Field of the Invention:

The present invention relates to method for purification of Dabigatran etexilate mesylate. Dabigatran etexilate mesylate is chemically known as l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide methanesulfonate represented by the following structural formula-1

Formula-1

Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors developed by Boehringer Ingelheim. Dabigatran etexilalte mesylate was approved by both in US and Europe and commercially available under the brand name of Pradaxa.

Background of the Invention:

Dabigatran and process for its preparation was first disclosed in WO 98/37075. The disclosed process involves the reaction of l-methyl-2-[N-[4-amidino phenyl] aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide hydrochloride with hexyl chloroformate in presence of potassium carbonate in tetrahydrofuran/water provides dabigatran etexilate and further conversion to mesylate salt is not disclosed. The purity of dabigatran etexilate prepared as per the disclosed process is not satisfactory, further it involves chromatographic purification. Hence this process was not suitable for commercial scale.

The process for the preparation of mesylate salt of dabigatran etexilate and its polymorphic forms was disclosed in US 2005/234104. The disclosed process involves the reaction of dabigatran etexilate with methane sulphonic acid in actone to provide dabigatran etexilate mesylate. The purity of the obtained crystalline dabigatran etexilate mesylate was not satisfactory i.e., around 97-98% by HPLC. There is no specific purification process disclosed for the purification of dabigatran etexilate mesylate.

It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself, or during the preparation of the API. Impurities in dabigatran or any active pharmaceutical ingredient (API) are undesirable and might be harmful. Regulatory authorities worldwide require that drug manufactures isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels, even if structural determination is not possible.

The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the active pharmaceutical ingredient, the product must be analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. Purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities limited to less than 0.1 percent.

Generally, impurities are identified by their spectral/analytical data and by other physical methods, and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention time" ("RT"). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use "relative retention time" ("RRT") to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.

So far there is no specific purification process disclosed for dabigatran etexilate mesylate in the art. Dabigatran etexilate mesylate is an important pharmaceutical drug used as anticoagulant. Hence it is necessary to obtain the same in high purity level by possibly identifying the impurities formed during the process and storage as well as developing a purification process to removing those impurities.

Dabigatran etexilate mesylate as prepared by the prior art processes may contain (E)-2-(N-(3-ethoxy-3-oxopropyl)-2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenyl amino)methyl)-1 -methyl-1H-benzo[d]imidazole-5-carboxamido)pyridine-1 -oxide (herein designated as "N-oxide impurity"); (E)-3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl) phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido) propanoic acid (herein designated as "Acid impurity") as impurities and represented by the following structural formula

N-oxide impurity

Other than the above impurities, two more impurities are observed in HPLC at 0.845 RRT and 1.278 RRT respectively. The impurity at 0.845 RRT is herein designated as impurity X and impurity at 1.278 RRT is herein designated as Impurity-Y. In the present invention N-oxide and acid impurities were isolated and characterized.

The main aspect of the present invention is to provide a purification method for dabigatran etexilate mesylate as well as the isolation, characterization and synthesis of impurities formed in the preparation of dabigatran etexilate and its salts.

Brief Description of the Invention:

The first aspect of the present invention is to provide (E)-2-(N-(3-ethoxy-3-oxopropyl)-2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-l-methyl-lH-benzo[d]imidazole-5-carboxamido)pyridine-l-oxide (N-oxide impurity) and (E)-3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido) propanoic acid (Acid impurity). The present inventors detected, isolated and characterized the said impurities which were observed in the preparation of dabigatran etexilate mesylate.

The second aspect of the present invention is to provide a purification process for dabigatran etexilate mesylate compound of formula-1, which comprises of the following steps,

a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in a suitable solvent by heating,
b) subjecting the reaction mixture to carbon treatment,

c) filtering the reaction mixture,
d) cooling the reaction mixture and stirring,
e) filtering off the obtained solid and washed with suitable solvent,
f) drying the solid to obtain pure compound of formula-1.

The third aspect of the present invention is to provide a purification process for dabigatran etexilate mesylate compound of formula-1, which comprises of the following steps,

a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in a suitable solvent at suitable temperature,
b) optionally subjecting the solution to carbon treatment,
c) adding suitable anti-solvent to precipitate the product,
d) filtering off the obtained solid and washed with suitable solvent,
e) drying the solid to obtain pure compound of formula-1.

The fourth aspect of the present invention is to provide an improved process for the preparation of highly pure dabigatran etexilate mesylate compound of formula-1, which comprises of the following steps,

a) Reacting ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate para toluene sulfonate compound of formula-3 with hexyl chloroformate in presence of a base in a suitable solvent provides 1 -methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminome thyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide compound of formula-2,
b) treating the compound of formula-2 with methane sulfonic acid in a suitable solvent to provide the compound of formula-1,
c) dissolving the obtained compound of formula-1 in a suitable solvent by heating,
d) subjecting the reaction mixture to carbon treatment,
e) filtering the reaction mixture,
f) cooling the reaction mixture and stirring,
g) filtering off the obtained solid and washed with suitable solvent,
h) drying the solid to obtain highly pure compound of formula-1.

Brief Description of the Drawings:

Figure-1: Powder X-ray diffraction pattern of dabigatran etexilate mesylate obtained as per the present invention

Figure-2: DSC chromatogram of dabigatran etexilate mesylate obtained as per the present invention

Detailed Description of the Invention:

As used herein the present invention the term "suitable solvents" refers to solvents selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like methylene chloride, chloroform and ethylene dichloride; "nitrile solvents" like acetonitrile and propionitrile; polar solvents like water; and mixtures thereof.

As used herein the present invention the term "suitable bases" refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures there of.

The first aspect of the present invention provides (E)-2-(N-(3-ethoxy-3-oxopropyl)-2-((4-(N,-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-l-methyl-lH-benzo[d]imidazole-5-carboxamido)pyridine-l-oxide (N-oxide impurity) and (E)-3-(2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoic acid (Acid impurity), compounds, which were observed in the synthesis of dabigatran and its pharmaceutically acceptable salts. The N-oxide and acid impurities are represented by the following structural formulas

N-oxide impurity

Acid impurity

The N-Oxide and acid impurities of the present invention are characterized by NMR, IR and Mass spectral data.

The N-oxide impurity was prepared by reacting dabigatran etexilate with a suitable oxidizing agent like hydrogen peroxide in a suitable solvent. The said impurity was observed at 1.118 RRT in HPLC.

The acid impurity was prepared by hydrolyzing the dabigatran etexilate with a suitable milder base in a suitable solvent. The said impurity was observed at 0.477 RRT in HPLC.

In addition to the above impurities, the dabigatran etexilate and its salts prepared by the prior art processes contain two more impurities which are observed in HPLC at 0.845 RRT (Impurity-X) and 1.278 RRT (Impurity-Y) respectively. The impurity at 0.845

RRT is having mass m/z value of 655 as characterized by LC-MS (Liquid chromatography-mass spectrum) analysis.

The second aspect of the present invention provides a purification process for dabigatran etexilate mesylate compound of formula-1, which comprises of the following steps,

a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in a suitable solvent selected from ketone, alcohols, ester solvent or mixtures thereof by heating,
b) subjecting the reaction mixture to carbon treatment,
c) filtering the reaction mixture,
d) cooling the filtrate and stirring,
e) filtering off the obtained solid and washed with suitable solvent as said in step-a,
f) drying the solid to obtain pure dabigatran etexilate mesylate compound of formula-1.

In a preferred embodiment of the present invention, the process for the purification of dabigatran etexilate mesylate compound of formula-1 comprises of,

a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in a mixture of methanol and acetone at 50-55°C,
b) subjecting the reaction mixture to carbon treatment,
c) filtering the reaction mixture,
d) cooling the reaction mixture to 20-25°C and stirring,
e) cooling the reaction mixture to 0-5°C and stirring,
f) filtering off the obtained solid and washed with of acetone,
g) drying the solid to obtain pure dabigatran etexilate mesylate compound of formula-1.

The third aspect of the present invention provides a purification process for dabigatran etexilate mesylate compound of formula-1, which comprises of the following steps,

a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in a suitable alcohol solvent at suitable temperature,
b) optionally subjecting the reaction mixture to carbon treatment,
c) adding suitable anti-solvent selected from ester solvent or ketone solvent to precipitate the product,
d) filtering off the obtained solid and washed with suitable ketone solvent or ester solvent,
e) drying the solid to obtain pure compound of formula-1.

In a preferred embodiment of the present invention, the process for the purification of dabigatran etexilate mesylate compound of formula-1 comprises of,

a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in methanol at 25-30°C,
b) subjecting the reaction mixture to carbon treatment,
c) filtering the reaction mixture,
d) adding acetone to the obtained filtrate,
e) cooling the reaction mixture to 0-5 °C and stirring,
f) filtering off the obtained solid and washed with of acetone,
g) drying the solid to obtain pure dabigatran etexilate mesylate compound of formula-1.

The dabigatran etexilate mesylate compound of formula-1 prepared as per the prior art process having purity around 97-98% and containing impurities such as N-oxide in the range of 1-1.5%, acid impurity in the range of 1-1.5%, Impurity-X and Y in the range of 0.2 -0.8% respectively by HPLC. The said impurities are washed out, even to not detectable level by HPLC by purifying the dabigatran etexilate mesylate compound of formula-1 by the present invention purification process.

The fourth aspect of the present invention provides a process for the preparation of Dabigatran etexilate mesylate compound of formula-1, which comprises of the following steps, a) Reacting ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate paratoluene sulfonate
compound of formula-3,

Formula-3 with hexyl chloroformate in presence of a suitable base in a suitable solvent provides 1 -methyl-2- [N- [4-(N-n-hexyloxycarbonylamidino)phenyl] aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide compound of formula-2,

Formula-2

b) treating the compound of formula-2 with methane sulfonic acid in a suitable solvent to provide the dabigatran etexilate mesylate compound of formula-1,
c) dissolving the obtained compound of formula-1 in a suitable solvent by heating,
d) subjecting the reaction mixture to carbon treatment,
e) filtering the reaction mixture,
f) cooling the reaction mixture and stirring,
g) filtering off the obtained solid and washed with suitable solvent,
h) drying the solid to obtain highly pure dabigatran etexilate mesylate compound of formula-1.

Dabigatran etexilate mesylate prepared as per the present invention is having purity greater than 99.50% by HPLC; preferably 99.75%; more preferably 99.95% by HPLC.

Dabigatran etexilate mesylate prepared as per the present invention containing less than 0.05% of impurity-X and Impurity-Y; preferably less than 0.01% by HPLC.

Dabigatran etexilate mesylate prepared as per the present invention containing less than 0.1% of "acid impurity" and "N-oxide impurity" by HPLC; preferably less than 0.05% by HPLC; more preferably less than 0.01% by HPLC.

Dabigatran etexilate mesylate prepared as per the present invention is substantially free of acid and N-Oxide impurities.

Dabigatran etexilate mesylate of the present invention can be further micronized or milled to get the desired particle size.

Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, with out limitation, ball, roller and hammer mills, and jet mills.

The related substances of dabigatran etexilate mesylate measured using HPLC with the following chromatographic conditions: Column: Inertsil C-8 (150x4.6 mm, 5 μ) or equivalent column. Other parameters of the method are as shown in the following table.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples: Reference Example:

a) Preparation of dabigatran etexilate:

55 g of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide tosylate was dissolved in 437 mL of acetone and 273 mL of water. 16.4 g of hexyl chloroformate and 34 g of potassium carbonate was added to it at a temperature of about 15° C. After the end of the reaction, the precipitated product is filtered off and washed with acetone/water. Dissolved the obtained solid in 270 ml of acetone under heating and then filtered. The title product was crystallized by the addition of 220 mL of water. The isolated substance is dried under reduced pressure at 45° C. Yield: 44 grams

b) Preparation of dabigatran etexilate mesylate:

100 g of l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide was dissolved in 890 mL of acetone under heating. A solution of 15 g of methanesulfonic acid in 200 mL of acetone was added to the reaction mixture. The solution is filtered and after the addition of 77 mL of acetone cooled to approximately 20° C. The precipitated product was filtered and washed with acetone then dried at 50° C under reduced pressure. Yield: 105 grams Purity by HPLC: 97.41%; Acid impurity: 1.04%; N-Oxide impurity: 1.16%; Impurity-X: 0.12%; Impurity-Y: 0.11%;

Example-1: Preparation of dabigatran etexilate mesylate compound of formula-1:

Potassium carbonate (24.7 grams) was added to a solution of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide tosylate (40 grams) in acetone (318 ml) and water (198.5 ml) at 20-25°C and stirred for 15 minutes. Cooled the reaction mixture to 5-10°C and hexyl chloroformate (11.9 grams) was added to it then stirred for 30 minutes at 10-15°C. Filtered the precipitated product and washed with acetone/water mixture. The obtained solid was dissolved in approximately 180 mL of acetone and stirred the reaction mixture for 15 min at reflux temperature. Cooled the reaction mixture to 25-30°C, added of water (175 ml) and stirred for 45 minutes. Filtered the precipitated solid and washed with acetone/water mixture. Acetone (267 ml) was added to the obtained solid and heated the reaction mixture to 50-55°C. Methanesulfonic acid (4.5 grams) in acetone (60 ml) was added to the reaction mixture at 50-55°C. The reaction mixture was subjected to carbon treatment and stirred for 30 minutes at 50-55°C. The reaction mixture was filtered through hyflow and the filtrate was cooled to 25-30°C and stirred for 45 minutes. Filtered the precipitated solid and washed with acetone. The obtained dabigatran etexilate mesylate was dissolved in a mixture of acetone (245 ml) and methanol (70 ml) at 50-55°C. The reaction mixture was subjected to carbon treatment. The reaction mixture was cooled to 25-30°C and stirred for 45 minutes. Cooled the reaction mixture to 0-5°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid and washed with acetone and dried the material to get the highly pure title compound. Yield: 28 grams

Purity by HPLC: 99.84%; Acid impurity: Not detected; N-Oxide impurity: Not detected; Impurity-X: 0.01%; Impurity-Y: 0.01%.

Example-2: Purification of dabigatran etexilate mesylate compound of formula-1:

A mixture of dabigatran etexilate mesylate (35 grams) obtained as per reference example, acetone (245 ml) and methanol (70 ml) was heated to reflux temperature. Carbon (3.5 grams) was added and stirred for 30 minutes. Filtered the reaction mixture through hyflow and the filtrate was cooled to 25-3 0°C then stirred for 45 minutes. Further cooled the reaction mixture to 0-5°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid and washed with acetone and then dried the material to get the highly pure title compound. Yield: 27 grams

Purity by HPLC: 99.90%; Acid impurity: Not detected; N-Oxide impurity: Not detected; Impurity-X: 0.01%; Impurity-Y: 0.01%.

Example-3: Purification of dabigatran etexilate mesylate compound of formula-1:

A mixture of dabigatran etexilate mesylate (35 grams) obtained as per reference example, acetone (245 ml) and ethanol (90 ml) was heated to reflux temperature. Carbon (3.5 grams) was added and stirred for 30 minutes. Filtered the reaction mixture through hyflow and the filtrate was cooled to 25-3 0°C then stirred for 45 minutes. Further cooled the reaction mixture to 0-5°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid and washed with acetone and then dried the material to get the highly pure title compound. Yield: 25 grams

Purity by HPLC: 99.83%; Acid impurity: 0.01%; N-Oxide impurity: 0.02%; Impurity-X: 0.03%; Impurity-Y: 0.02%.

Example-4: Purification of dabigatran etexilate mesylate compound of formula-1:

Dabigatran etexilate mesylate (25 grams) obtained as per reference example was dissolved in methanol (75 ml) at 25-30°C. Carbon (3.5 grams) was added and stirred for 30 minutes. Filtered the reaction mixture through hyflow. Acetone (200 ml) was added to the filtrate and stirred for 45 minutes. Filtered the precipitated solid and washed with acetone and then dried the material to get the highly pure title compound. Yield: 17.1 grams

Purity by HPLC: 99.73%; Acid impurity: 0.01%; N-Oxide impurity: 0.015%; Impurity-X: 0.025%; Impurity-Y: 0.02%.

Example-5: Purification of dabigatran etexilate mesylate compound of formula-1:

Dabigatran etexilate mesylate (25 grams) obtained as per reference example was dissolved in methanol (75 ml) at 25-30°C. Carbon (3.5 grams) was added and stirred for 30 minutes. Filtered the reaction mixture through hyflow. Methylisobutylketone (200 ml) was added to the filtrate and stirred for 45 minutes. Filtered the precipitated solid and washed with methylisobutylketone and then dried the material to get the highly pure title compound. Yield: 16.6 grams

Example-6: Purification of dabigatran etexilate mesylate compound of formula-1:

Dabigatran etexilate mesylate (25 grams) obtained as per reference example was dissolved in ethanol (95 ml) at 25-30°C. Carbon (3.5 grams) was added and stirred for 30 minutes. Filtered the reaction mixture through hyflowbed. Ethylacetate(200 ml) was added to the filtrate and stirred for 45 minutes. Filtered the precipitated solid and washed with acetone and then dried the material to get the highly pure title compound. Yield: 17 grams

Example-7: Process for the preparation of N-oxide impurity:

Hydrogen peroxide solution (50%) (20 ml) was added to a solution of l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide (5 grams) in methanol (30 ml). The reaction mixture was stirred for 24 hours at 25-30°C. Quenched the reaction mixture with 10% aqueous sodium sulfite solution and stirred for 15 minutes. Methyl tertiary butyl ether was added to the reaction mixture and separated the both aqueous and organic layers. The solvent from the organic layer was evaporated to get the title compound. Yield: 2.3 grams; Mass m/z: 644

We claim:

1. (E)-2-(N-(3-ethoxy-3-oxopropyl)-2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl) phenylamino)methyl)-1-methyl-1 H-benzo[d]imidazole-5-carboxamido)pyridine-1 -oxide compound represented by the following structural formula

2. A purification process for dabigatran etexilate mesylate compound of formula-1,
which comprises of the following steps,

a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in a suitable solvent selected from ketone solvents, alcohol solvents, ester solvents or mixtures thereof by heating,
b) subjecting the reaction mixture to carbon treatment,
c) filtering the reaction mixture,
d) cooling the reaction mixture and stirring,
e) filtering off the obtained solid and washing with suitable solvent as said in step-a,
f) drying the solid to obtain pure dabigatran etexilate mesylate compound of formula-1.
3. A process for the purification of dabigatran etexilate mesylate compound of
formula-1, which comprises of,
a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in a mixture
of methanol and acetone at 50-55°C,
b) subjecting the reaction mixture to carbon treatment,
c) filtering the reaction mixture,

d) cooling the reaction mixture to 20-25°C and stirring,
e) cooling the reaction mixture to 0-5 °C and stirring,
f) filtering off the obtained solid and washed with acetone,
g) drying the solid to obtain pure dabigatran etexilate mesylate compound of formula-1.

4. A purification process for dabigatran etexilate mesylate compound of formula-1,
which comprises of the following steps,

a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in a suitable alcohol solvent at a suitable temperature,
b) optionally subjecting the reaction mixture to carbon treatment,
c) adding suitable anti-solvent selected from ester solvent or ketone solvent to precipitate the product,
d) filtering off the obtained solid and washed with suitable ketone solvent or ester solvent,
e) drying the solid to obtain pure compound of formula-1.

5. A process for the purification of dabigatran etexilate mesylate compound of
formula-1, which comprises of,
a) Dissolving the dabigatran etexilate mesylate compound of formula-1 in methanol at 25-30°C,
b) subjecting the reaction mixture to carbon treatment,
c) filtering the reaction mixture,
d) adding acetone to the above reaction mixture,
e) cooling the reaction mixture to 0-5 °C and stirring,
f) filtering off the obtained solid and washed with of acetone,
g) drying the solid to obtain pure dabigatran etexilate mesylate compound of formula-1.

6. An improved process for the preparation of highly pure Dabigatran etexilate mesylate compound of formula-1, which comprises of the following steps,

a) Reacting ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-
(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate para toluene
sulfonate compound of formula-3, Formula-3 with hexyl chloroformate in presence of suitable base in a suitable solvent provides 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2,

Formula-2

b) treating the compound of formula-2 with methane sulfonic acid in a suitable solvent to provide the dabigatran etexilate mesylate compound of formula-1,
c) dissolving the obtained compound of formula-1 in a suitable solvent by heating,
d) subjecting the reaction mixture to carbon treatment,
e) filtering the reaction mixture,
f) cooling the reaction mixture and stirring,

g) filtering off the obtained solid and washed with suitable solvent, h) drying the solid to obtain highly pure dabigatran etexilate mesylate compound of formula-1.

7. Dabigatran etexilate mesylate is having purity greater than 99.50% by HPLC; preferably 99.75%; more preferably 99.95% by HPLC.

8. Dabigatran etexilate mesylate containing less than 0.05% of impurity-X and Impurity-Y; preferably less than 0.01% by HPLC.

9. Dabigatran etexilate mesylate containing less than 0.1% of "acid impurity" and "N-oxide impurity" by HPLC; preferably less than 0.05% by HPLC; more preferably less than 0.01% by HPLC.

10. Dabigatran etexilate mesylate substantially free of acid impurity and N-Oxide impurity.