TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for the preparation of β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-l-methyl-lH-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate represented by formula (I), commonly known as Dabigatran Etexilate Mesylate.
The process provides Dabigatran Etexilate Mesylate in higher yield and purity compared to the previously known processes.
BACKGROUND OF THE INVENTION
Dabigatran Etexilate Mesylate is direct thrombin inhibitor and is used for treatment of risk of stroke and systemic embolism, Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE).
U.S. Patent No. 6,087,380, hereinafter referred to as '380 patent, discloses a variety of disubstituted bicyclic heterocycle derivatives and their pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof.
The synthesis of Dabigatran Etexilate was first defined in the '380 patent. The process describes a method of preparation of Dabigatran Etexilate, a compound of formula (E) and its intermediates. The patent exemplifies the process for preparation of an intermediate such as l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5- yl-carboxylic

acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, a compound of formula (C) by reacting 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, a compound of formula (A) with N-(4-cyanophenyl)-glycine, a compound of formula (B).
The said reaction between compounds of formulae (A) and (B) occurs at reflux temperature for five hours in presence of tetrahydrofuran; the step further involves use of glacial acetic acid. Use of such reflux condition, use of flammable solvent like tetrahydrofuran as well as use of corrosive organic acid like acetic acid makes the process more time consuming, hazardous and commercially unviable for industrial purpose.
The '380 patent further exemplifies the process to prepare Dabigatran Etexilate
intermediate i.e. l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride, a
compound of formula (D) prepared from compound of formula (C), followed by converting a compound of formula (D) to Dabigatran Etexilate, a compound of formula (E).

The '380 patent also describes the purification of Dabigatran Etexilate and its intermediate of formula (D) using column chromatography. Column chromatography makes the process more tedious, time consuming, expensive and commercially unviable.
International Publication No. WO 2012/004396 discloses preparation of Dabigatran Etexilate Mesylate intermediate of formula (C) by reacting a compound of formula (A) with a compound of formula (B) in presence of a coupling agent and subsequent cyclization with acetic acid.
The processes for the preparation of Dabigatran Etexilate and its intermediates, as defined in the aforementioned prior arts suffer from several disadvantages such as the use of highly flammable solvents; use of tedious and expensive column chromatographic purifications and use of excessive amounts of corrosive organic acids like acetic acid. Therefore, there is a need for a simple, efficient and commercially viable process for preparation of Dabigatran Etexilate Mesylate and/or intermediates thereof with higher purity levels which avoids the above mentioned drawbacks.
The present invention provides such an improved process for the preparation of Dabigatran Etexilate Mesylate and/or intermediates thereof, avoiding the above mentioned drawbacks.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of Dabigatran Etexilate Mesylate, a compound of formula (I), comprising

(b) purifying the compound of formula (C) obtained in step (a);
(c) converting the compound of formula (C) to a compound of formula (D);
(d) converting the compound of formula (D) obtained in step (c) to Dabigatran Etexilate, a compound of formula (E); and

(e) converting Dabigatran Etexilate, the compound of formula (E) to Dabigatran Etexilate Mesylate, a compound of formula (I).
Another object of the present invention is to provide an improved process for preparation of the Dabigatran Etexilate Mesylate intermediate represented by a compound of formula (C), by reacting a compound of formula (A) with a compound of formula (B) in presence of suitable solvent and coupling agent, and subsequent cyclization using oxalic acid.
Another object of the present invention is to provide an improved process for preparation of highly purified Dabigatran Etexilate Mesylate while avoiding the use of column chromatography and hazardous solvents.
DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification, the term "suitable solvent" refers to, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert. butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 4-hydroxy-4-methyl pentanone and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water or mixtures thereof.

As used throughout the specification, the term "suitable base" refers to organic and inorganic bases. An organic, base includes, but is not limited, to primary, secondary or tertiary amines such as methylamine, ethylamine, n-propylamine, isopropylamine, triethylamine, N,N-diisopropylethylamine, tertiary butylamine and the like. Inorganic base includes, but is not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, caesium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.
In one embodiment, the present invention provides a process for preparation of Dabigatran Etexilate Mesylate, a compound of formula (I), comprising
(a) reacting a compound of formula (A) with a compound of formula (B) in presence of a suitable solvent and a coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C);
(b) purifying the compound of formula (C) obtained in step (a);
(c) converting the compound of formula (C) to a compound of formula (D);

(d) converting the compound of formula (D) obtained in step (c) to Dabigatran Etexilate, a compound of formula (E); and
(e) converting Dabigatran Etexilate, the compound of formula (E) to Dabigatran Etexilate Mesylate, a compound of formula (I).
In one embodiment, step (a) comprises reacting a compound of formula (A) with a compound of formula (B) in presence of a suitable solvent and a coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C).
The suitable solvent used in step (a) is as defined supra. Preferably, the solvent used for the process in step (a) is an ester solvent. More preferably, the solvent used in step (a) is ethyl acetate.
The coupling agent used in step (a) is selected from group consisting of
isobutylchloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid,
sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride,
phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide,
N-hydroxysuccinimide, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole,
triphenylphosphine, carbon tetrachloride, triphenylphosphine/diethylazodicarboxylate and mixtures thereof. Preferably, the coupling agent used in step (a) may be N,N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, or a mixture thereof.

In one embodiment, the coupling agent used for the said reaction is a mixture of N,N'-dicyclohexylcarbodiimide and N,N'-carbonyldiimidazole.
In one embodiment, the coupling agent used for the said reaction is N,N'-carbonyldiimidazole.
In one embodiment, the reaction between a compound of formula (A) and a compound of formula (B) in step (a) may be performed in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent.
In one embodiment, the step (a) comprises adding compound of formula (B) to a suitable solvent, optionally under stirring at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C, more preferably at a temperature of about 25°C to about 30°C. The suitable solvent used is as discussed supra. In one embodiment, the suitable solvent used is an ester solvent, preferably ethyl acetate. N,N'-carbonyldiimidazole was added to the reaction mass at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C, more preferably at a temperature of about 25°C to about 30°C. The reaction mass was stirred for about 1-3 hours, preferably for about 1-2 hours. Compound of formula (A) may be added under stirring. After completion of reaction, water may be added to the reaction mass and the organic layer obtained may be treated with water. Oxalic acid may be added to the organic layer obtained and the reaction mixture obtained is heated, optionally under stirring, at a temperature of about 60°C to about 85°C, preferably at a temperature of about 65°C to about 80°C, more preferably at a temperature of about 70°C to about 75°C.
After the completion of the reaction in step (a), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of reaction in step (a), the reaction mixture is cooled to a temperature of about 5°C to about 25 °C, preferably to a temperature of about 10°C to about 20°C. Further, the reaction mass is filtered and washed with a suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used is an ester solvent. More preferably, the solvent used is ethyl acetate. The wet cake

obtained may be treated with water and the pH of the reaction mass may be adjusted to 7-9 using inorganic base as defined supra; preferably sodium bicarbonate solution to obtain a compound of formula (C). .
In one embodiment, step (a) comprises reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent to obtain a compound of formula (C).
In one embodiment, step (a) comprises reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C, more preferably at a temperature of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 60°C to about 85°C, preferably at a temperature of about 65°C to about 80°C, more preferably at a temperature of about 70°C to about 75 °C to obtain a compound of formula (C).
In one embodiment, the present invention provides a process of preparation of Dabigatran Etexilate Mesylate intermediate of formula (C) comprising reacting a compound of formula (A) with a compound of formula (B) in presence of a suitable solvent and a coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C).
In one embodiment, the present invention provides a process of preparation of Dabigatran Etexilate Mesylate intermediate of formula (C) comprising reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C).
In one embodiment, the present invention provides a process of preparation of Dabigatran Etexilate Mesylate intermediate of formula (C) comprising reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C, more preferably at a temperature

of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 60°C to about 85°C, preferably at a temperature of about 65°C to about 80°C, more preferably at a temperature of about 70°C to about 75°C to obtain a compound of formula (C).
In one embodiment, the present invention provides a process of preparation of Dabigatran Etexilate Mesylate intermediate of formula (C) comprising reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent at a temperature of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 70°C to about 75°C to obtain a compound of formula (C).
In one embodiment, the present invention provides a process of preparation of Dabigatran Etexilate Mesylate comprising reacting a compound of formula (A) with a compound of formula (B) in presence of a suitable solvent and a coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C).
In one embodiment, the present invention provides a process of preparation of Dabigatran Etexilate Mesylate comprising reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C).
In one embodiment, the present invention provides a process of preparation of Dabigatran Etexilate Mesylate comprising reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent at a temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C, more preferably at a temperature of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 60°C to about 85°C, preferably at a temperature of about 65°C to about 80°C, more preferably at a temperature of about 70°C to about 75 °C to obtain a compound of formula (C).

In one embodiment, the present invention provides a process of preparation of Dabigatran Etexilate Mesylate comprising reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent at a temperature of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 70°C to about 75°C to obtain a compound of formula (C).
The process of for preparation of compound of formula (C) as described in prior art patent US '380 involves use of hazardous tetrahydrofuran as a solvent and reaction between compound of formula (A) and (B) is performed at reflux temperature, whereas the present invention involves use of ethyl acetate which is safer and reaction between compound of formula (A) and (B) is performed at considerably lower temperature as described above. Also, US '380 involves the use of column chromatography for the isolation of a compound of formula (C) while, the present invention gives desired quality and higher yield of a compound of formula (C) as compared to '380 patent without using expensive column chromatography. Further, '380 patent uses acetic acid as a cyclization agent whereas, the present invention avoids the use of hazardous acetic acid and makes the process safer as compared to the processes known in the art by using oxalic acid for cyclization.
In one embodiment, compound of formula (C) may be purified before further treatment or reaction.
In one embodiment, compound of formula (C) may not be purified and used as such before further treatment or reaction.
In one embodiment, the step (b) comprises purifying a compound of formula (C) obtained in step (a).
The compound of formula (C) obtained in step (a) may be treated with a suitable solvent. The suitable solvent is as defined supra. Preferably, the solvent used is a halogenated solvent; more preferably the solvent used is dichloromethane. The mixture obtained may be stirred, the organic layer may be separated and concentrated under vacuum. To the mass obtained, a suitable solvent may be added. Suitable solvent used is as defined supra.

Preferably, the suitable solvent added to the reaction mixture is a ketone solvent. More preferably, the solvent used is acetone. The mixture obtained may be optionally distilled and degassed and treated with a suitable solvent as defined supra. Preferably, the suitable solvent used is a ketone solvent; more preferably the solvent used is acetone. In another embodiment, the reaction mass obtained may be then stirred, filtered and dried under vacuum at a temperature of about 50°C to about 65°C, preferably at a temperature of about 55°C to about 60°C to obtain a compound of formula (C). The compound of formula (C) obtained after step (b) has HPLC purity not less than 98.0%.
In one embodiment, the present invention provides process of purification of a compound of formula (C) comprising treating a compound of formula (C) with a halogenated solvent, followed by treatment with a ketone solvent.
In one embodiment, the present invention provides process of purification of a compound of formula (C) comprising treating a compound of formula (C) with dichloromethane and subsequent removal of dichloromethane, followed by treatment with acetone and subsequent removal of acetone.
In one embodiment, the present invention provides process of preparation of Dabigatran Etexilate Mesylate comprising purifying a compound of formula (C) by a process comprising treating a compound of formula (C) with a halogenated solvent, followed by treatment with a ketone solvent.
In one embodiment, the present invention provides process of preparation of Dabigatran Etexilate Mesylate comprising purifying a compound of formula (C) by a process comprising treating a compound of formula (C) with dichloromethane and subsequent removal of dichloromethane, followed by treatment with acetone and subsequent removal of acetone.
The present invention provides a process for preparation of Dabigatran Etexilate Mesylate intermediate, a compound of formula (C) comprising:

(a) reacting a compound of formula (A) with a compound of formula (B) in presence of a suitable solvent and a coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C), and
(b) purifying the compound of formula (C) obtained in step (a) by a process comprising treating the compound of formula (C) with a halogenated solvent; followed by treatment with a ketone solvent.
In one embodiment, the present invention provides a process for preparation of Dabigatran Etexilate Mesylate intermediate, a compound of formula (C) comprising:
(a) reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C); and
(b) purifying the compund of formula (C) obtained in step (a) by a process comprising treating a compound of formula (C) with dichloromethane, followed by treatment with acetone.
In one embodiment, the present invention provides a process for preparation of Dabigatran Etexilate Mesylate intermediate, a compound of formula (C) comprising:
(a) reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent at a temperature of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 70°C to about 75 °C to obtain a compound of formula (C); and
(b) purifying the compund of formula (C) obtained in step (a) by a process comprising treating a compound of formula (C) with dichloromethane and subsequent removal of dichloromethane, followed by treatment with acetone and subsequent removal of acetone.
In one embodiment, the present invention provides a process for preparation of Dabigatran Etexilate Mesylate, a compound of formula (I) comprising:

(a) reacting a compound of formula (A) with a compound of formula (B) in presence of a suitable solvent and a coupling agent and subsequent cyclization using oxalic acid to obtain a compound of formula (C); and
(b) purifying the compund of formula (C) obtained in step (a) by a process comprising treating a compound of formula (C) with a halogenated solvent; followed by treatment with a ketone solvent.
In one embodiment, the present invention provides a process for preparation of Dabigatran Etexilate Mesylate, a compound of formula (I) comprising:
(a) reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as a solvent and N,N'-carbonyldiimidazole as a coupling agent at a temperature of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 70°C to about 75 °C to obtain a compound of formula (C);and
(b) purifying the compund of formula (C) obtained in step (a) by a process comprising treating a compound of formula (C) with dichloromethane and subsequent removal of dichloromethane, followed by treatment with acetone and subsequent removal of acetone
In one embodiment, step (c) comprises converting a compound of formula (C) to a compound of formula (D).
In one embodiment, the step (c) comprises reacting a compound of formula (C) with alcoholic hydrochloric acid and subsequent addition of ammonium carbonate. Preferably, the alcoholic hydrochloric acid may be ethanolic hydrochloric acid. In one embodiment, the step (b) comprises reacting a compound of formula (C) with ethanolic hydrochloric acid to obtain a compound of formula (D). The reaction between a compound of formula (C) and ethanolic hydrochloric acid may be performed for about 18 hours to about 36 hours; preferably for about 24 hours to about 30 hours. After the completion of reaction, ethanol is removed under vacuum and the wet cake obtained may be treated with ethanol and ammonium carbonate at a temperature of about 5°C to about 25°C, preferably at a temperature of about 10°C to about 20°C, more preferably at a temperature of about 10°C

to about 15°C. The reaction mixture obtained may be stirred for about 12 hours to about 24 hours at a temperature of about 20°C to about 40°C; preferably for about 16 hours to about 20 hours at a temperature of about 25°C to about 35°C. The obtained reaction mass was filtered and washed with suitable solvent as defined supra. Preferably, the suitable solvent used is an alcoholic solvent; more preferably the solvent used is ethanol. The filtrate obtained may be concentrated under vacuum and treated with a suitable solvent as defined supra. Preferably, the suitable solvent used is a mixture of alcohol and an ester solvent. More preferably, the suitable solvent used is mixture of ethanol and ethyl acetate. The reaction mixture may be stirred at a temperature of about 5°C to about 25°C, preferably at a temperature of about 10°C to about 20°C for about 2 hours; preferably for about 1 hour. The product obtained may be filtered and washed with suitable solvent as defined supra. Preferably, the suitable solvent used is an ester solvent. More preferably, the suitable solvent used is ethyl acetate. In another embodiment, the product obtained may be further dried at a temperature of about 45°C to about 60°C, preferably at a temperature of about 40°C to about 50°C.
The process of step (c) as defined in prior art patent '380 involves the use of column chromatography for the purification of a compound of formula (D) while, the present invention as defined in step (c) gives desired quality and higher yield of a compound of formula (D) as compared to '380 patent, by using chemical processes known in the art and by avoiding expensive column chromatography. In one embodiment, the product obtained in step (c) may be purified by techniques known in the art such as crystallization, fractional crystallization, liquid-liquid extraction and the like.
In one embodiment, step (d) comprises converting a compound of formula (D) to Dabigatran Etexilate of formula (E). In one embodiment, step (d) comprises reacting a compound of formula (D) with n-hexyl chloroformate in presence of a suitable solvent and a suitable base.
In one embodiment, step (d) comprises cooling a mixture of a suitable base in a suitable solvent to a temperature of about 5°C to about 15°C; preferably, to a temperature of about 5°C to about 10°C. The solvent used is a mixture of ketone solvent and polar solvent and

a base used is an alkali metal carbonate. More preferably, the solvent used in the reaction is a mixture of acetone and water and the base used is potassium carbonate. To the reaction mass obtained, a compound of formula (D) and n-hexyl chloroformate in a suitable solvent, preferably in acetone, may be added. The obtained reaction mass may be further stirred for about 2 hours at a temperature of about 0°C to about 15°C; preferably for about 1 hour at a temperature of about 5°C to about 10°C. The reaction mass may be filtered and washed with water to obtain a wet cake. The wet cake obtained may be further treated with a suitable solvent as defined supra. Preferably, a suitable solvent used is a polar solvent; followed by a ketone solvent or a mixture thereof. More preferably, the solvent used is water; followed by treatment with acetone. The reaction mass may be further stirred for about 2 hours at a temperature of about 15°C to about 40°C, preferably for about 1 hour at a temperature of about 20°C to about 35°C. The obtained reaction mass may be filtered and washed with suitable solvent as defined supra. Preferably, the suitable solvent used for washing is a mixture of polar solvent and a ketone solvent; more preferably, the suitable solvent used for the washing is a mixture of water and acetone to obtain a wet cake.
In one embodiment, to the wet cake obtained, a suitable solvent and a suitable base may be added, as defined supra. Preferably, the suitable solvent used is a mixture of polar solvent and ketone solvent and suitable base used is an alkali metal carbonate; more preferably, the suitable solvent used is a mixture of acetone and water and suitable base used is sodium bicarbonate. The reaction mass may be further stirred at a temperature of about 35°C to about 40°C; cooled to a temperature of about 20°C to about 25°C and again stirred at a temperature of about 20°C to about 25°C for 1 about hour. Preferably, the reaction mass may be stirred at a temperature of about 25°C to about 30°C, cooled to a temperature of about 10°C to about 15°C and again stirred at a temperature of about 10°C to about 15°C. The solid obtained may be filtered and washed with a suitable solvent as defined supra. Preferably, the suitable solvent used for washing is water. The obtained wet cake may be further treated with water, optionally under stirring, at a temperature of about 20°C to about 35°C for about 1 hour; preferably at a temperature of about 25°C to about 30°C for about thirty minutes. The reaction mass obtained may be further treated, under stirring, with a halogenated solvent as defined supra. Preferably, the halogenated solvent used is dichloromethane.

In one embodiment, the organic layer may be separated and concentrated. To the obtained solid, a suitable solvent, as defined supra, may be added and heated at a temperature of about 55°C to about 80°C, preferably at a temperature of about 60°C to about 75°C and more preferably at a temperature of about 65°C to about 70°C to get a clear solution. Preferably, the suitable solvent used is an ester solvent. More preferably, the solvent used is ethyl acetate. The reaction mass obtained may be then cooled and stirred at a temperature of about 15°C to about 45°C for about 120 minutes, preferably at a temperature of about 20°C to about 35°C for about 90 minutes and more preferably at a temperature of about 25°C to about 30°C for about 60 minutes. The product obtained may be further filtered to obtain Dabigatran Etexilate, a compound of formula (E).
The process of step (d) as defined in prior art patent '380 involves use of hazardous tetrahydrofuran for the completion of reaction, whereas the present invention involves use of acetone which is safer with respect to toxicity and fire hazards. Also, the process of purification of Dabigatran Etexilate as defined in prior art patent '380 involves the extraction of product in dichloromethane and purification using expensive column chromatography, whereas, in the present invention, the product is isolated using filtration method and purified by chemical processes as defined supra.
In one embodiment, step (e) comprises converting Dabigatran Etexilate of formula (E) to Dabigatran Etexilate Mesylate of formula (I).
In one embodiment, step (e) comprises reacting Dabigatran Etexilate of formula (E) with a suitable solvent, as defined supra, at a temperature of about 20°C to about 40°C; preferably at a temperature of about 25°C to about 35°C. The solvent used for the reaction is a ketone solvent, more preferably, the solvent used is acetone. To the obtained reaction mass, methane sulfonic acid may be added, under stirring, in presence of suitable solvent at a temperature of about 20°C to about 40°C; preferably at a temperature about 25°C to about 35°C. The reaction mass may be cooled to a temperature of about 10°C to about 25°C; preferably to a temperature about 15°C to about 20°C and stirred for about 60 minutes to about 120 minutes.

After the completion of above reaction in step (e), suitable work up may be performed, as known to a skilled artisan and the product obtained may be filtered and washed with a suitable solvent as defined supra. The suitable solvent used is a ketone solvent, preferably the suitable solvent used is acetone. In one embodiment, to the wet cake obtained, a suitable solvent may be added as defined supra, under stirring, at a temperature of about 20°C to about 35°C; preferably at a temperature of 20°C to about 30°C. The suitable solvent used is a ketone solvent, preferably the suitable solvent used is acetone. The product obtained may be filtered and dried at a temperature of about 35°C to about 55°C; preferably at a temperature of about 40°C to about 50°C to obtain Dabigatran Etexilate Mesylate, a compound of formula (I).
In one embodiment, the present invention provides a process for preparation of Dabigatran Etexilate Mesylate, a compound of formula (I), comprising
(a) reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as solvent and N,N'-carbonyldiimidazole as coupling agent, and subsequent cyclization using oxalic acid to obtain a compound of formula (C);

(b) purifying the compound of formula (C) obtained in step (a) by treating the compound of formula (c) obtained in step (a) with a dichloromethane, followed by treatment with acetone;
(c) converting the compound of formula (C) to a compound of formula (D);
(d) converting the compound of formula (D) obtained in step (c) to Dabigatran Etexilate, a compound of formula (E); and

(e) converting Dabigatran Etexilate, the compound of formula (E) to Dabigatran Etexilate Mesylate, a compound of formula (I).
In one embodiment, the present invention provides a process for preparation of Dabigatran Etexilate Mesylate, a compound of formula (I), comprising
(a) reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as solvent and N,N'-carbonyldiimidazole as a coupling agent at a

temperature of about 15°C to about 40°C, preferably at a temperature of about 20°C to about 35°C, more preferably at a temperature of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 60°C to about 85°C, preferably at a temperature of about 65°C to about 80°C, more preferably at a temperature of about 70°C to about 75°C to obtain a compound of formula (C);
(b) purifying the compund of formula (C) obtained in step (a) by a process comprising treating a compound of formula (C) with dichloromethane and subsequent removal of dichloromethane, followed by treatment with acetone and subsequent removal of acetonc.
(c) converting the compound of formula (C) to a compound of formula (D);
(d) converting the compound of formula (D) obtained in step (c) to Dabigatran Etexilate, a compound of formula (E); and
(e) converting Dabigatran Etexilate, the compound of formula (E) to Dabigatran Etexilate Mesylate, a compound of formula (I).
In one embodiment, the present invention provides a process for preparation of Dabigatran Etexilate Mesylate, a compound of formula (I), comprising
(a) reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate as solvent and N,N'-carbonyldiimidazole as a coupling agent at a temperature of about 25°C to about 30°C, and subsequent cyclization using oxalic acid at a temperature of about 70°C to about 75 °C to obtain a compound of formula (C);
(b) purifying the compund of formula (C) obtained in step (a) by a process comprising treating a compound of formula (C) with dichloromethane and subsequent removal

of dichloromethane, followed by treatment with acetone and subsequent removal of acetone.
(c) converting the compound of formula (C) to a compound of formula (D);
(d) converting the compound of formula (D) obtained in step (c) to Dabigatran Etexilate, a compound of formula (E); and
(e) converting Dabigatran Etexilate, the compound of formula (E) to Dabigatran Etexilate Mesylate, a compound of formula (I).
The present invention is explained in detail by referring to examples, which are not to be construed as limitative.
Example-1: Preparation of l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5- yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyI)-amide
38.5 gm of (0.218 mol) N-(4-cyanophenyl)-glycine was added to 500 ml of ethyl acetate and stirred for about at about 25 to 30°C. To the reaction mass, was added 42.5 gm of (0.262 mol) N,N'-carbonyldiimidazole and stirred for about 2 to 3 hours at 25 to 30°C. After completion of reaction, 50 g of (0.146 mol) 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide was added to the reaction mass and stirred the reaction mass overnight at about 25 to 30°C. On completion of this reaction, 125 ml of water was added, stirred and the layers were separated. The organic layer was then washed with 125 ml water and 50 gm of (0.555 mol) oxalic acid was added to the organic layer; followed by heating the same to about 70 to 75°C. On completion of the reaction, the reaction mass was cooled to aboutlO to 20°C. The reaction mass was then filtered and washed with ethyl acetate; followed by addition of water to the wet cake. The pH of the obtained reaction mass was adjusted to 7-8 with sodium bicarbonate solution. The reaction mass was then stirred and the solids were filtered.
Example-2: Purification of l-Methyl-2-[N-(4-cyanophenyI)-aminomethyl]-benzimidazoI-5- yl-carboxylic acid-N-(2-pyridyI)-N-(2-ethoxycarbonylethyl)-amide

To the wet cake obtained in Example-1, 500 ml of dichloromethane was added; followed by stirring and separation of layers. The obtained organic layer was concentrated under vacuum to dryness; acetone was added to this and distilled under vacuum and acetone was added to the the degassed mass. The reaction mass was then again stirred at about 10 to 15 °C for about 1 hour, filtered and the product was dried under vacuum at 55 to 60 °C to get l-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5- yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. (Yield: 65 gm and HPLC Purity: NLT 98%)
ExampIe-3: Preparation of l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-
benzimidazol-5-yl-carboxyIicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyI)-amide-
hydrochloride
The solid residue obtained in Example-2 was added to 750 ml of 30% ethanolic hydrochloric acid and stirred for about 24 hours. After completion of reaction, ethanol was removed under vacuum. To the reaction mass, was added 500 ml of fresh ethanol and 100 g of ammonium carbonate at about 10 to 15°C; followed by stirring for about 16 to 18 hours at about 25 to 30°C. The solid obtained was then filtered, washed with ethanol and the filtrate was concentrated under vacuum. The residue was further charged with 250 ml ethanol and 500 ml ethyl acetate. The reaction mass was stirred, filtered, washed the product with ethyl acetate and dried at about 45 to 50°C to get l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride. (Yield: 37.5 gm and HPLC Purity: NLT 93%)
Example-4: Preparation of l-Methyl-2-[N-[4-(N-n-
hexyloxycarbonyIamidino)phenyl]-aminomethyl]-benzimidazoI-5-yl-carboxyIic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (Dabigatran Etexilate)
The reaction mass of 629 ml acetone, 370 ml water and 30.46 g of (0.22 mol) potassium
carbonate was stirred at about 25 to 30°C, cooled to about 5 to 10°C and 37 g of (0.074
mol) l-Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-
carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride was added to it. 18.10 g of (0.110 mol) n- Hexyl chlorofaormate in 37 ml acetone was added. The reaction mass was stirred at about 5 to 10°C for about 1 hour, filtered and washed with

water. Water and acetone were added to the wet cake obtained, followed by stirring at about 25 to 30° for aboutl hour and filtration. The filtrate obtained was further washed with acetone and water mixture.
The residue as obtained above, was added to 370 ml water, 370 ml acetone, 21 g (0.25 mol) sodium bicarbonate and stirred at about 25 to 30°C. The reaction mass was further cooled to about 10 to 15°C and stirred at about 10 to 15°C for about 30 minutes. The solids obtained were then filtered, washed with water, stirred with water for about 30 minutes at about 25 to 30°C and filtered. Dichloromethane was added to the residue obtained, the reaction mass was stirred and layers were separated. The dichloromethane layer was further concentrated to get a white solid. To the white solid, ethyl acetate was added and heated to about 65 to 70°C to get a clear solution. The reaction mass was cooled to about 25 to 30°C, stirred at same temperature for about 1 hour and filtered to obtain Dabigatran Etexilate. (Yield: 33.5 gm and HPLC Purity: NLT 99%)
Example-5: Preparation of Dabigatran Etexilate Mesylate
To the 33 g of (0.053 mol) Dabigatran Etexilate, 660 ml of acetone was added at about 25 to 30°C followed by drop wise addition of 5.05 g of (0.053 mol) methane sulphonic acid in 5 ml acetone at about 25 to 30°C. The reaction mixture was stirred at about 25 to 30°C for about 1 hour and cooled to about 15 to 20°C The product was then filtered and washed with of acetone. 165 ml of acetone was added to the wet cake obtained; followed by stirring for about 1 hour at about 25 to 30°C. The product was filtered and dried at about 45 to 50°C to get Dabigatran Etexilate Mesylate. (Yield: 35 gm and HPLC Purity: NLT 99%)

We claim:
1. A process for preparation of Dabigatran Etexilate Mesylate, a compund of formula (I), comprising:
(a) reacting a compound of formula (A) with a compound of formula (B) in presence of a suitable solvent and a coupling agent and subsequent cyclization using oxalic acid to obtain a compound of formula (C);
(b) purifying the compound of formula (C) obtained in step (a);
(c) converting the compound of formula (C) to a compound of formula (D);
(d) converting the compound of formula (D) obtained in step (c) to Dabigatran Etexilate, a compound of formula (E); and

(e) converting Dabigatran Etexilate, the compound of formula (E) to Dabigatran Etexilate Mesylate, a compound of formula (I).
2. A process according to claim 1, wherein the suitable solvent used in step (a) is an ester solvent.
3. A process according to claim 1, wherein step (b) comprises treating a compound of formula (C) with a halogenated solvent, followed by treatment with a ketone solvent.
4. A process for purification of a compound of formula (C) comprising treating a compound of formula (C) with a halogenated solvent, followed by treatment with a ketone solvent.
5. A process according to claim 4, wherein the halogenated solvent used is dichloromethane and ketone solvent used is acetone.
6. A process for preparation of a compound of formula (C) comprising:

(a) reacting a compound of formula (A) with a compound of formula (B) in presence of a suitable solvent and a coupling agent and subsequent cyclization using oxalic acid to obtain a compound of formula (C) and
(b) purifying the compund of formula (C) by a process comprising treating a compound of formula (C) with a halogenated solvent; followed by treatment with a ketone solvent.

7. A process according to claim 6, wherein the suitable solvent used in step (a) is ethyl acetate.
8. A process according to claim 6, wherein in step (b), the halogenated solvent used is dichloromethane and the ketone solvent used is acetone.
9. A process for preparation of Dabigatran Etexilate Mesylate comprising purifying a compound of formula (C) by a process comprising treating a compound of formula (C) with dichloromethane; followed by treatment with acetone.
10. A process for preparation of Dabigatran Etexilate Mesylate, a compund of formula (I), comprising;

(a) reacting a compound of formula (A) with a compound of formula (B) in presence of ethyl acetate and N,N'-carbonyldiimidazole and subsequent cyclization using oxalic acid to obtain a compound of formula (C);
(b) purifying the compound of formula (C) obtained in step (a) by a process comprising treating a compound of formula (C) with dichloromethane; followed by treatment with acetone;
(c) converting the compound of formula (C) to a compound of formula (D);
(d) converting the compound of formula (D) obtained in step (c) to Dabigatran Etexilate, a compound of formula (E) and;

(e) converting Dabigatran Etexilate, the compound of formula (E) to Dabigatran Etexilate Mesylate, a compound of formula (I).