Field of Invention:

The present invention relates to an improved process for the preparation of 1-methyl-2- [N- [4-(N-n-hexyloxycarbonylamidino)phenyl] aminomethyl]benzimidazol-5 -yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amidemethanesulfonate, represented by the structural formula-1. Further, the present invention also provides a novel salts of l-methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide, preferably oxalate salt, represented by the structural formula-3a, an useful intermediate in the synthesis of highly pure compound of formula-1.

Formula-1 Formula-3 a

Background of the Invention:

Dabigatran etexilate and process for its preparation was first disclosed in WO 98/37075. The disclosed process involves the reaction of l-methyl-2-[N-[4-amidinophenyl] aminomethyl]benzimidazol-5-yl carboxylicacid-N-(2-pyridyl)- N-(2-ethoxycarbonylethyl) amide hydrochloride (herein after referred as dabigatran hydrochloride) with hexylchloroformate in presence of potassium carbonate in tetrahydrofuran/water provides 1 -methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonylethyl)amide and further conversion to mesylate salt is not disclosed. The purity & yield of dabigatran etexilate prepared as per the disclosed process is not satisfactory and also the said process involves chromatographic purification. As the chromatographic purification is expensive and difficult to implement in the large scale, hence the said process is not suitable for commercial scale up.

Moreover, the said process involves the usage of dabigatran hydrochloride, which degrades to form impurities and results in the formation of dabigatran etexilate with low purity. In view of intrinsic fragility of dabigatran hydrochloride, there is a need in the art to develop a stable salt form of l-methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide, which enhances the purity of the final compound i.e., dabigatran etexilate.

The process for the preparation of mesylate salt of dabigatran etexilate was disclosed in US 2005/234104. The disclosed process involves the reaction of dabigatran etexilate with methane sulphonic acid in acetone 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

Hence there is a need in the art, to provide an improved process for the preparation of dabigatran etexilate mesylate with a high purity and yield.

Brief Description of the Invention:

The main object of the present invention is to provide an improved process for the preparation of dabigatran etexilate mesylate compound of formula-1 in pure form, which ameliorates the problems of the prior art. The process of the present invention is simple, operates in moderate reaction conditions, yields highly pure dabigatran etexilate mesylate compound of formula-1.

The first aspect of the present invention is to provide the novel acid addition salts of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of general formula-3, as intermediates for preparing dabigatran etexilate compound of formula-4 or its pharmaceutically acceptable salt, preferably its mesylate salt compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation ofcompound of general formula-3.

The third aspect of the present invention is to provide a novel crystalline form of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a, herein designated as crystalline form-M.

The fourth aspect of the present invention is to provide a process for the purification of 1 -methyl-2-[N-[4-aniidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a.

The fifth aspect of the present invention is to provide a novel process for the preparation of crystalline form-I of dabigatran etexilate mesylate compound of formula-1.

The sixth aspect of the present invention is to provide an improved process for the preparation of dabigatran etexilate mesylate compound of formula-1.

Brief description of Drawings:

Figure-1: Illustrates the powder X-ray diffraction of crystalline form-M of l-methyl-2-
[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-
(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a.

Figure-2: Illustrates the DSC thermogram of crystalline form-M of l-methyl-2-[N-[4-
amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-
ethoxycarbonylethyl)amide oxalate compound of formula-3a.

Figure-3: Illustrates the powder X-ray diffraction of crystalline form-I of Dabigatran
etexilate mesylate compound of formula-1.

Detailed Description of 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, ethylformate, methyl propionate, propylacetate and the like; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, 1,2-dimethoxy ethane and the like; "hydrocarbon solvents" like toluene, hexane, heptane, perfluorobenzene, cyclohexane and the like; "polar aprotic solvents" like dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone, 4-hydroxy-4-methyl pentanone and the like; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like dichloro methane, chloroform and dichloro ethane; "nitrile solvents" like acetonitrile and propionitrile; "nitro solvents" like nitromethane, nitroethane and the like; 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.

As used herein the present invention the term "suitable acid" refers to the acid selected from oxalic acid, 2,5-dihydroxy benzoic acid, benzene sulfonic acid, isoethionic acid, cyclamic acid, ethanedisulfonic acid, D-glucaronoic acid, glycolic acid, mandelic acid, palmitic acid, oleic acid, stearic acid, cinnamic acid, camphor sulfonic acid, adipic acid, naphthalene-2-sulfonic acid and naphthalene-1,5-disulfonic acid.

l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of general formula-2 used in the presentinvention is prepared from the any known methods in the prior art or by the process of present invention.

The main objective of the present invention is to provide novel acid addition salts of 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of general formula-3, which in-turn result in the preparation of highly pure Dabigatran etexilate mesylate compound of formula-1. Further, the present invention also provides polymorphs for the novel acid addition salts.

The first aspect of the present invention is to provide novel acid addition salts of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of general formula-3, Formula-3 as intermediate compound used in the preparation of dabigatran etexilate mesylate compound of formula-1.

A preferred embodiment of the present invention provides an oxalate salt of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-3 a.

The second aspect of the present invention is to provide a process for the preparation of novel acid addition salts of l-methyl-2-[N-[4-amidinophenyl] aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)amide compound of general formula-3, which comprising of:

a) Treating 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a

Formula-2a with a suitable acid in a suitable solvent to provide its corresponding acid addition salt compound of general formula-3,

b) isolating the solid obtained in step-a) to provide compound of general formula-3. Wherein, in step-a) the suitable solvent is selected from alcoholic solvents, chloro solvents, ether solvents, nitro solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents.

In a preferred embodiment of the present invention provides a process for the preparation of 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a comprising of:

a) Treating l-methyl-2-[N-[4-amidinophenyl] aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with oxalic acid in ethanol to provide oxalate salt compound of formula-3a,

b) isolating the solid obtained in step-a) to provide pure compound of formula-3a.

The advantage of making an oxalate salt of l-methyl-2-[N-[4-amidinophenyl] aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)amide compound of formula-3a is to reduce the impurities formed during the preparation of dabigatran etexilate, according to the prior art process. Further, isolation of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a as a crystalline form provides the compound of formula-3 with high purity i.e., greater than 99% by HPLC. Further it results in the formation of highly pure dabigatran etexilate compound of formula-4 with purity of 99.58% and its mesylate salt compound of formula-1 with purity of 99.64% by HPLC.

We the present inventors have surprisingly found that, the l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate salt compound of formula-3 a, can be isolated as a pure solid.

It has been found that the oxalate salt compound of formula-3 a has certain advantages over the other salts reported in the prior-art. Moreover, the synthesis of oxalate salt of l-methyl-2-[N-[4-amidinophenyl] aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)amide compound of formula-3a is simple, ecofriendly, robust and well suited oncommercial scale up.

Further the present invention also provides a process for the preparation of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl) N-(2-ethoxycarbonylethyl)amide or its hydro halide salts compound of general formula-2 comprising of:

a) Reacting 4-aminobenzonitrile compound of formula-5 with sodium 2-chloroacetate in presence of a suitable base in presence or absence of phase transfer catalyst in a suitable solvent to provide 2-(4-cyanophenylamino) acetic acid compound of formula-6,

b) condensing the compound of formula-6 with ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate compound of formula-7 in presence of carbonyldiimidazole in a suitable solvent to provide l-methyl-2-[N-(4-cyanophenyl)aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl) amide compound of formula-8,

c) reacting the compound of formula-8 with ammonium carbonate in presence of Lewis acid and hydrochloride gas in a suitable solvent to provide l-methyl-2-[N-[4-amidino phenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl) amide or its hydro halide salts compound of general formula-2.

Wherein in step a) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates preferably sodium bicarbonate and the suitable solvent is selected from alcohol solvents, ketone solvents, polar solvents or their mixtures thereof; preferably water; and the suitable phase transfer catalyst is tertiary butyl ammonium bromide in step b) the suitable solvent is selected from ether solvents, hydrocarbon solvents, ester solvents, ketone solvents or their mixtures thereof; preferably tetrahydrofuran in step c) the suitable Lewis acid is selected from aluminium chloride(AlCl3), aluminium bromide(AlBr3), boran trifluoride(BCl3), boran trichloride(BF3), Iron(III) chloride(FeCl3), Tin(IV) chloride (SnCl4), calcium chloride dihydrate (CaCl2.2H2O), calcium chloride (CaCl2) etc; preferably calcium chloride dihydrate; and the suitable solvent is selected from alcohol solvents, ether solvents, ketone solvents or their mixtures thereof; preferably ethanol;

The third aspect of the present invention is to provide a novel crystalline form of l-methyl-2-[N-[4-amidinophenyl]aminomethyllbenzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)amide oxalate salt compound of formula-3a, herein designated as crystalline form-M. Further, the crystalline form-M of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate in accordance with the present invention is characterized by its powder XRD pattern having peaks at about 7.6, 11.7, 14.5, 18.0, 18.2, 22.8, 24.8 and 25.3 ± 0.2 degrees two-theta; Further the PXRD of crystalline form-M of the present invention is shown in figure-1.

The crystalline form-M of l-methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a is further characterized by DSC thermogram showing endotherm at about 203.53°C and is shown in figure-2.

The fourth aspect of the present invention is to provide a process for purification of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a, which comprising of the following steps:

a) Treating 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]beiizimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with a suitable acid in a suitable solvent to provide its corresponding acid addition salt of compound of general formula-3,

b) treating the compound of general formula-3 in with a suitable base in a suitable solvent and isolating the compound to provide pure compound of general formula-2.

Wherein, in step-a) the suitable solvent is same as the suitable solvent used in step-a) of second aspect, in step-b) is organic solvent selected from ethersolvents like tetrahydrofuran, methyl tert-butyl ether, diethylether, ester solvents like methyl acetate, ethylacetate, isopropylacetate; ketone solvents like acetone, propanone, methylethyl ketone, methylisobutylketone; polar aprotic solvents like dimethylformamide, acetonitrile, or mixtures of water and organic solvent; and the base is selected from alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate and the like.

pyridyl)-N-(2-ethoxycarbonyl ethyl)amide oxalate salt compound of formula-3a, herein designated as crystalline form-M. Further, the crystalline form-M of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate in accordance with the present invention is characterized by its powder XRD pattern having peaks at about 7.6, 11.7, 14.5, 18.0, 18.2, 22.8, 24.8 and 25.3 ± 0.2 degrees two-theta; Further the PXRD of crystalline form-M of the present invention is shown in figure-1.

The crystalline form-M of l-methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a is further characterized by DSC thermogram showing endotherm at about 203.53°C and is shown in figure-2.

The fourth aspect of the present invention is to provide a process for purification of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a, which comprising of the following steps:

a) Treating 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with a suitable acid in a suitable solvent to provide its corresponding acid addition salt of compound of general formula-3,

b) treating the compound of general formula-3 in with a suitable base in a suitable solvent and isolating the compound to provide pure compound of general formula-2.

Wherein, in step-a) the suitable solvent is same as the suitable solvent used in step-a) of second aspect, in step-b) is organic solvent selected from ethersolvents like tetrahydrofuran, methyl tert-butyl ether, diethylether, ester solvents like methyl acetate, ethylacetate, isopropylacetate; ketone solvents like acetone, propanone, methylethyl ketone, methylisobutylketone; polar aprotic solvents like dimethylformamide, acetonitrile, or mixtures of water and organic solvent; and the base is selected from alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate and the like.

In a preferred embodiment of the present invention provides a process for purification of 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a, which comprising of the following steps:

a) Treating 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with oxalic acid in ethanol to provide oxalate salt compound of formula-3a,

b) treating the compound of formula-3a with potassium carbonate in aqueous acetonitrile and isolating the compound to provide pure compound of general formula-2a.

The fifth aspect of the present invention is to provide a novel process for the preparation of crystalline form-I of dabigatran etexilate mesylate compound of formula-1, which comprising of:

a) Dissolving dabigatran etexilate in an ester solvent by heating to a suitable temperature,

b) filtering the reaction mixture,

c) cooling the obtained filtrate and adding an alcoholic solvent to it,

d) adding a solution of methane sulfonic acid in ester solvent to the reaction mixture,

e) stirring the reaction mixture,

f) filtering the solid and washing with an ester solvent,

g) drying the solid to get crystalline form-I of dabigatran etexilate mesylate compound of formula-1.

In a preferred embodiment of the present invention is to provide a process for the preparation of crystalline form-I of dabigatran etexilate mesylate compound of formula-1, which comprising of: a) Dissolving dabigatran etexilate in an ethylacetate by heating to 40°C,

a) filtering the reaction mixture and cooling the filtrate to 25-3 0°C,

b) adding ethanol to the filtrate,

c) adding a solution of methane sulfonic acid in ethylacetate to the reaction mixture,

d) stirring the reaction mixture at 25-35°C,

e) filtering the solid and washing with ethylacetate,

f) drying the solid to get crystalline form-I of dabigatran etexilate mesylate compound of formula-1.

The sixth aspect of the present invention is to provide an improved process for the preparation of dabigatran etexilate mesylate compound of formula-1, which comprising of following steps:

a) Treating 1 -methyl-2-pS[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with a suitable acid in a suitable solvent to provide its corresponding acid addition salt compound of general formula-3,

b) reacting the compound of general formula-3 with n-hexylchloroformate in presence of a base in a suitable solvent to provide dabigatran etexilate compound of formula-4,

c) optionally purifying the compound obtained in step-b) in a suitable solvent to provide pure compound of formula-4,

d) treating the pure compound of formula-4 with methane sulfonic acid in a suitable solvent to provide dabigatran etexilate mesylate compound of formula-1.

Wherein, the suitable solvent used

In step-a) is same as a suitable solvent used in step-a of fourth aspect,

In step-b) is same as a suitable solvent used in step-b of fourth aspect,

In step-c) is selected from chloro solvents, ketone solvents, ester solvents, alcoholic
solvents, polar solvents like water and/or mixtures thereof,

In step-d) is selected from ester solvents, alcoholic solvents or mixtures thereof.

In a preferred embodiment of the present invention provides an improved process for the preparation of dabigatran etexilate mesylate compound of formula-1, which comprising of:

a) Treating 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-
carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with oxalic acid in ethanol to provide oxalate salt compound of formula-3a,

b) reacting the compound of formula-3a with n-hexylchloroformate in presence of potassium carbonate in aqueous acetonitrile to provide dabigatran etexilate compound of formula-4,

c) treating the compound of formula-4 with methane sulfonic acid in a mixture of ethyl acetate and ethanol to provide dabigatran etexilate mesylate compound of formula-1.

In another preferred embodiment of the present invention provides an improved process for the preparation of dabigatran etexilate mesylate compound of formula-1, which comprising of:

a) Treating 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with oxalic acid in ethanol to provide oxalate salt compound of formula-3a,

b) reacting the compound of formula-3a with n-hexylchloroformate in presence of potassium carbonate in aqueous methyl ethyl ketone to provide dabigatran etexilate compound of formula-4,

c) treating the compound of formula-4 with methane sulfonic acid in a mixture of ethyl acetate and ethanol to provide dabigatran etexilate mesylate compound of formula-1.

The present invention is schematically represented as follows: Scheme-

Scheme-2:

The compound of formula-7 can be prepared by the known methods which schematically represented as follows

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

Examples:

Example-1: Process for the preparation of l-methyl-2-[N-[4-amidinophenyl] aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyI)-N-(2-ethoxycarbonyl ethyl)amide oxalate (Formula-3a)

A mixture of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a (100 g) and ethanol (1200 ml) was heated to 50-60°C. A solution of oxalic acid (25.25 g) in ethanol (1500 ml) was added to the above reaction mixture at 50-60°C and stirred for 45 minutes. The reaction mixture was cooled to 25-35°C and stirred for 6 hours at 25-35°C. Filtered the solid, washed with ethanol and then dried to get the title compound.

Yield: 140 g; Purity by HPLC: 99.11%

Example-2: Process for the preparation of Dabigatran etexilate (Formula-4)

A solution of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a (100 g) in a mixture of acetonitrile (1200 ml) and water (800 ml) was cooled to 12-18°C. Potassium carbonate (66.24 g) was added to the above reaction mixture and stirred for 15 minutes at 12-18°C. n-hexylchloroformate (28.95 g) was added to the reaction mixture and stirred for 4 V2 hours at 12-18°C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the obtained solid, washed with acetonitrile and water. Dried the solid to get the title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35°C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35°C to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35°C to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Yield: 98 g; Purity by HPLC: 99.58% Example-3: Process for the preparation of Dabigatran etexilate (Formula-4)

A solution of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a (100 g) in a mixture of methyl ethyl ketone (1200 ml) and water (800 ml) was cooled to 12-18°C. Potassium carbonate (66.24 g) was added to the above reaction mixture and stirred for 15 minutes at 12-18°C. n-hexylchloroformate (28.95 g) was added to the reaction mixture and stirred for 4 Vi hours at 12-18°C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the obtained solid, washed with methyl ethyl ketone and water. Dried the solid to get the title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35°C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35°C to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35°C to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Yield: 98 g; Purity by HPLC: 99.58%

Example-4: Purification of Dabigatran etexilate (Formula-4)

A mixture of Dabigatran etexilate compound of formula-4 (100 g) and Ethyl acetate (600 ml) was heated to reflux temperature and then stirred for 2 hours at the same temperature. Filtered the reaction mixture through hyflow bed. Washed the bed twice with hot ethyl acetate and ethanol (8 ml) was added to the obtained filtrate. The reaction mixture was further heated to reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-35°C and stirred for 3 hours. Filtered the solid, washed with ethylacetate and then dried to get pure title compound.

Yield: 83 g; MP: 126-128°C; Purity by HPLC: 99.58%

The melting point of Dabigatran etexilate obtained in this example is similar to the melting point of Dabigatran etexilate obtained in JMC, 2002, 45(9), 1757-1766.

Example-5: Process for the preparation of Dabigatran etexilate mesylate (Formula-
1)

A solution of Dabigatran etexilate compound of formula-4 (100 g) in ethyl acetate (600 ml) was heated to 40°C and stirred for 45 minutes at 40°C. Filtered the reaction mixture through hyflow bed and cooled to 25-30°C. Ethanol (60 ml) was added to the filtrate at 25-35°C. A solution of methane sulfonic acid (15 g) in ethyl acetate (1000 ml) was slowly added to the above reaction mixture over a period of 2 hours at 25-35°C and stirred for 6 hours at the same temperature. Filtered the obtained solid, washed with ethyl acetate and then dried to get the title compound. Yield: 105 g; Purity by HPLC: 99.64%
PXRD of Dabigatran etexilate mesylate obtained in this example is matches with the crystalline form-I of Dabigatran etexilate mesylate.

Example-6: Process the preparation of l-methyl-2-[N-[4-amidinophenylJaminom ethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl) amide (Formula-2a)

Dissolved l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a (100 g) in a mixture of acetonitrile (1200 ml) and water (800 ml) and cooled to 10-15°C. Potassium carbonate (66.24 g) was added to the reaction mixture and stirred for 60 minutes at 10-15°C. Filtered the obtained solid, washed with water and then dried to get title compound. Yield: 80 g.

Example-7: Preparation of 2-(4-cyanophenylamino)acetic acid compound of formula-6 Sodium bicarbonate (21.35 g) was added to a mixture of 4-aminobenzonitrile compound of formula-5 (100 g) and water (1000 ml) followed by sodium 2-chloroacetate (197.42 g). Potassium iodide (5 g) followed by tertiary butyl ammonium bromide (2.5 g) were added to the reaction mixture. The reaction mixture was heated to the 90-95 °C and stirred for 24 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 20-25°C and pH was adjusted to 7.5 with ammonia. The reaction mixture was stirred for 20 minutes at 20-30°C. Filtered the reaction mixture and ethyl acetate was added to the filtrate. The reaction mixture was stirred for 15 minutes. Both the ethyl acetate and aqueous layers were separated and the pH of aqueous layer was adjusted to 2.5 using hydrochloric acid. The reaction mixture was stirred for 3 hours at 20-3 0°C to precipitate the solid. Filtered the precipitated solid, water followed by hydrochloric acid were added to the reaction mixture and stirred for 4 hours at 25-30°C. Filtered the solid, water was added to it and stirred for 30-45 minutes. Filtered the solid, washed with water and then dried to get the title compound. The same process can be repeated another time to eliminates the impurities if present. Yield: 131g

Example-8: Preparation of l-methyl-2-[N-(4-cyanophenyl) aminomethyl] benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-8

A mixture of 2-(4-cyanophenylamino)acetic acid (139 g) and tetrahydrofuran (750 ml) was heated to 50-55°C. A solution of N,N'-carbonyldiimidazole (177.6 g) in tetrahydrofuran (1000 ml) was added to the above reaction mixture at the same temperature over a period of 1 hour and stirred for 2 hours at 50-55°C. A solution of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate compound of formula-7 (250 g) in tetrahydrofuran (1500 ml) was added over a period of 2 hours at 50-55°C and heated to 60-65°C. The reaction mixture was stirred for 50 hours at 60-65°C.

After completion of the reaction, distilled off the solvent from the reaction mixture. Acetic acid was added to the reaction mixture and heated to 95-100°C. The reaction mixture was stirred for 5 hours at 95-100°C. Distilled off the solvent completely under the reduced pressure and the reaction mixture was cooled to 25-30°C. Water was added to the reaction mixture and the product was extracted with dichloromethane. Both the dichloromethane and aqueous layers were separated and the dichloromethane layer was washed with water followed by sodium chloride. Distilled off the solvent completely from the dichloromethane layer to obtain title compound.

Yield: 300 g

Example-9: Preparation of l-methyl-2-[N-[4-amidino phenyl] aminomethyl] benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide hydrochloride compound of formula-2b

Calcium chloride dihydrate (12.5 g) was added to a mixture of l-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)amide compound of formula-8 (50 g) and ethanol (750 ml) and stirred for 20 minutes. The reaction mixture was cooled to 0-5°C and HC1 gas was passed into the reaction mixture over a period of 5 hours at a temperature below 10°C. The temperature of the reaction mixture was raised to 25-30°C and stirred for 8 hours at the same temperature. After completion of the reaction, the solvent was expelled out under N2 pressure. The reaction mixture was cooled to 0-5°C and slowly added ammonium formate (150 g). The reaction mixture was stirred for 30 minutes and ammonium carbonate (300 g) was added. The temperature of the reaction mixture was raised to 25-35°C and stirred for 10 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was distilled under reduced pressure. A solution of 10% ethanol in ethyl acetate was added to the reaction mixture and stirred for 3 hours to obtain a solid. Filtered the obtained solid, washed with ethyl acetate and then dried to get the title compound. Yield: 45 g

We Claim:

1. 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate salt compound of formula-3a as a solid.

2. According to claim-1, the l-methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate salt compound of formula-3a is a crystalline solid.

3. A crystalline form-M of l-methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate salt compound of formula-3a characterized by

a) its powder XRD pattern having peaks at about 7.6, 11.7, 14.5, 18.0, 18.2, 22.8,
24.8 and 25.3 ± 0.2 degrees two-theta as illustrated in figure-1; or

b) its DSC thermogram showing endotherm at about 203.53°C and is shown in
figure-2.

4. Novel acid addition salts of l-methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of general formula-3

5. A process for the preparation of novel acid addition salts of l-methyl-2-[N-[4-
amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-
ethoxycarbonyl ethyl)amide compound of general formula-3, which comprising of:

a) Treating the l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of with a suitable acid in a suitable solvent selected from alcohol solvents, chloro solvents, ether solvents, nitro solvents, ketone solvents, ester solvents, nitrile solvents and hydrocarbon solvents to provide its corresponding acid addition salt compound of general formula-3,

b) isolating the solid obtained in step-a) to provide compound of general formula-3.

6. An improved process for the preparation of dabigatran etexilate compound of formula-4, which comprising of the following steps:

a) Treating 1 -methyl-2-[N-[4-amidinophenyl]ammomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with a suitable acid in a suitable solvent and selected from alcohol solvents, chloro solvents, ether solvents, nitro solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents to provide its corresponding acid addition salt compound of general formula-3,

b) reacting the compound of general formula-3 with n-hexylchloroformate in presence of a base selected from alkali metal hydroxide, alkali metal carbonates and alkali metal bicarbonates in a suitable solvent selected from ether solvents, ketone solvents, alcohol solvents, polar solvents or their mixtures thereof to provide dabigatran etexilate compound of formula-4

7. According to claim 4, 5 and 6, wherein the suitable acid is selected from oxalic acid, 2,5-dihydroxy benzoic acid, benzene sulfonic acid, cyclamic acid, ethanedisulfonic acid, ethane sulfonic acid, D-glucaronoic acid, glycolic acid, mandelic acid, palmitic acid, oleic acid, stearic acid, cinnamic acid, camphor sulfonic acid, adipic acid, naphthalene-2-sulfonic acid and naphthalene-1,5-disulfonic acid;

8. A process for the preparation of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl) N-(2-ethoxycarbonylethyl)amide or its hydro halide salts compound of general formula-2 comprising of:

a) Reacting 4-aminobenzonitrile compound of formula-5 with sodium 2-chloroacetate in presence of a suitable base selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates in presence of tertiary butyl ammonium bromide in a suitable solvent selected from alcohol solvents, ketone
solvents, polar solvents or their mixtures thereof to provide 2-(4-cyanophenylamino) acetic acid compound of formula-6,

b) condensing the compound of formula-6 with ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate compound of formula-7 in presence of carbonyldiimidazole in a suitable solvent selected from ether solvents,hydrocarbon solvents, ester solvents, ketone solvents or their mixtures thereof to provide 1 -methyl-2-[N-(4-cyanophenyl)aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl) amide compound of formula-8,

c) reacting the compound of formula-8 with ammonium carbonate in presence of Lewis acid selected from aluminium chloride(AlCl3), aluminium bromide(AlBr3), boran trifluoride (BC13), boran trichloride (BF3), Iron(III) chloride(FeCl3), Tin(IV) chloride (SnCl4), calcium chloride dihydrate (CaCl2.2H2O), calcium chloride(CaCl2) etc., and in presence of hydrochloride gas in a suitable solvent selected
from alcohol solvents, ether solvents, ketone solvents or their mixtures thereof, to
provide l-methyl-2-[N-[4-amidino phenyl] aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl) amide or its hydro halide salts compound of general formula-2.

9. A process for purification of l-methyl-2-[N-[4-amidinophenyl] aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a, which comprising of the following steps:

a) Treating 1 -methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of general formula-2 with a suitable acid in a suitable solvent to provide acid addition salt of compound of general formula-3,

b) treating the compound of general formula-3 with a suitable base in a suitable solvent and isolating the compound to provide pure compound of formula-2a.

10. A process for purification of l-methyl-2-[N-[4-amidinophenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a, which comprising of the following steps:

a) Treating the l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-2a with oxalic acid in ethanol to provide oxalate salt compound of formula-3 a,

c) treating the compound of formula-3 a with potassium carbonate in aqueous acetonitrile and isolating the compound to provide pure compound of formula-2a.