl- lH-benzimidazole-6-carboxylic acid in reaction with N-methyl-O-phenylenediamine preferably in the form of salt, by charcoal treatment of said crude reaction product.

In WO patent application WO2005/10837, the alkylation and hydrolysis steps are combined and Telmisartan is isolated after alkaline hydrolysis by acidifying of the reaction mixture in water & extraction with dichloromethane and precipitation with acetone. Both the ways of isolation are unsuitable for industrial production.

Another method has been described in WO2006/0044754, where 4-methyI-6 (1-methylbenzimidazol-2-yl)-2-n-propyl-lH-benzimidazole is reacted with methyl 4' (bromo-methyl)-biphenyl-2-carboxylate in Acetone and potassium hydroxide followed by preparation of hydrochloride of Telmisartan ester using methanolic hydrochloride and
purifying the Telmisartan ester hydrochloride using huge amounts of acetonitrile. This is further hydrolyzed to produce the potassium salt of Telmisartan , which is acidified in aqueous acetonitrile after isolation. The telmisartan thus obtained is crystallized from a dichloromethane/methanol/mixture and finally from methanol, wherein a pressure apparatus is used for the dissolution in methanol at a temperature above its boiling point to reduce the sulfated ash. The result of this complex procedure, which manifests the already above mentioned shortcomings, is a low yield of the product.

The method as described in WO2006/044648 is in many aspects similar to the above mentioned procedure, where in the last two steps of the synthesis are also combined. The method comprises phase separations, besides increased tediousness.

WO 2007/010558 describes the preparation of Telmisartan methyl ester hydrochloride and conversion of this into Telmisartan dihydrochloride, which in turn, by action of aqueous ammonia in methanol, provides Telmisartan. This process also looks very lengthy for industrial production.

WO 2006/044648 disclose the method of preparation of telmisartan by the condensation of pure 4-methyl-6(l -methyl benzimidazole-2-yl)-2-n-propyl-lH-benzimidazole with methyl 4' (bromo-methyl-biphenyl-2-carboxylate using phase transfer catalyst at 80°C followed by acidic hydrolysis.

The solvents previously used to prepare Telmisartan, especially in alkylation step, such as dimethyl formamide or DMSO have a high boiling point of greater than about 150°C.

These solvents are difficult to remove from the reaction using various evaporation techniques known in the art. These reaction conditions are less environmentally friendly, and harsher on the product. Other previously used solvents to prepare Telmisartan alkyl ester are miscible with water and therefore cause difficulties in extracting the organic

Telmisartan alkyl ester intermediate products from the reaction. Other solvents are toxic or unsafe for other reasons. Also, the expense of the bases, such as potassium tertiary butoxide, which is also highly hygroscopic and difficult to handle at large scales in the
preparation of Telmisartan alkyl ester results in a more expensive overall synthesis of Telmisartan.

Thus, there is a need in the art to develop a process for preparing Telmisartan alkyl ester and telmisartan that is environmentally friendly, easy to practice and can be adapted to industrial scale.

Summary of the Invention:

Accordingly, the present invention discloses an improved process for preparing methyl 4'-(4-methyl-6 - (1 -methyl-lH-benzimidazole-2-yl)-2-propyl-l H-benzimidazole-1 –y1] biphenyl-2-carboxylate intermediate useful in the manufacture of Telmisartan.

In another aspect, the objective of present invention is met by providing efficient, simpler, cost effective solvents for the preparation of telmisartan thereby increasing the yield and achieving the process economics.

In another aspect, the invention provides the usage of alcohols especially tertiary butanol resulting in good yields for the synthesis of a key carboxylate intermediate, which is further hydrolyzed to obtain telmisartan.

In a further aspect, the invention relates to a process for proficiently preparing Telmisartan substantially free of ash content.

According to preferred aspect, preparation of telmisartan comprises reacting 2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl) benzimidazole of formula VII with methyl 4'-(bromomethyl) biphenyl-2-carboxylate of formula VIII in presence of suitable alcohol and base to yield methyl 4'-[(4-methyl-6-(1-methyl-1H-benzimidazole-2-yl)-2-propyl-lH benzimidazole-1-yl] biphenyl-2-carboxylate (IX), and hydrolyzing the formula IX using a base and alcohol as solvent to obtain telmisartan. Telmisartan thus obtained is treated with a weak base such as citric acid to reduce the sulphated ash content substantially below 0.1%

In accordance with the above, the invention provides a process for preparing Telmisartan, which comprises

a) Reduction of methyl-4-butyrylamino-3-methyl-5-nitrobenzoate to form methyl-3-amino-4-butyrylarnino-5-methyl benzoate, which on subsequent cyclization and hydrolysis to form 2-n-propyl-4-methyl-6-carboxy benzimidazole;

b) Condensation of 2-n-propyl-4-methyl-6-carboxy benzimidazole with N-methyl-O-phenylenediamine dihydrochloride to yield 2-n-propyl-4-methyl-6-(l -methyl benzimidazole)-2-yl) benzimidazole;

c) Alkylation of 2-n-propyl-4-methyl-6-(l -methyl benzimidazole) 2-yl) benzimidazole with methyl 4'-(bromomethyl) biphenyl-2-carboxylate in the presence of a base to obtain methyl 4'-(4-methyl-6 - (1 -methyl-lH-benzimidazole-2-yl)-2-propyl-1 H-benzimidazole-1-yl] biphenyl-2-carboxylate; and

d) Hydrolysis of methyl 4'-(4-methyl-6 - (1-methyl-lH-benzimidazole-2-yl)-2-propyl-lH-benzimidazole-1-yl] biphenyl-2-carboxylate with a base to form 4'-[(4-methyl-6-(l-methyl-lH-benzimidazole-2-yl)-2-propyl-lH-benzimidazole-l-yl] methyl] biphenyl-2-carboxylic acid (Telmisartan).

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.

Accordingly, the invention provides a process for the preparation of methyl 4'-(4-methyl-6 - (1-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl] biphenyl-2-carboxylate with high yield employing efficient, simpler, cost effective solvents for the preparation of telmisartan thereby increasing the yield and achieve economic process. Telmisartan obtained according to the present invention is substantially free of ash.

According to preferred embodiment, preparation of telmisartan comprises reacting 2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl) benzimidazole of formula VII with methyl 4'-(bromomethyl) biphenyl-2-carboxylate of formula VIII in presence of suitable alcohol and base to yield methyl 4"-[(4-methyl-6-(l -methyl-1 H-benzimidazole-2-yl)-2-propyl-lH benzimidazole-1-yl] biphenyl-2-carboxylate (IX), and hydrolyzing the formula IX using a base and alcohol as solvent to obtain telmisartan. Telmisartan thus obtained is treated with a weak base such as citric acid to reduce the sulphated ash content substantially below 0.1%

Thus the present invention, describes a process for the preparation of Telmisartan of formula-1 comprising following steps;

a) hydrogenating methyl-4-n-butyrylamino-3-methyl-5-nitrobenzoate for formula II
using palladium on charcoal in a solvent such as methanol, to give methyl-3-amino-4-butyrylamino-5- methyl benzoate of formula- III, which on subsequent cyclization using an acid to yield 2-n-propyl-4-methyl-6-carboxybenzimidazole methyl ester of formula - IV

b) hydrolyzing the formula-IV using a base in methanol gives 2-n-propyl-4-methyl-6-carboxy benzimidazole of formula V;

c) condensing 2-n-propyl-4-methyl-6-carboxy benzimidazole of formula V with N-methyl-ortho phenylenediamine dihydrochloride of formula VI in presence of a polyphosphoric acid to give 2-n-propyl-4-methyl-6-(l -methyl benzimidazole)-2-yl) benzimidazole of formula VII;

d) alkylating of 2-n-propyl-4-methyl-6-(l -methyl benzimidazole)-2-yl) benzimidazole of formula VII with methyl 4'-(bromomethyl) biphenyl-2-carboxylate of formula VIII
in the presence of a suitable base in a suitable solvent to give methyl 4'-(4-methyl-6 - (1-
methyl-lH-benzimidazoIe-2-yl)-2-propyl-lH-benzimidazole-l-yl] biphenyl-2carboxylate of formula-IX;

e) Hydrolysing methyl 4'-(4-methyl-6 - (1-methyl-lH-benzimidazole-2-yl)-2-propyl-lH-benzimidazole-1-yl] biphenyl-2-carboxylate of formula-IX using a base and aqueous methanol to form Telmisartan of formula -I

The hydrogenation of methyl-4-butyrylamino-3-methyl-5-nitro benzoate with 5% palladium on charcoal (containing about 50% water) in methanol to give methyl-3-amino-4-butyrylamino-5-methyl benzoate of formula -III, which on cyclization in a mixture of methanol and Acetic acid and further hydrolysis after removal of solvents, using inorganic bases , preferably hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide in suitable alcoholic solvent , such as methanol, ethanol or isopropanol in presence of water to give 2-n-propyl-4-methyl-6-carboxy benzimidazole of formula V.

Further, the condensation of 2-n-propyl-4-methyI-6-carboxy benzimidazole of formula V with N-methyl-O-phenylenediamine or N-methyl-O-phenylenediamine dihydrochloride or a mixture of mono and dihydrochloride of N-methyl-O-phenylenediamine in presence of a suitable dehydrating agent, to give 2-n-propyl-4-methyl-6-(l -methyl benzimidazole)-2-yl) benzimidazole of formula VII.Suitable temperature for conducting the reaction can range from 100-160°C, preferably between 120-150°C.

The condensation reaction can also be carried out by using known methods as described in Jr. of. Med. Chem. Vol 136, Page 4040-4051 (1993).

The novel and inventive aspects of the present invention lies in the alkylation of 2-n-propyl-4-methyl-6-(l-methyl benzimidazole)-2-yl) benzimidazole of formula VII with methyl 4'-(bromomethyl) biphenyl-2-carboxylate of formula -VIII in presence of suitable base in a suitable organic solvent to give methyl 4'-(4-methyl-6 - (1-methyl-lH-benzimidazole-2-yl)-2-propyl-lH-benzimidazole-l-yl] biphenyl-2-carboxylate.of formula IX.

Suitable base that can be used in the alkylation is an inorganic base, preferably, the inorganic base is selected from the group consisting of a metal hydroxide or alkoxide, and the metal hydroxide is sodium hydroxide or potassium hydroxide or sodium or potassium tertiary butoxide.

Suitable organic solvent is selected from C1-C6 alcohols, more preferred solvent is tertiary butanol. Suitable temperature for the reaction can range from 15-55°C or 15-35°C preferably 25-35°C.

After completion of reaction allowing the reaction mixture to precipitate at 5-30°C, preferably between 18-22°C, followed by recovering the precipitate by filtration.
The compound is re-crystallized from mixture of solvents, preferably an aromatic hydrocarbon and a ketene, more preferably in toluene and acetone at a temperature ranging from 50-70°C and allowing the mass to cool to 0-5°C and recovered the precipitate by filtration to obtain formula IX.

The hydrolysis of methyl 4'-(4-methyl-6 - (1-methyl-lH-benzimidazole-2-yl)-2-propyl-lH-benzimidazole-1-yl] biphenyl-2-carboxylate.of formula IX in the presence of a suitable base in a solvent to give Telmisartan formula-I

Bases that are useful for the hydrolysis reaction are hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide and the suitable solvents are methanol, ethanol or water or mixture of methanol and water or ethanol and water at reflux temperature. Telmisartan is preferably isolated by acidifying with HC1 or acetic acid. It has been

observed that Telmisartan obtained from the above step frequently contains ash, in an amount ranging from 0.5% to 2.0%. This ash content is taken care of by the present invention by reducing the same to below 0.1% by boiling the Telmisartan using water and citric acid and filtering the mass at same temperature.

The suitable temperature can range from 40°C-100°C or 50°C-80°C or more preferably 50°C-55°C. Citric acid can range from 1% to 6% with respect to the weight of the

Telmisartan, preferably between 3-5% is used.
The mixture can be stirred for about 2-4 hours and filtered at a temperature ranging from 50-55°C.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the compounds of the present invention. It will be apparent to those skilled in the art that many modifications and methods may be practiced without departing from the scope of the invention.

EXAMPLE:

STEP -1;
Preparation of 2-n- propyl -4-methyl -6- carboxy benzimidazole To 100.0 gm methyl 4-n-butyryl amino -3-methyl -5-nitro benzoate, 1400.0ml methanol, 6.5 gm Palladium carbon (5%) were added and stirred at 4.0-4.5 kg /cm2 H2 Pressure at 25-35°c in an Autoclave for 6-6'/2 hours. After completion of reaction, filtered the Palladium carbon, Concentrated the reaction mass to half the original volume. To the above reaction mixture added 266.0 ml Acetic acid and distilled the solvent mixture (methanol & Acetic acid ) in 3.0-5.0 hours between 70-80 c. .After completion of reaction, remaining Acetic acid was removed by distillation. The reaction mass was treated with a mixture of 300.0 ml methanol, 34.0 gm sodium hydroxide & 336.0ml water at reflux temperature for 3.0-4.0 hours. Methanol was removed and the product. 2-n-propyl-4-methyl-6-carboxy benzimidazole was isolated in presence of excess water (600.0 ml) by adjusting the PH = 4.5-5.0 with 60.0 to 65.0ml of Acetic acid between 25-35°c to obtain as a pale yellow crystalline solid which melts at about 295°c. Weight: 66.0 gm

STEP-2: Preparation of 2-n-propyl -4-methyl -6-[l-methyl benzimidazole-2-yl] benzimidazole(VII) 130.0 gm of polyphosphoric acid was heated to 85°c and 32.5 gm of 2-n-propyl-4-methyl-6-carboxy benzimidazole was added slowly and heated to 120-130°c and N-methyl - o -phenylene diamine dihydro chloride was added in 1.0 to 2.0 hours by controlling the frothing of the reaction mass. An anti frothing agent silicon oil (1.5 ml) was also added to Control the frothing. The reaction mass was further heated to 150°c and the thick mass was stirred for 5-10 hours between 150-155°c. After completion of reaction as monitored by TLC, the mass was cooled to 70-80°c and 300 ml water was charged. 10 gm neutral activated charcoal was added and stirred between 70-80°c for an hour. The reaction mass was filtered hot and pH was adjusted to 5.7 + 0.25 by using dilute NaOH solution to precipitate the product. This was filtered at 50°c and wet cake was stirred using water at 75-80°c and filtered to obtain 2-n-propyl -4-methyl -6-[l-methyl benzimidazole-2-yI] benzimidazole. .The compound was dried until the water content in the product reaches 5.5 -6.5 % w/w. Further the product was re -crystallized in a mixture of water and isopropyl alcohol. Weight: 38.0 gm

STEP- 3;
Preparation of methyl 4'-(4-methyl-6 - (l-methyl-lH-benzimidazole-2-yl)-2-propyl-
1H-benzimidazole-1-yl] biphenyl-2-carboxylate(IX) 50.0 gm 2-n-propyl -4-methyl -6-[l-methyl benzimidazole-2-yI] benzimidazole in 400 ml of tertiary butanol were stirred to obtain a clear solution and 11.5gm of NaOH and 10ml of water were added. . 60 gm methyl 4'-(bromomethyl) biphenyl-2-carboxylate was added slowly and stirred for 4 hours at 25-30°c .After completion of reaction, this suspension was cooled to 20°c; stirred for 1.0 to 2.0 hours; filtered and washed with tertiary butanol (50ml). The compound was further washed with water (600ml) to neutral pH and dried to obtain methyl 4'-(4-methyl-6 - (l-methyl-lH-benzimidazole-2-yl)-2-propyl-lH-benzimidazole-1-yl] biphenyl-2-carboxylate 60gm. . This compound was added to a mixture of toluene (153ml) and acetone (140ml) and stirred at 60-65°c for an hour and cooled slowly to 0-5°c, filtered, washed with chilled mixture of toluene and acetone to obtain a cream colour crystalline powder. Weight: 48.0 gm

STEP- 4:
Preparation of 4'-[(4-methyl-6-(1-methyl-lH-benzimidazole-2-yI)-2-propyl-1H-
benzimidazole-1-yl] methyl] biphenyl-2-carboxylic acid (Telmisartan I) To a mixture of 20.0 gm methyl 4'-(4-methyl-6-(l-methyl-1H-benzimidazole-2-yl)-2-propyl-1H-benzimidazole-1-yl] biphenyI-2-carboxylate and 144 ml of methanol, 31.5 gm of 14% NaOH solution was added slowly and refluxed for about 8 hrs. The conversion of ester to acid was monitored by HPLC. The resultant mass was allowed to return to ambient temperature and pH was adjusted to 4.0 -5.0 using dil.Hcl. The precipitated material was further stirred for 1 % hour, filtered and washed with methanol. To the wet material, 200ml water and 0.75 gm of citric acid were added and stirred at 50-55°c of temperature for two hours, filtered, washed with water and dried at 50-55°c to obtain telmisartan as white crystalline powder. Weight: 19.0 gm
Ash content: less than 0.10 % w/w

We Claim,

1. A process for preparing telmisartan of formula I, comprising the steps of:

a) preparing methyl 4’-[(4-methyl-6-( 1-methyl-1H-benzimidazole-2-yl)-2-propyl-lH-benzimidazole-1-yl] biphenyl-2-carboxylate of formula IX by reacting 2-n-propyl-
4-methyl-6-(l-methylbenzimidazol-2-yl) benzimidazole of formula VII with methyl
4'-(bromomethyl) biphenyl-2-carboxylate of formula VIII using a suitable alcohol and base;

b) hydrolyzing the formula IX using base and alcohol as solvent to obtain telmisartan of formula I; and

c) treating the telmisartan with a weak organic acid to reduce the content of sulphated ash to below 0.1%.

2. The process as claimed in claim 1, step a) alcohol is tertiary butanol and base is alkali metal hydroxide.

3. The process as claimed in claim 1, wherein hydrolysis of formula IX is carried out using aqueous methanol as solvent.

4. The process as claimed in claim 1, wherein the step of reducing sulphated ash content using weak organic acid is conducted in presence of water.

5. The process of claim 4, wherein weak organic acid is citric acid.