Field of the Invention:

The present invention relates to novel salts of benzimidazole derivatives, preferably mesylate salt of benzimidazole derivatives which are useful intermediates in the synthesis of pure l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]amino methyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide mesylate represented by following structural formula-1.

Background of the invention:

l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benz imidazol-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 of Pradaxa.

Dabigatran etexilate and process for its preparation was first disclosed in WO 98/37075. The disclosed process involves the reaction of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate with 2-(4-cyanophenylamino) acetic acid in the presence of N,N-carbonyldiimidazole in tetrahydrofuran to provide ethyl 3-(2-((4-cyanophenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d] imidazole-5-carboxamido)propanoate, which is further converted into l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride by reacting with ammonium carbonate in ethanol, followed by treating with ethanolic hydrochloric acid. The obtained compound was reacted with n-hexyl chloroformate in presence of potassium carbonate in tetrahydrofuran/water provides Dabigatran etexilate and further conversion into its mesylate salt was not disclosed. The purity of Dabigatran etexilate prepared as per the disclosed process is not satisfactory, and also the said process involves chromatographic purification which 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 proceeds through the 1 -methyl -2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride (herein after referred as "Dabigatran hydrochloride"), which degrades to form impurities and resulting 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 novel salt form of l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)amide, which enhances the purity of the final compound.

The prior reported processes disclosed in WO2012004396 and WO2008095928 A1 involves the usage of inorganic salts like hydrochloride and hydrobromide salts of ethyl 3-(2-((4-cyanophenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d] imidazole-5-carboxamido) propanoate (herein after referred as "cyano intermediate") and ethyl 3 -(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1H- benzo[d] imidazole-5-carboxamido)propanoate (herein after referred as "amidino intermediate"). The inorganic acid addition salts are less stable when compared to the organic acid addition salts and also the process for the preparation of organic acid addition salts is very much easy when compared to inorganic acid addition salt. Inorganic acid addition salts of amidine intermediate seem to be hygroscopic in nature. Therefore, organic acid addition salts are always preferable to synthesize stable salts which in-turn enhances the purity of the final compound.

The oxalate salt of cyano intermediate was disclosed in WO2009111997. However as on date, there is no other organic acid addition salts of cyano intermediate were reported in the prior art for preparing pure Dabigatran etexilate. Henceforth, there is a need to develop a novel organic acid addition salt of cyano intermediate compound which is very much efficient when compared to its corresponding oxalate salt and that result in the formation of final compound with high purity and yield.

The prior reported process involves the usage of acetic acid and p-toluene sulfonic acid addition salts of amidine intermediate.

Summary of the Invention:

The first embodiment of the present invention relates to ethyl 3-(2-((4-cyano phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido) propanoate mesylate compound of formula-4.

The second embodiment of the present invention is to provide a process for the preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d] imidazole-5-carboxamido)propanoate mesylate compound of formula-4.

The third embodiment of the present invention relates to ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)- lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5.

The fourth embodiment of the present invention is to provide a process for the preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5.

The fifth embodiment of the present invention is to provide a 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)amide compound of formula-6 from ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5.

The sixth embodiment of the present invention is to provide a process for the purification of crystalline form-N of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5.

Brief description of drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of ethyl 3-(2-((4-cyano phenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)- lH-benzo[d]imidazole-5-carboxamido) propanoate mesylate compound of formula-4.

Figure-2: Illustrates the IR spectrum of crystalline form-M of ethyl 3-(2-((4-cyano phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido) propanoate mesylate compound of formula-4.

Figure-3: Illustrates the DSC thermogram of crystalline form-M of ethyl 3-(2-((4- cyanophenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5- carboxamido)propanoate mesylate compound of formula-4.

Figure-4: Illustrates the PXRD pattern of crystalline form-N of ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole- 5-carboxamido)propanoate mesylate compound of formula-5.

Figure-5: Illustrates the IR spectrum of crystalline form-N of ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole- 5-carboxamido) propanoate mesylate compound of formula-5.

Figure-6: Illustrates the DSC thermogram of crystalline form-N of ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole- 5-carboxamido) propanoate mesylate compound of formula-5.

Detailed description of the invention:

As used herein the present invention the term "suitable solvent" refers to solvent selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate 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 and the like; "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, isobutanol and the like; "chloro solvents" like dichloro methane, chloroform and dichloro ethane, carbon tetrachloride and the like; "nitrile solvents" like acetonitrile, propionitrile and the like; "nitro solvents" like nitro methane, nitro ethane and the like; polar solvents like water; and mixtures thereof.

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

As used herein the present invention the term "suitable condensing agent" refers to a reagent selected from pivaloyl chloride, polyphosphoric acid, carbodiimides such as N,N!-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N, N'-dicyclohexyl carbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), di phenylphosphoroazidate (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), 1-hydroxy-7-azatriazole (HOAt), 1 -hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base.

As used herein the present invention the term "suitable ammonia source" is selected from formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate and t-butyl carbamate.

The main object of the present invention is to provide novel salts of benzimidazole derivatives, preferably mesylate salt of ethyl 3-(2-((4-cyanophenylamino) methyl)-1 -methyl-N-(pyridin-2-yl)- lH-benzo[d]imidazole-5-carboxamido)propanoate compound of formula-4 and ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)- lH-benzo[d]imidazole-5-carboxamido)propanoate compound of formula-5.

The first embodiment of the present invention relates to ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carbox amido)propanoate mesylate compound of formula-4.

Further, the present invention also provides the crystalline form of ethyl 3-(2-((4-cyanophenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-4 (herein designated as crystalline form-M). The crystalline form-M of compound of formula-4, which is characterized by its powder XRD having peaks at about 4.9, 14.0, 14.6, 16.3, 18.4 and 22.4 ± 0.2 degrees two-theta and substantially as shown in figure-1; (or) by IR spectrum showing absorption peaks at about 2216, 3345, 1032 and 1174 cm"1 and substantially as shown in figure-2; (or) by its DSC thermogram showing endotherm at about 195.24°C as shown in figure-3.

The crystalline form-M of compound of formula-4 is further characterized by powder XRD having additional peaks at 16.5, 17.8, 20.8 and 24.0 ± 0.2 degrees two-theta and substantially as shown in figure-1.

The usage of crystalline solid of compound of formula-4 enhances the purity and yield of final compound i.e. Dabigatran etexilate mesylate.

The second embodiment of the present invention is to provide a process for the preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-4, comprising of reacting ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate compound of formula-2 with 2-(4-cyanophenyl amino)acetic acid compound of formula-3 in presence of a suitable condensing agent in a suitable solvent, and the obtained compound is in-situ converted into its mesylate salt compound of formula-4 as a crystalline solid by reacting with methane sulfonic acid in a suitable solvent.

Wherein, the suitable solvent used for the reaction of compound of formula-2 and compound of formula-3 is selected from ether solvents, hydrocarbon solvents, chloro solvents, ester solvents, ketone solvents and polar aprotic solvent or mixtures thereof; the suitable solvent for mesylate formation is selected from ester solvents, alcoholic solvents, ether solvents, chloro solvents and ketone solvents; and the suitable condensing agent is selected from pivaloyl chloride, polyphosphoric acid, carbodiimides such as N.N1-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N,N '-dicyclohexyl carbodiimide (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), di phenylphosphoroazidate (DPPA), P205, 3-(diethoxyphosphoryloxy)-l,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-1H-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.

In a preferred embodiment of the present invention is to provide a process for the preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-4, comprising of reacting ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate compound of formula-2 with 2-(4-cyano phenyl amino)acetic acid compound of formula-3 in presence of N,N-carbonyldiimidazole in tetrahydrofuran, and the obtained compound is in-situ converted into its mesylate compound of formula-4 as a crystalline solid by reacting with methane sulfonic acid in acetone.

The third embodiment of the present invention relates to ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5.

Further, the present invention also provides the crystalline form of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5 (herein designated as crystalline form-N). The crystalline form-N of compound of formula-5, which is characterized by its powder XRD having peaks at about 3.6, 10.8, 22.9 and 32.6± 0.2 degrees two-theta and substantially as shown in figure-4; (or) by its IR spectrum showing absorption peaks at about 1044, 1179 and 3155 cm-1 and substantially as shown in figure-5; (or) by its DSC thermogram showing endotherm peak at about 199.65°C as shown in figure-6.

The crystalline form-N of compound of formula-5 is further characterized by powder XRD having additional peaks at 12.8, 15.4, 20.2, 27.0 and 46.8 ± 0.2 degrees two-theta and substantially as shown in figure-4.

The usage of crystalline solid of compound of formula-5 enhances the purity and yield of final compound i.e. Dabigatran etexilate mesylate.

The fourth embodiment of the present invention is to provide a process for the preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5, comprising of treating ethyl 3-(2-((4-cyanophenylamino)methyl)-l -methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-4 with a suitable ammonia source and/or ammonia gas in presence of hydrogen chloride gas and lewis acid in a suitable solvent to provide compound of formula-5 as a crystalline solid.

Wherein, the suitable solvent used is selected from alcoholic solvents, chloro solvents, ether solvents, ketone solvents or mixtures thereof; and the lewis acid used is selected from aluminium chloride (AICI3), aluminium bromide (AlBr3), boron trifluroide (BF3), boron trichloride (BC13), Ferric chloride (FeCl3), Tin(IV) chloride (SnCl4 ), Calcium chloride (CaCk) and calcium chloride dihydrate (CaCl2.2H20), preferably calcium chloride and calcium chloride dehydrate or mixture there of; the suitable ammonia source is selected from ammonium carbonate, ammonium formate, formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate and t-butyl carbamate.

In a preferred embodiment of the present invention is to provide a process for the preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5, comprising of treating ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-4 with ammonium carbonate in presence of ammonia gas, hydrogen chloride gas and calcium chloride in ethanol to provide compound of formula-5 as a crystalline solid.

The fifth embodiment of the present invention is to provide a 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)amide compound of formula-6, comprising of:

a) Reacting n-hexanol and N,N-carbonyldiimidazole in a suitable solvent to provide an amide compound,

b) reacting the amide compound of step-a) in-situ with the crystalline solid of ethyl 3-(2-((4-carbamimidoylphenylarriino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5 in presence of a suitable base in a suitable solvent.

Wherein,

in step-a) the suitable solvent is selected form chloro solvents, ester solvent, ether solvents, ketone solvents, polar aprotic solvents and nitrile solvents; and

in step-b) the suitable solvent is organic solvent selected from polar aprotic solvent, ether solvents, ester solvents, nitrile solvents and ketone solvent, or mixture of water and organic solvent; and the suitable base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate and the like. The step-b) of above aspect can be carried out at a temperature ranging from 10-50°C, preferably 25-35°C.

In a preferred embodiment of the present invention is to provide a process for the preparation of 1 -methyl-2-pST-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-6, comprising of:

a) Reacting n-hexanol and N, N-carbonyldiimidazole in dichloromethane to provide an amide compound,

b) reacting the amide compound of step-a) in-situ with the crystalline solid of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1H-benzo[d] imidazole-5-carboxamido)propanoate mesylate compound of formula-5 in presence of potassium carbonate in aqueous acetonitrile.

The mesylate salt of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)- lH-benzo[d] imidazole-5-carboxamido)propanoate compound of formula-5 will results in the formation of Dabigatran etexilate with purity 99.6 % by HPLC, which in-turn enhances the purity of final compound i.e. Dabigatran etexilate mesylate.

Alternatively, 1 -methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl]amino methyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide compound of formula-6 can be prepared from crystalline solid of ethyl 3-(2-((4-carbamimidoylphenyl amino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido) propanoate mesylate compound of formula-5 and n-hexylchloroformate in presence of a suitable base in a suitable solvent.

Wherein, the suitable base is selected from alkali metal carbonate such as sodium carbonate, potassium carbonate; and alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; organic bases selected from triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and mixtures thereof.

Alternatively, 1 -methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl] amino methyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-6 can be prepared from crystalline solid of ethyl 3-(2-((4-carbamimidoylphenylamino) methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5 and n-hexanol in presence of a suitable condensing agent and a suitable base in a suitable solvent.

Wherein, the suitable condensing agent is selected from pivaloyl chloride, polyphosphoric acid, carbodiimides such as N2-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylamino propyl)carbodiimide (EDC), N2-dicyclohexyl carbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), di phenylphosphoroazidate (DPPA), P2O5, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT). The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azatriazole (HOAt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-l-yl)-1,1,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base.

The sixth embodiment of the present invention is to provide a process for the purification of crystalline form-N of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5, comprising of:

a) Dissolving the ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate mesylate salt compound of formula-5 in alcoholic solvent,

b) adding a suitable non-polar solvent to the reaction mixture,

c) stirring the reaction mixture,

d) filtering the obtained solid and drying to get the pure crystalline form-N of compound of formula-5.

Wherein, the suitable non-polar solvent is selected from ether solvents, ester solvents, ketone solvents, nitrile solvents, hydrocarbon solvents, chloro solvents etc.

Compound of formula-2 and compound of formula-3 of the present invention can be prepared as per known methods.

The present invention schematically represented as follows:

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:

Example-1: Preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N- (pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate mesylate (Formula-4)

A solution of N, N-carbonyldiimidazole in tetrahydrofuran (prepared by dissolving die 161.04 g of N,N-carbonyldiimidazole in 1000 ml of tetrahydrofuran under nitrogen atmosphere) was added to a solution of 2-(4-cyanophenylamino)acetic acid compound of formula-3 (154.32 g) in tetrahydrofuran (600 ml) under nitrogen atmosphere and stirred for 3 hours at 25-35°C to form an amide compound. A solution of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate compound of formula-2 (200 g) in tetrahydrofuran (1000 ml) was added to the above reaction mixture containing amide compound and stirred for 24 hours at 25-35°C. After completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure and then acetic acid (1200 ml) was added to the reaction mixture. The reaction mixture was heated to 55-65°C and then stirred for 7 hours at 55-65°C. After completion of the reaction, the reaction mixture was quenched with water and then extracted into dichloromethane. The dichloromethane layer was concentrated to get residue and then acetone (1200 ml) was added to the obtained residue. A solution of methane sulfonic acid (28.4 ml) in acetone (400 ml) was added to the reaction mixture at 0-10°C and then stirred for 3 hours at 0-10°C. Filtered the obtained solid and further purified from acetone (1000 ml) to get pure title compound. MR: 188-190°C; Yield: 220 g; purity by HPLC: 98%; 1H NMR (DMSO-d6, TMS as internal standard) δ: 1.09-1.13 (3H, t), 2.32 (3H, s), 2.67-2.72 (2H, t), 3.92 (3H, brs), 3.95-4.00 (2H, q), 4.19-4.24 (2H, t), 4.49 (1H, brs), 4.91 (2H, brs), 6.83-6.86 (2H, d), 7.05-7.08 (1H, d), 7.14-7.18 (1H, q), 7.38-7.41 (1H, d), 7.53-7.64 (4H, m), 7.78-7.80 (1H, d), 8.36-8.37 (1H, brd).

PXRD, IR spectrum and DSC thermogram of the obtained compound of formula-4 is illustrated in figure-1, figure-2 and figure-3 respectively.

ExampIe-2: Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate (Formula-5) Calcium chloride (125 g) was added to ethanolic hydrochloric acid (1500 ml) at 25-35°C followed by ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d] imidazole-5-carboxamido)propanoate mesylate compound of formula-4 (500 g) at -15 to -5°C. The temperature of the reaction mixture was raised to 25-35°C and then stirred for 10 hours at that temperature. After completion of the reaction, ethanol (2500 ml) was added to the reaction mixture at 25-35°C. Ammonium carbonate (2000 g) was added to the reaction mixture followed by ammonia gas was purged into the reaction mixture at 20-40°C and stirred for 20 hours. After completion of the reaction, filtered the reaction mixture and the filtrate was concentrated to get title compound. The obtained compound was further dissolved in ethanol (500 ml), ethyl acetate (2500 ml) was added to the reaction mixture and then stirred for 2 hours at 25-35°C. Filtered the solid and then dried to get pure title compound. Yield: 400 g; MR: 198-202°C; purity by HPLC: 95%; 1H NMR (DMSO-d6, TMS as internal standard) δ: 1.08-1.13 (3H, t), 2.32 (3H, s), 2.64-2.69 (2H, t), 3.76 (3H, brs), 3.92-3.99 (2H, m), 4.19-4.23 (2H, t), 4.63-4.64 (2H, brd), 6.84-6.90 (3H, m), 7.09-7.16 (2H, m), 7.38-7.41 (2H, m), 7.46 (1H,brs), 7.51-7.57 (1H, t), 7.62-7.65 (2H, bit), 8.37-8.38 (1H, brd), 8.51 (1H, brs), 8.82 (2H, brs). PXRD, IR spectrum and DSC thermogram of the obtained compound of formula-5 is illustrated in figure-4, figure-5 and figure-6 respectively.

Example-3: Preparation of l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl]aminomethyl]benzimidazol-5-yI-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonylethyI)amide (FormuIa-6)

n-hexanol (38.76 g) was added to a solution of N,N-carbonyldiimidazole (76;95 g) in dichloromethane (400 ml) and stirred for 3 hours at 15-25°C. The dichloromethane was distilled under reduced pressure to form an amide compound. To a mixture of acetonitrile (420 ml), water (280 ml) and ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)- lH-benzo[d]imidazole-5-carboxamido) propanoate mesylate compound of formula-5 (100 g), added potassium carbonate (128.7 g) at 25-35°C and stirred for 15 minutes. To this reaction mixture, a solution of obtained amide compound in acetonitrile (150 ml) was added at 25-3 5°C and stirred for 24 hours. After completion of the reaction, filtered the solid and purified from ethyl acetate (500 ml) to get title compound. Yield: 68 grams; MR: 128-131°C; purity by HPLC: 99.6 %

We claim:
1. Ethyl 3-(2-((4-cyanophenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d] imidazole-5-carboxamido)propanoate mesylate compound of formula-4.

2. Ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-1H-benzo[d] imidazole-5-carboxamido)propanoate mesylate compound of formula-5.

3. A crystalline form-M of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-4, which is characterized by:

a) its PXRD pattern having peaks at about 4.9, 14.0, 14.6, 16.3, 18.4 and 22.4 ± 0.2 degrees two-theta as illustrated in figure-1 (or)

b) its IR spectrum having absorption peaks at about 2216, 3345, 1032 and 1174 cm-1 as illustrated in figure-2 (or)

c) its DSC thermogram showing an endotherm peak at about 195.24°C as illustrated in figure-3.

4. A crystalline form-N of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl- N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5, which is characterized by

a) its PXRD pattern having peaks at about 3.6, 10.8, 22.9 and 32.6± 0.2 degrees two-theta as illustrated in figure-4 (or)

b) its IR spectrum showing absorption peaks at about 1044, 1179 and 3155cm" as illustrated in figure-5 (or)

c) its DSC thermogram showing an endotherm peak at about 199.65°C as illustrated in figure-6.

5. A process for the preparation of ethyl 3-(2-((4-cyanophenyl amino)methyl)-l-methyl- N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-4, comprising of reacting ethyl 3-(3-amino-4-(methylarnino)- N-(pyridin-2-yl) benzamido)propanoate compound of formula-2 with 2-(4-cyanophenylamino)acetic acid compound of formula-3 in presence of a suitable condensing agent in a suitable solvent, and the obtained compound is in-situ converted into its mesylate salt compound of formula-4 as a crystalline solid by reacting with methane sulfonic acid in a suitable solvent.

6. A process for the preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)- 1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5, comprising of reacting the crystalline solid of ethyl 3-(2-((4-cyanophenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d] imidazole-5-carboxamido)propanoate mesylate salt compound of formula-4 with a suitable ammonia source and/or ammonia gas in presence of hydrogen chloride gas and lewis acid in a suitable solvent to provide compound of formula-5 as a crystalline solid.

7. A process for the preparation of l-methyl-2-[N -[ -[4-(N-n-hexyloxycarbonylamidino) phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonylethyl)amide compound of formula-6, comprising of:

a) Reacting n-hexanol and N,N-carbonyldiimidazole in a suitable solvent to provide an amide compound,

b) reacting the amide compound of step-a) in-situ with the crystalline solid of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5 in presence of a suitable base in a suitable solvent to provide compound of formula-6.

8. A process for the preparation of l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonylethyl)amide compound of formula-6, comprising of:

a) Reacting ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate compound of formula-2 with 2-(4-cyanophenylamino)acetic acid compound of formula-3 in presence of suitable condensing agent in a suitable solvent, and the obtained compound is in-situ converted into its mesylate salt compound of formula-4 as crystalline solid by reacting with methane sulfonic acid in a suitable solvent,

b) reacting the compound of formula-4 with a suitable ammonia source and/or ammonia gas in presence of hydrogen chloride gas and lewis acid in a suitable solvent to provide ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate mesylate compound of formula-5 as crystalline solid,

c) reacting n-hexanol and N,N-carbonyldiimidazole in a suitable solvent to provide an amide compound,

d) reacting the amide compound of step-c) in-situ with the compound of formula-5 of step-b) in presence of a suitable base in a suitable solvent to provide compound of formula-6.

9. A process according to claim 8,

in step-a) the suitable solvent for the reaction of compound of formula-2 and compound of formula-3 is selected from ether solvents, hydrocarbon solvents, chloro solvents, ester solvents, ketone solvents and polar aprotic solvents or mixtures thereof; the suitable solvent for mesylate formation is selected from ester solvents, alcoholic solvents, ether solvents, chloro solvents and ketone solvents; the suitable condensing agent is selected from pivaloyl chloride, polyphosphoric acid, carbodiimides such as N , N1- diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), NjN'-dicyclohexyl carbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), di phenylphosphoroazidate (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 (HO At), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-l-yl)-1,1,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base.

in step-b) the suitable solvent is selected from alcoholic solvents, chloro solvents, ether solvents, ketone solvents or mixtures thereof; and lewis acid is selected from AICI3, AlBr3, BF3, BCl3, FeCl3, SnCl4 CaCl2 and CaCl2.2H20; the suitable ammonia source is selected from formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate and t-butyl carbamate, in step-c) the suitable solvent is selected from chloro solvents, ester solvents, ether solvents, ketone solvents, polar aprotic solvents and nitrile solvents; and

in step-d) the suitable solvent is organic solvent selected from polar aprotic solvents, ether solvents, ester solvents, nitrile solvents and ketone solvents, or mixture of water and organic solvent; and the suitable base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate and the like.

10. A process for the purification of crystalline form-N of ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate salt compound of formula-5, comprising of:

a) Dissolving the ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido)propanoate mesylate salt compound of formula-5 in alcoholic solvent,

b) adding a suitable non-polar solvent selected from ether solvents, ester solvents,

ketone solvents, nitrile solvents, hydrocarbon solvents and chloro solvents to the reaction mixture,

c) stirring the reaction mixture,

d) filtering the obtained solid and drying to get crystalline form-N of compound of formula-5.