Field of the Invention:

The present invention relates to an improved process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (diamine compound) compound of formula-7, which is a key intermediate in the synthesis of benzimidazole derivatives such as l-methyl-2-|TN-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide mesylate represented by structural formula-la.

The present invention also provides novel camphor sulfonate salt of l-methyl-2-[N-[4-(N-n-hexyloxy carbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-1 and their polymorphs.
Further, the present invention provides novel crystalline forms of l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidmo)phenyl]aminomemyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide salts, preferably oxalate and fumarate salts.

Background of the Invention:

l-memyl-2-(T^-[4-(N-n-hexyloxycarbonylamidmo)phenyl]aminomethyl]benz imidazole-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide mesylate is commonly known as Dabigatran etexilate mesylate. Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors developed by Boehringer Ingelheim and is used for the treatment of thrombosis, cardiovascular diseases, and the like. Dabigatran etexilalte mesylate was approved in both US and Europe and commercially available under the brand name Pradaxa.

Dabigatran etexilate and process for its preparation was first disclosed in WO 98/37075.

The disclosed process involves the reduction of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-4-yl)benzamido)propanoate (herein after referred as "nitro compound") using Pd-C in a mixture of dichloromethane and methanol under hydrogen pressure to provide ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (herein after referred as "diamine compound").

The reduction of nitro compound through catalytic hydrogenation in the presence of tertiary amine under hydrogen pressure was also disclosed in WO2009153214.

The reduction of nitro compound through catalytic hydrogenation in the presence of inorganic base under hydrogen pressure was also disclosed in WO2012004397.

However, the all the prior art processes proceed through catalytic hydrogenation which involves the pressure reactions. Handlings of these pressure reactions are not suitable for the large scale process. Therefore, there is a significant need in the art to provide a simple reduction process which avoids the difficulties associated with catalytic hydrogenation.

JMC, 2002,45(9), 1757-1766 disclosed a process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (diamine compound) starting from 4-(methylamino)-3-nitrobenzoic acid. The disclosed process involves the conversion of 4-(methylamino)-3-nitrobenzoic acid into its acid chloride using thionyl chloride and the obtained compound was reacted with ethyl 3-(pyridin-2-ylamino)propanoate to provide nitro compound, followed by catalytic reduction using Pd-C to provide diamine compound.

However, particularly in large scale synthesis the reduction reaction occasionally stops due to catalyst poisoning which leads to incomplete reaction and requires additional catalyst to complete the reaction. Moreover the sulfur impurities which are present in nitro compound formed due to the reaction with thionyl chloride in the previous stages of the synthesis of diamine compound are strongly influence the reaction time, quality and catalyst consumption in the manufacturing process.

Surprisingly, the problem associated with the catalytic hydrogenation and catalyst poisoning is solved by the present invention by adopting Fe-acetic acid as a reducing agent.

The crystalline forms-I, II, V and VI of Dabigatran etexilate oxalate were disclosed in WO2008043759 and WO2011110876.

The crystalline forms-Ill, IV and V of Dabigatran etexilate fumarate were disclosed in WO2008043759 and WO2011110876.

Various different salts for Dabigatran etexilate and their polymorphs were reported in WO 98/37075, WO03074056, WO2005028468, WO2006114415, WO2008043759, WO2011110876, WO2012027543 and WO2012044595.

The process for the preparation of crystalline form-I of Dabigatran etexilate mesylate was described in WO2005028468 and WO2012027543.

Brief description of the Invention:

The first aspect of the present invention is to provide a process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (diamine compound) compound of formula-7, comprising of reducing ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-4-yl)benzamido)propanoate (nitro compound) compound of formula-6 with Fe-acetic acid in a suitable solvent.

The second aspect of the present invention is to provide an improved process for the preparation of diaime compound of formula-7, comprising of:

a) Reacting 4-chloro-3-nitrobenzoic acid compound of formula-8 with methyl amine to provide 4-(methylamino)-3-nitrobenzoic acid compound of formula-5,

b) reacting 2-aminopyridine compound of formula-2 with ethyl acrylate compound of formula-3 at a temperature of 95-100°C provides ethyl 3-(pyridin-2-ylamino)propanoate compound of formula-4,

c) condensing the compound of formula-5 obtained in step-(a) with ethyl 3-(pyridin-2-ylamino) propanoate compound of formula-4 obtained in step-(b) in a suitable solvent to provide nitro compound of formula-6,

d) reducing the nitro compound of formula-6 in-situ with Fe-acetic acid (or) Fe-hydrochloric acid in a suitable solvent to provide its corresponding diamine compound of formula-7.

The third aspect of the present invention is to provide a process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (diamine compound) compound of formula-7, comprising of reducing ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-4-yl)benzamido)propanoate (nitro compound) compound of formula-6 with Fe-hydrochloric acid in a suitable solvent.

The fourth aspect of the present invention relates to (-)-camphor sulfonate salt of Dabigatran etexilate compound of formula-1 and its process for the preparation.

The fifth aspect of the present invention relates to crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate and its process for the preparation.

The sixth aspect of the present invention relates to amorphous form of Dabigatran etexilate (-)-camphor sulfonate and its process for the preparation.

The seventh aspect of the present invention relates to novel crystalline form-S of Dabigatran etexilate oxalate and its process for the preparation.

The eighth aspect of the present invention relates to novel crystalline form-N of Dabigatran etexilate fumarate and its process for the preparation.

The ninth aspect of the present invention is to provide a process for the preparation of crystalline form-I of Dabigatran etexilate mesylate compound of formula-la from acetonitrile solvent.

Advantages of the present invention:

• Avoids the usage of hydrogenation and pressure reactions.

• Avoids costly metal catalysts like Pd-C.

• Provides simple, safer, environmental friendly and cost-effective process.

Brief description of drawings:

Figure-1: Illustrates the photographs of microscopic Dabigatran etexilate mesylate compound of formula-la.

Figure-2: Illustrates the PXRD pattern of crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate.

Figure-3: Illustrates the PXRD pattern of amorphous Dabigatran etexilate (-)-camphor sulfonate.

Figure-4: Illustrates the PXRD pattern of crystalline form-S of Dabigatran etexilate oxalate.

Figure-5: Illustrates the PXRD pattern of crystalline form-N of Dabigatran etexilate fumarate.

Detailed description of the Invention:

The term "suitable solvent" used herein the present invention refers, but not limited to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet.ether, benzene, toluene, xylene and the like; "chloro solvents" such as dichloromethane, dichloroethane, carbon tetrachloride, chloroform and the like; "ester solvents" such as ethyl acetate, methyl acetate, propyl acetate and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, dioxane, acetonitrile and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxy ethane, tetrahydrofuran and the like; "alcoholic solvents" such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "ketone solvents" such as acetone, propanone, methylisobutyl ketone, methylisopropyl ketone and the like; and "polar solvents" such as water; and/or their mixtures.

The term "suitable base" used herein the present invention refers, but not limited to "inorganic bases" selected from alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and "organic bases" like diisopropyl amine, diisopropyl ethyl amine, diisobutyl amine, triethyl amine, pyridine, 4-dimethylamino pyridine and the like.

The term "suitable condensing agents" used herein the present invention refers, but not limited to carbodiimides such as HN'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), NjN'-dicyclohexylcarbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), diphenyl phosphoroazidate (DPPA), P2O5, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT), N.N'-carbonyl diimidazole. The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), 1 -hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base.

The conversion of acid to acid chloride wherever necessary in the present invention is carried out by using thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride and the like.

The present invention provides an improved process for the preparation of diamine compound of formula-7, which is a key intermediate in the synthesis of Dabigatran etexilate mesylate compound of formula-la. The present invention also provides a novel camphor sulfonate salt of Dabigatran etexilate and its polymorphs. Further, the present invention provides novel crystalline forms of Dabigatran etexilate salts, preferably oxalate and fumarate salts.

The first aspect of the present invention is to provide a process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (diamine compound) compound of formula-7, comprising of reducing the ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-4-yl)benzamido) propanoate (nitro compound) compound of formula-6 with Fe-acetic acid in a suitable solvent.

Wherein, the suitable solvent is selected from ether solvents, hydrocarbon solvents, chloro solvents, ester solvents, alcoholic solvents, polar solvents, polar aprotic solvents and/or mixtures thereof.

The amount of Fe used in the present invention for the reduction of 1 mole of nitro compound (formula-6) is in the range of 2-8 molar equivalents, preferably 3-7 molar equivalents.

The amount of acetic acid used in the present invention for reduction of 1 mole of nitro compound (formula-6) is in the range of 1-7 molar equivalents, preferably 2-6 molar equivalents and more preferably 3-5 molar equivalents.

The reduction was carried out at a temperature ranging from 10°C to 120°C, preferably at 40°C to 75°C.

A preferred embodiment of the present invention provides a process for the preparation of diamine compound of formula-7, comprising of reducing the nitro compound of formula-6 with Fe-acetic acid in aqueous tetrahydrofuran at a reflux temperature.

The second aspect of the present invention is to provide an improved process for the preparation of diamine compound of formula-7, comprising of: a) Reacting 4-chloro-3-nitrobenzoic acid compound of formula-8 with methyl amine to provide 4-(methylamino)-3-mtrobenzoic acid compound of formula-5,


b) reacting 2-aminopyridine compound of formula-2 with ethyl acrylate compound of formula-3 at a temperature of 95-100°C provides ethyl 3-(pyridin-2-ylamino)propanoate compound of formula-4,

c) condensing the compound of formula-5 obtained in step-(a) with ethyl 3-(pyridin-2-ylamino) propanoate compound of formula-4 obtained in step-(b) in a suitable solvent to provide nitro compound of formula-6,

d) reducing the nitro compound of formula-6 in-situ with Fe-acetic acid (or) Fe-hydrochloric acid in a suitable solvent to provide its corresponding diamine compound of formula-7.

Wherein, the suitable solvent used, in step-c) is selected from hydrocarbon solvents, ester solvents, ether solvents, polar aprotic solvents and/or their mixtures thereof, in step-d) is selected from ether solvents, hydrocarbon solvents, chloro solvents, ester solvents, alcoholic solvents, polar solvents, polar aprotic solvents and their mixtures thereof.

The condensation of compound of formula-4 with compound of formula-5 in the step-(c) of above aspect is carried out by using a suitable condensing agent (or) by converting the acid compound of formula-5 into its corresponding acid chloride (or) its derivatives by the known methods in the art and then condensed with compound of formula-4 in the presence or absence of a suitable base selected from alkali and alkaline earth metal hydroxides, alkoxides, carbonates, bicarbonates and organic bases to provide nitro compound of formula-6.

The nitro compound of formula-6 in the above aspect can be isolated from a suitable solvent and then reduced with Fe-acetic acid (or) Fe-hydrochloric acid in a suitable solvent selected from ether solvents, hydrocarbon solvents, chloro solvents, ester solvents, alcoholic solvents, polar solvents, polar aprotic solvents and their mixtures thereof to provide its corresponding diamine compound of formula-7.

A preferred embodiment of the present invention is to provide an improved process for the preparation of diamine compound of formula-7, comprising of:

a) Reacting 4-chloro-3-nitrobenzoic acid compound of formula-8 with methyl amine to provide 4-(methyl amino)-3-nitrobenzoic acid compound of formula-5,

b) reacting 2-aminopyridine compound of formula-2 with ethyl acrylate compound of formula-3 at a temperature of 95-100°C provides ethyl 3-(pyridin-2-ylamino)propanoate compound of formula-4,

c) reacting the compound of formula-5 obtained in step-(a) with thionyl chloride in a mixture of toluene and dimethylformamide to provide its corresponding acid chloride,

d) condensing the acid chloride compound obtained in step-(c) in-situ with ethyl 3-(pyridin-2-ylamino)propanoate compound of formula-4 obtained in step-(b) in the presence of triethyl amine in toluene to provide nitro compound of formula-6,

e) reducing the compound of formula-6 in-situ with Fe-acetic acid in aqueous tetrahydrofuran to provide diamine compound of formula-7.

The third aspect of the present invention is to provide a process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (diamine compound) compound of formula-7, comprising of reducing the ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-4-yl)benzamido) propanoate (nitro compound) compound of formula-6 with Fe-hydrochloric acid in a suitable solvent.
Wherein, the suitable solvent and reaction temperature are same as defined in first aspect.

The mole ratios of Fe and hydrochloric acid used in the present aspect are same as defined for Fe and acetic acid in the first aspect respectively.

A preferred embodiment of the present invention provides a process for the preparation of diamine compound of formula-7, comprising of reducing the nitro compound of formula-6 with Fe-hydrochloric acid in aqueous tetrahydrofuran at a reflux temperature.

The 2-amino pyridine compound of formula-2, ethyl acrylate compound of formula-3 and 4-chloro-3-nitrobenzoic acid compound of formula-8 are commercially available.

Further, the ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido) propanoate compound of formula-7 obtained by the present invention can be utilized in the synthesis of Dabigatran etexilte mesylate compound of formula-la and also in the preparation of novel salts of Dabigatran etexilate.

The fourth aspect of the present invention relates to (-) camphor sulfonate salt of Dabigatran etexilate compound of formula-1.

Further, the fourth aspect of the present invention also provides a process for the preparation of Dabigatran etexilate (-)-camphor sulfonate comprising of reacting Dabigatran etexilate with (-)-camphor sulfonic acid in a suitable solvent to provide (-)-camphor sulfonate salt of Dabigatran etexilate.

Wherein, the suitable solvent is selected from ketone solvents, ether solvents, alcoholic solvents, ester solvents, polar aprotic solvents, polar solvents and/or their mixtures thereof.

The fifth aspect of the present invention relates to novel polymorph of Dabigatran etexilate (-)-camphor sulfonate herein designated as crystalline form-M, which is characterized by its powder X-ray diffraction pattern having peaks at about 4.9, 5.3 and 18.6 ± 0.2 degrees of 29 values. The crystalline form-M is further characterized by the PXRD pattern having peaks at about 6.2, 11.6, 17.3, 18.8 and 20.5 ± 0.2 degrees of 20 values as illustrated in figure-2.

Further, the fifth aspect of the present invention also provides a process for the preparation of crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate, comprising of:

a) Reacting Dabigatran etexilate with (-)-camphor sulfonic acid in a suitable solvent selected from ketone solvents, ether solvents, alcoholic solvents, ester solvents, polar aprotic solvents, polar solvents and/or mixtures thereof,

b) distilling off the solvent completely from the reaction mixture,

c) adding alcoholic solvent to the reaction mixture,

d) adding an ether solvent to the reaction mixture,

e) stirring the reaction mixture,

f) filtering the precipitated solid and then dried to get crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate.

A preferred embodiment of the present invention is to provide a process for the preparation of crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate, comprising of:

a) Reacting Dabigatran etexilate with (-)-camphor sulfonic acid in acetone,

b) distilling off acetone completely from the reaction mixture,

c) adding ethanol to the reaction mixture,

d) adding methyl tertiary butyl ether to the reaction mixture,

e) stirring the reaction mixture,

f) filtering the precipitated solid and then dried to get crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate.

The sixth aspect of the present invention relates to an amorphous form of Dabigatran etexilate (-)-camphor sulfonate, which is characterized by its powder X-ray diffraction pattern as illustrated in figure-3.

Further, the sixth aspect of the present invention also provides a process for the preparation of an amorphous Dabigatran etexilate (-)-camphor sulfonate, comprising of:

a) Reacting Dabigatran etexilate with (-)-camphor sulfonic acid in a suitable solvent selected from ketone solvents, ether solvents, alcoholic solvents, ester solvents, polar aprotic solvents, polar solvents and/or mixtures thereof,

b) concentrating the reaction mixture,

c) adding a suitable solvent selected from ketone solvents, ester solvents and ether solvents, followed by a hydrocarbon solvent to the reaction mixture,

d) heating the reaction mixture,

e) stirring the reaction mixture,

f) filtering the solid and then dried to get amorphous Dabigatran etexilate (-)-camphor sulfonate.

A preferred embodiment of the present invention is to provide a process for the preparation of an amorphous Dabigatran etexilate (-)-camphor sulfonate, comprising of:

a) Reacting Dabigatran etexilate with (-)-camphor sulfonic acid in acetone,

b) concentrating the reaction mixture,

c) adding acetone followed by n-heptane to the reaction mixture,

d) heating the reaction mixture,

e) stirring the reaction mixture,

f) filtering the solid and then dried to get amorphous Dabigatran etexilate (-)-camphor sulfonate.

In fourth, fifth and sixth aspects of the present invention (-)-camphor sulfonic acid can be replaced with (+)-camphor sulfonic acid to provide its corresponding (+)-camphor sulfonate salt.

The seventh aspect of the present invention is to provide novel polymorph of Dabigatran etexilate oxalate herein designated as crystalline form-S, which is characterized by its powder X-ray diffraction pattern having peaks at about 3.9, 7.5, 7.8, 11.9, 18.2, 20.0 and 27.0 ± 0.2 degrees of 20 values. The crystalline form-S is further characterized by the PXRD pattern as illustrated in figure-4.

Further, the seventh aspect of the present invention also provides a process for the preparation of crystalline form-S of Dabigatran etexilate oxalate, comprising of:

a) Dissolving Dabigatran etexilate compound of formula-1 in a suitable ketone solvent,

b) adding a solution of oxalic acid dissolved in a suitable ketone solvent,

c) stirring the reaction mixture,

d) filtering the solid and then dried to get crystalline form-S of Dabigatran etexilate oxalate.

A preferred embodiment of the present invention is to provide a process for the preparation of crystalline form-S of Dabigatran etexilate oxalate, comprising of:

a) Dissolving Dabigatran etexilate compound of formula-1 in acetone,

b) adding a solution of oxalic acid dissolved in acetone,

c) stirring the reaction mixture,

d) filtering the solid and then dried to get crystalline form-S of Dabigatran etexilate oxalate.

The eighth aspect of the present invention relates to a novel polymorph of Dabigatran etexilate fumarate herein designated as crystalline form-N, which is characterized by its powder-X-ray diffraction pattern having peaks at about 4.9 and 5.2 ± 0.2 degrees of 29 values. The crystalline form-N is further characterized by PXRD pattern as illustrated in figure-5.

Further, the eighth aspect of the present invention also provides a process for the preparation of crystalline form-N of Dabigatran etexilate fumarate, comprising of:

a) Dissolving Dabigatran etexilate compound of formula-1 in a suitable ketone solvent,

b) adding a solution of fumaric acid dissolved in a suitable ketone solvent,

c) stirring the reaction mixture,

d) filtering the solid and then dried to get crystalline form-N of Dabigatran etexilate fumarate.

A preferred embodiment of the present invention is to provide a process for the preparation of crystalline form-N of Dabigatran etexilate fumarate, comprising of:

a) Dissolving Dabigatran etexilate compound of formula-1 in acetone,

b) adding a solution of fumaric acid dissolved in acetone,

c) stirring the reaction mixture,

d) filtering the solid and then dried to get crystalline form-N of Dabigatran etexilate fumarate.

The ninth aspect of the present invention is to provide a process for the preparation of crystalline form-I of Dabigatran etexilate mesylate compound of formula-la, comprising
of:

a) Dissolving Dabigatran etexilate in acetonitrile,

b) adding a solution of methane sulfonic acid dissolved in acetonitrile,

c) stirring the reaction mixture,

d) filtering the precipitated solid and then dried to get crystalline form-I of Dabigatran etexilate mesylate compound of formula-la.

The PXRD analysis of crystalline compounds and amorphous compounds of the present invention was carried out using BRUKER/AXS X-ray diffractometer using CuKa radiation of wavelength 1.5406 A0 and continuous scan speed of 0.037min.
Dabigatran etixalate mesylate compound of formula-la produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.

Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.

The present invention is schematically represented as follows:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of ethyl 3-(pyridin-2-ylamino)propanoate (Formula-4)

A mixture of 2-aminopyridine (100 g) and ethyl acrylate (234 g) was heated to 95-100°C and then stirred for 75 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-35°C. Ethyl acetate was added to the reaction mixture and treating the reaction mixture with hydrochloric acid followed by ammonia. Both the organic and aqueous layers were separated, the organic layer was washed with sodium chloride solution and then distilled off the solvent completely from the organic layer to get title compound as a residue. The obtained residue was isolated from pet.ether to provide crude title compound. The obtained compound was further purified by column chromatography using pet.ether and ethyl acetate. The obtained pure compound was further recrystallized using pet.ether. Yield: 75 g; MP: 52-54°C.

Example-2: Preparation of 4-(methylamino)-3-nitrobenzoic acid (Formula-5)

A mixture of 4-chloro-3-nitrobenzoic acid compound of formula-8 (200 g) and methyl amine (660 ml) was taken into autoclave and heated to 85-90°C and stirred for 5 hours at the same temperature under pressure of 2.0-2.5 kg. After completion of the reaction, the reaction mixture was cooled to 25-35°C. Water was added to the reaction mixture and acidified with hydrochloric acid. Filtered the precipitated solid and then dried to get title compound. Yield: 190 g.

Example-3: Preparation of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-
4-yl)benzamido)propanoate(Formula-6)

A mixture of 4-(methylamino)-3-nitrobenzoic acid compound of formula-5 (151.4 g), thionyl chloride (64 ml), dimethyl formamide (5 ml) and toluene (400 ml) was heated to 65-75°C and stirred for 2 hours at the same temperature. After completion of the reaction, the solvent from the reaction mixture was completely distilled off under reduced pressure and followed by co-distilled with toluene to get the corresponding acid chloride compound as a residue. Toluene (300 ml) was added to the obtained residue. Triethyl amine (157.5 ml), followed by a solution of ethyl 3-(pyridin-2-ylamino)propanoate compound of formula-4 (100 g) and toluene (200 ml) were added to the reaction mixture and stirred for 3 hours at 20-30°C. Filtered the unwanted solid, the filtrate was washed with sodium bicarbonate solution followed by water and sodium chloride solution. The organic layer was concentrated to give title compound.

Example-4: Preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yI)benzamido)propanoate (Formula-7)

Iron powder (57.45 g) was added to a mixture of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-4-yl)benzamido)propanoate compound of formula-6 obtained in example-3, tetrahydrofuran (100ml) and water (100 ml) and heated the reaction mixture to reflux temperature. Acetic acid (44.35 ml) was slowly added to the reaction mixture at the same temperature over a period of 2 hours. After completion of the reaction, the reaction mixture was cooled to 25-35°C and dichloromethane and water were added. Filtered the reaction mixture through hyflow bed and both organic and aqueous layers were separated from the filtrate. The organic layer was washed with sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent completely from the organic layer and then co-distilled with ethyl acetate to obtain the title compound. The obtained compound was recrystallized from ethyl acetate. Yield: 61.0 g; MR: 103-108°C.

ExampIe-5: Preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (Formula-7)

Iron powder (57.45 g) was added to a mixture of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-4-yl)benzamido)propanoate compound of formula-6 obtained in example-3, tetrahydrofuran (100ml) and water (100 ml) and heated the reaction mixture to reflux temperature. Hydrochloric acid (40 ml) was slowly added to the reaction mixture at the same temperature over a period of 2 hours. After completion of the reaction, the reaction mixture was cooled to 25-35°C and dichloromethane and water were added. Filtered the reaction mixture through hyflow bed and both organic and aqueous layers were separated from the filtrate. The organic layer was washed widi sodium bicarbonate solution followed by sodium chloride solution. Distilled off the solvent completely from the organic layer and then co-distilled with ethyl acetate to obtain the title compound. The obtained compound was recrystallized from ethyl acetate. Yield: 61.0g; MR: 103-108°C.

Example-6: Preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate (Formula-10)
2-(4-cyanophenylamino)acetic acid compound of formula-9 (64.32 g) was added to toluene (400 ml) and distilled off the solvent under azeotropic conditions at 70°C. The reaction mixture was cooled to 15-20°C. Tetrahydrofuran (1000 ml), followed by N,N-carbonyldiimidazole (71.03 g) were added to the reaction mixture at 10-20°C under nitrogen atmosphere and then stirred for 60 minutes. Ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate compound of formula-7 (100 g) was added to the reaction mixture and the temperature of the reaction mixture was raised to 20-3 0°C and then stirred for 16 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture and acetic acid was added to the reaction mixture. The reaction mixture was heated to 55-65°C and stirred for 7 hours. The reaction mixture was cooled to 20-30°C and water followed by dichloromethane was added to the reaction mixture. The organic and aqueous layers were separated, the organic layer was washed with water followed by sodium chloride solution and the solvent from the organic layer was completely distilled off and then co-distilled with acetone. The obtained compound was dissolved in acetone (700 ml) and then cooled to -5 to +5°C. Methane sulfonic acid (14.2 ml) was added to the reaction mixture at -5 to +5°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and then dried to get title compound. Yield: 115 g; MR: 188-190°C.

Example-7: Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate (Formula-11)

Hydrochloric acid gas was passed into a mixture of calcium chloride dihydrate (12.5 g) and ethanol (150 ml). Ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-10 (50 g) was added to the reaction mixture and hydrochloric acid gas was again purged into the reaction mixture at -15 to -5°C. The temperature of the reaction mixture was raised to 25-35°C and stirred for 10 hours at the same temperature. The reaction mixture was added to the solution containing ammonium carbonate (50 g), ammonia gas and ethanol (250 ml) at -35 to -25°C and stirred for 20 minutes. The temperature of the reaction mixture was raised to 25-35°C and stirred for 3 hours. The reaction mixture was heated to reflux temperature and stirred for 2 hours. Filtered the reaction mixture and distilled off the solvent completely from the filtrate to obtain crude title compound. The obtained crude compound was dissolved in ethanol (50 ml) and then precipitated by the addition of ethyl acetate (250 ml) into the reaction mixture. Filtered the precipitated solid and then dried to get pure title compound. Yield: 46 g; MR: 198-202°C.

Example-8: Preparation of Dabigatran etexilate (Formula-1)

n-hexanol (34.28 g) was added to a solution of N,N-carbonyldiimidazole (68.06 g) and dichloromethane (400 ml) at 15-25°C and stirred for 3 hours at the same temperature. Water followed by sodium chloride solution was added to the reaction mixture and both organic and aqueous layers were separated, the solvent from the organic layer was distilled off completely to get amide compound. Acetonitrile (25 ml) was added to the obtained amide compound. This was added to a mixture of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-11 (100 g), potassium carbonate (69.57 g), acetonitrile (420 ml) and water (280 ml) at 25-35°C. The reaction mixture was heated to 40-50°C and stirred for 8 hours at the same temperature. Both the organic and aqueous layers were separated; the organic layer was cooled to -5 to +5°C. Filtered the precipitated solid and then dried to get title compound. The obtained compound was dissolved in a mixture of acetone (300 ml) and acetonitrile (300 ml) and then precipitated again by the addition of water (40 ml) to it. The precipitated solid was dissolved in ethyl acetate (800 ml) by heating it to 70-80°C, the reaction mixture was cooled to 35-45°C and ethanol (8 ml) was added to the reaction mixture. The reaction mixture was stirred for 3 hours. Filtered the precipitated solid and then dried to get pure title compound. Yield: 60 g; MR: 128-131°C.

Example-9: Dabigatran etexilate Mesylate (Formula-la)

Dabigatran etexilate compound of formula-1 (50 g) was dissolved in acetone (500 ml) by heating to 50-60°C. The reaction mixture was filtered and the filtrate was cooled to 30-40°C. A solution of methane sulfonic acid (5.06 ml) dissolved in ethyl acetate (200 ml) was added to the reaction mixture at 26-32°C and stirred for 4 hours at 25-35°C. Filtered the precipitated solid and then dried to get title compound. Yield: 54 g; MR: 179-181°C.

The PXRD of the obtained compound matches with crystalline form-I of Dabigatran etexilate mesylate of WO2005028468.

Example-10: Preparation of crystalline form-I of Dabigatran etexilate mesylate (Formula-la) from tetrahydrofuran

Dabigatran etexilate (10 g) was dissolved in tetrahydrofuran (120 ml) and added methane sulfonic acid (1.5 g) to the reaction mixture. The reaction mixture was stirred for 5 hours at 25-30°C. Filtered the precipitated solid and then dried to get crystalline form-I of Dabigatran etexilate mesylate. Yield: 11 g; MR: 176-180°C.

The PXRD of the obtained compound matches with crystalline form-I of Dabigatran etexilate mesylate of WO2005028468.

Example-11: Preparation of crystalline form-I of Dabigatran etexilate mesylate (Formula-la) from acetonitrile

A mixture of Dabigatran etexilate (10 g) and acetonitrile (100 ml) was heated to 50-60°C and methane sulfonic acid (1.5 g) was added to the reaction mixture at 25-30°C and stirred for 5 hours at 25-30°C. Filtered the precipitated solid and then dried to get crystalline form-I of Dabigatran etexilate mesylate. Yield: 10.6 g; MR: 179-181°C.

The PXRD of the obtained compound matches with crystalline form-I of Dabigatran etexilate mesylate of WO2005028468.

Example-12: Preparation of crystalline form-M Dabigatran etexilate (-)-camphor sulfonate salt

A mixture of Dabigatran etxilate compound of formula-1 (50 g), acetone (250 ml) and (-)-camphor sulfonic acid (20.18 g) was stirred for 3 hours at 25-35°C. After completion of the reaction, the solvent from the reaction mixture was completely distilled off and then cooled to 25-30°C. Ethanol (50 ml), followed by methyl tertiary butyl ether (500 ml) were added to the obtained residue at 25-35°C and stirred for 12 hours at the same temperature. Filtered the precipitated solid and then dried to get crystalline form-M of title compound. Yield: 52 g; MR: 158-160°C.

The PXRD of the obtained compound is illustrated in figure-2.

Example-13: Preparation of amorphous Dabigatran etexilate (-)-camphor sulfonate salt
A mixture of Dabigatran etexilate compound of formula-1 (10 g), acetone (50 ml) and (-)-camphor sulfonic acid (4.09 g) was stirred for 3 hours at 25-35°C. After completion of the reaction, the solvent from the reaction mixture was concentrated to 10 ml and then cooled to 25-35°C. Acetone (5 ml) and followed by n-heptane (100 ml) was added to the reaction mixture at 25-3 5°C and stirred for 3 hours at the same temperature. The reaction mixture was heated to 50-55°C and stirred for 10 hours at the same temperature. Filtered the precipitated solid and then dried to get amorphous Dabigatran etexilate (-)-camphor sulfonate. Yield: 12 g; MR: 64-66°C.

The PXRD of the obtained compound is illustrated in figure-3.

Example-14: Preparation of crystalline form-S of Dabigatran etexilate oxalate.

Dabigatran etexilate (10 g) was dissolved in acetone (100 ml) at 25-35°C. A solution of oxalic acid (1.62 g) dissolved in acetone (25 ml) was added to the reaction mixture at 25-3 5°C and stirred for 5 hours at the same temperature. Filtered the precipitated solid and then dried to get crystalline form-S of Dabigatran etexilate oxalate. Yield: 91.3%; MR: 158-160°C.

The PXRD of the obtained compound is illustrated in figure-4.

Example-15: Preparation of crystalline form-N of Dabigatran etexilate fumarate.
Dabigatran etexilate (10 g) was dissolved in acetone (100 ml) at 25-35°C. A solution of fumaric acid (2.08 g) dissolved in acetone (25 ml) was added to the reaction mixture at 25-35°C and stirred for 5 hours at the same temperature. Filtered the precipitated solid and then dried to get crystalline form-N of Dabigatran etexilate fumarate. Yield: 73.91%; MR: 148-151°C.

The PXRD of the obtained compound is illustrated in figure-5.

We claim:

1. A process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-4-yl)benzamido)propanoate (diamino compound) compound of formula-7
comprising of reducing the ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-4-yl)benzamido) propanoate (nitro compound) compound of formula-6 with Fe-acetic acid in a suitable solvent.

2. Dabigatran etexilate (-)-camphor sulfonate salt.

3. Crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate which is characterized by its PXRD pattern having peaks at about 4.9, 5.3, 18.6, 6.2, 11.6, 17.3, 18.8 and 20.5 ± 0.2 degrees of 29 values as illustrated in figure-2.

4. Amorphous form of Dabigatran etexilate (-)-camphor sulfonate.

5. Crystalline form-S of Dabigatran etexilate oxalate which is characterized by PXRD pattern having peaks at about 3.9, 7.5, 7.8, 11.9, 18.2, 20.0 and 27.0 ± 0.2 degrees 26 values as illustrated in figure-4.

6. Crystalline form-N of Dabigatran etexilate fumarate which is characterized by PXRD pattern peaks at about 4.9 and 5.2 ± 0.2 degrees 29 values as illustrated in figure-5.

7. A process for the preparation of crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate, comprising of:

a) Reacting Dabigatran etexilate with (-)-camphor sulfonic acid in a suitable solvent selected from ketone solvents, ether solvents, ester solvents, alcoholic solvents, polar aprotic solvents, polar solvents and/or mixtures thereof,

b) distilling off the solvent completely from the reaction mixture,

c) adding alcoholic solvent to the reaction mixture,

d) adding an ether solvent to the reaction mixture,

e) stirring the reaction mixture,

f) filtering the precipitated solid and then dried to get crystalline form-M of Dabigatran etexilate (-)-camphor sulfonate.

8. A process for the preparation of amorphous Dabigatran etexilate (-)-camphor sulfonate, comprising of:

a) Reacting Dabigatran etexilate with (-)-camphor sulfonic acid in a suitable solvent selected from ketone solvents, ether solvents, ester solvents, alcoholic solvents, polar aprotic solvents, polar solvents and/or mixtures thereof,

b) distilling off the solvent from the reaction mixture,

c) adding a suitable solvent selected from ketone solvents, ester solvents and ether solvents, followed by hydrocarbon solvent to the reaction mixture,

d) heating the reaction mixture,

e) stirring the reaction mixture,

f) filtering the solid and then dried to get amorphous Dabigatran etexilate (-) -camphor sulfonate.

9. A process for the preparation of crystalline form of Dabigatran etexilate salt, comprising of:

a) Dissolving Dabigatran etexilate compound of formula-1 in acetone,

b) adding a solution of a suitable acid dissolved in acetone wherein the suitable acid is selected from oxalic acid and fumaric acid,

c) stirring the reaction mixture,

d) filtering the solid and then dried to get crystalline form of its corresponding Dabigatran etexilate salt.

10. A process for the preparation of crystalline form-I of Dabigatran etexilate mesylate compound of formula-la, comprising of:

a) Dissolving Dabigatran etexilate in acetonitrile,

b) adding a solution of methane sulfonic acid dissolved in acetonitrile,

c) stirring the reaction mixture,

d) filtering the precipitated solid and then dried to get crystalline form-I of Dabigatran etexilate mesylate compound of formula-la.