Field of the Invention
The present invention relates to the process for the preparation of N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl ethyl ester known as dabigatran etexilate or its methanesulfonate salt commonly known as dabigatran etexilate mesylate.
Background of the Invention
N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl ethyl ester methanesulfonate is commonly known as dabigatran etexilate mesylate. Dabigatran etexilate mesylate is an anticoagulant drug selected 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 etexilate mesylate was approved both in US and Europe and commercially available under the brand name of Pradaxa. Dabigatran etexilate (I) and its methanesulfonate salt (Ia) is represented by the following structural formulas:

Dabigatran Etexilate (I)

Dabigatran etexilate mesylate (Ia)
Dabigatran etexilate and process for its preparation was first disclosed in WO 98/37075. According to the process disclosed in WO 98/37075, 4-methylamino-3-nitro-benzoyl chloride (2) was reacted with 3-(pyridin-2-ylamino)propionic acid ethyl ester in the presence of a base and a solvent to give 3-[(4-methylamino-3-nitrophenyl)carbonyl-pyridin-2-yl-amino]propionic acid ethyl ester (3). Compound (3) was hydrogenated to yield 3-[{[3-amino-4-(methylamino)phenyl)carbonyl}(pyridin-2-yl)amino]propionic acid ethyl ester (4) which on further cyclization in presence of a cyclising agent and 4-cyanophenyl glycine (5) yield 3-({2-[(4-cyanophenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl ester (6). The compound of formula (6) was treated with saturated ethanolic hydrochloric acid and ammonium carbonate to give a 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonylethyl)amide hydrochloride (7) which on further hydrolysis with a base in the presence of ethanol provides compound of formula (8). Compound of formula (7) can be coupled with n-hexyl chloroformate and a base to yield dabigatran etexilate (I), (Scheme 1)

WO2006/000353 provides the process for the preparation of dabigatran etexilate mesylate starting from 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (9). Compound of formula (9) was condensed with 3-[{[3-amino-4-(methylamino)phenyl)carbonyl}(pyridin-2-yl)amino]propionic acid ethyl ester (4) in presence of CDI / PPA / pivaloyl chloride to give a compound of formula (10) which was reduced with palladium/charcoal in presence of hydrogen to give 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide, and further treated with PTSA to give salt of formula (11). Compound of formula (11) was treated with n-hexyl chloroformate in the presence of a base to yield dabigatran etexilate (I) which on further treatment with methanesulphonic acid yields dabigatran etexilate mesylate (Ia), (Scheme 2).

The process for the preparation of mesylate salt of dabigatran etexilate and its polymorphic forms was disclosed in US 2005/234104. The disclosed process involves the reaction of dabigatran etexilate with methanesulphonic acid in acetone to provide dabigatran etexilate mesylate (Ia).
US20060183779A1 discloses process for the preparation of mesylate salt of dabigatran etexilate and its oral administration application. The disclosed process involves the reaction of dabigatran etexilate with methanesulphonic acid in ethylacetate to provide dabigatran etexilate mesylate (Ia).
US20110082299A1 provides a process for the preparation of dabigatran etexilate (I). 4-Methylamino-3-nitrobenzoic acid compound of formula (12) was reacted with ethyl-3-(pyridin-2-ylamino)propanoate, and was converted to the hydrochloride using a hydrogen chloride solution to give ethyl 3-[(4-methylamino)-3-nitrobenzoyl)pyridine-2-ylamino]propionate compound of formula (13), in which the nitro group is reduced by means of reaction with sodium dithionite. The resulting compound ethyl 3-[(4-methylamino)-3-aminobenzoyl)pyridine-2-ylamino]propionate of formula (4) is reacted with [(4-cyanophenyl)amino]acetic acid (5) in presence of carbonyldiimidazole/THF/acetic acid/oxalic acid to give a compound of formula (14). The compound of formula (14) is hydrolyzed in presence of an acid, which on further reaction with ammonium carbonate provides the intermediate of formula (7). The intermediate compound of formula (7) was further converted to dabigatran etexilate (I) by reacting with n-hexyl chloroformate, (Scheme 3).

US2007185333A1, US2010210845A1, US2011/0118471A1, US2011/0275824A1, US2011/0224441A1, US2011/0295018A1, US7880016B2 etc also discloses the possible methods of preparing dabigatran etexilate, its salts and intermediates thereof.
It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in a compound may arise from degradation of the compound itself, or during the preparation of the API. Impurities in dabigatran etexilate or any active pharmaceutical ingredient (API) are undesirable and might be harmful, as they would be carried over to pharmaceutical compositions, used for human consumption.
Regulatory authorities worldwide require drug manufactures to isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug substance obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels and within the limits, even if structural determination is not possible.
The processes disclosed above for the preparation of dabigatran, its esters and salts thereof have one or other drawbacks, ranging from low yields, low purity, complicated purifying operations and extremely onerous process with respect to manufacturing as it generates large amount of solid waste to be disposed etc.
Thus, there remains a need to develop an industrial friendly, substantially free of impurities process for the preparation of dabigatran, its esters and salts thereof on commercially economical scale and yielding high purity with higher yields.

Description of the Drawings

FIG. 1 depicts a powder X-ray diffractogram of J1 of methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V)
FIG. 2 depicts a powder X-ray diffractogram of J2 of methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V)
FIG. 3 represents IR spectrum of J2 of methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V)
FIG. 4 represents differential scanning calorimetry (DSC) of J2 of methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V)
FIG. 5 represents thermogravimetric analysis (TGA) J2 of methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V)
FIG. 6 depicts a powder X-ray diffractogram of J1 of [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI)
FIG. 7 depicts a powder X-ray diffractogram of J2 of [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI)
FIG. 8 represents IR spectrum of J2 of [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI)
FIG. 9 represents differential scanning calorimetry (DSC) of J2 of [(4-{N-[(Hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI)
FIG. 10 represents thermogravimetric analysis (TGA) J2 of [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI)
FIG. 11 depicts a powder X-ray diffractogram of J1 of dabigatran etexilate (I)
FIG. 12 depicts a powder X-ray diffractogram of J2 of dabigatran etexilate (I)
FIG. 13 depicts a powder X-ray diffractogram of J2 of dabigatran etexilate (I)
FIG. 14 depicts a powder X-ray diffractogram of J1 of dabigatran etexilate mesylate (Ia)
FIG. 15 depicts a powder X-ray diffractogram of J2 of dabigatran etexilate mesylate (Ia)

Summary of the Invention
The present invention relates to the process for the preparation of N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl ethyl ester known as dabigatran etexilate compound of formula (I) or its salt; preferably methanesulfonate salt (Ia).
It is an another object of the present invention to provide a simple, convenient, commercially viable, industrial friendly process for synthesizing dabigatran etexilate or its salt thereof.

It is another object of the present invention to provide novel intermediate compounds of formula (V) and (VI)

wherein, R in compound of formula (V) is an acid protecting group which can be selected preferably from C1-6 alkyl, aryl and heteroaryl.

In yet another embodiment R in compound of formula (V) is preferably methyl.

In yet another embodiment the invention provides a process for producing a novel intermediate compound of formula (V) or (VI).

A yet another object of the present invention provides a process for producing dabigatran etexilate (I) or its methanesulfonate salt (Ia) employing the use of the novel intermediates methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V) and [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI).

In an another object of present invention, it provides a process for preparation of dabigatran etexilate (I) or its methanesulfonate salt (Ia) which comprises the steps of: (a) reacting 4-aminobenzonitrile with ethyl bromoacetate in the presence of a suitable solvent to provide [(4-cyanophenyl)amino]acetic acid (II); (b) treating compound of formula (II) with a suitable solvent and HCl to provide methyl ({4-[imino(methoxy)methyl]phenyl}amino)acetate hydrochloride (III); (c) reacting compound of formula (III) with ammonia or any source of ammonia in the presence of a suitable solvent to provide methyl [(4-carbamimidoylphenyl)amino]acetate (IV); (d) treating compound (IV) obtained in step (c) with n-hexyl chloroformate, a base and a solvent to get an ester derivative methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V); (e) deprotection of an acid protecting group of compound (V) to get an acid intermediate [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI); (f) reacting compound of formula (VI) with ethyl 3-[{[3-amino-4-(methylamino)phenyl]carbonyl}(pyridin-2-yl)amino]propanoate (VII) in presence of the coupling reagent, a solvent and with or without the presence of a additive to get dabigatran etexilate (I); (g) optionally, converting dabigatran etexilate into to its salt (Ia).

The above and other objects are further attained and supported by the following embodiments described herein. However the scope of the invention is not restricted to described embodiments herein after.

Detailed Description of the Invention
In an object the present invention provides a process for preparation of dabigatran etexilate (I) or its salts preferably methanesulfonate salt (Ia) (Scheme 4) comprising the steps of:
(i) treating [(4-cyanophenyl)amino]acetic acid (II) with an alkylating agent in presence of a suitable solvent and acid to provide alkyl ({4-[imino(methoxy)methyl]phenyl}amino)acetate or salt thereof (III);
(ii) reacting compound of formula (III) or salt thereof with ammonia or any source of ammonia in the presence of a suitable solvent to provide alkyl [(4-carbamimidoylphenyl)amino]acetate (IV);
(iii) treating compound of formula (IV) obtained in step (ii) with n-hexyl chloroformate, a base and a solvent to get an ester derivative methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V);
(iv) deprotection of an acid protecting group of compound (V) to get an acid intermediate [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI);
(v) reacting compound of formula (VI) with ethyl 3-[{[3-amino-4-(methylamino)phenyl]carbonyl}(pyridin-2-yl)amino]propanoate (VII) in the presence of the coupling reagent, a solvent and with or without the presence of a additive to get dabigatran etexilate (I);
(vi) optional purification of dabigatran etexilate (I) using a suitable solvent or mixture thereof;
(vii) optionally, converting dabigatran etexilate into to its salt (Ia).
(viii) optionally purifying of dabigatran etexilate mesylate (Ia) using a suitable solvent or mixture thereof.

In yet another object the present invention provides a process for preparing dabigatran or its salts thereof from compound of formula (V) comprising the steps of:
(i) deprotection of an acid protecting group of methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate compound (V) to get an acid intermediate [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)-amino]acetic acid (VI);
(ii) reacting compound of formula (VI) with ethyl 3-[{[3-amino-4-(methylamino)phenyl]carbonyl}(pyridin-2-yl)amino]propanoate (VII) in the presence of the coupling reagent, a solvent and with or without the presence of a additive to get dabigatran etexilate (I);
(iii) optional purification of dabigatran etexilate (I) using a suitable solvent or mixture thereof;
(iv) optionally, converting dabigatran etexilate into to its salt (Ia).
(v) optionally purifying of dabigatran etexilate mesylate (Ia) using a suitable solvent or mixture thereof.

In yet another object the present invention provides a process for preparing methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate compound of formula (V) from [(4-cyanophenyl)amino]acetic acid (II) comprising the steps of:
(i) treating [(4-cyanophenyl)amino]acetic acid (II) with an alkylating agent in presence of a suitable solvent to provide alkyl ({4-[imino(methoxy)methyl]-phenyl}amino)acetate or salt thereof (III);
(ii) reacting compound of formula (III) or salt thereof with ammonia or any source of ammonia in the presence of a suitable solvent to provide alkyl [(4-carbamimidoylphenyl)amino]acetate (IV);
(iii) treating compound of formula (IV) obtained in step (ii) with n-hexyl chloroformate, a base and a solvent to get an ester derivative methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V);

In yet another object the present invention provides a process for preparing [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid compound of formula (VI) from [(4-cyanophenyl)amino]acetic acid (II) comprising the steps of:
(i) treating [(4-cyanophenyl)amino]acetic acid (II) with an alkylating agent in presence of a suitable solvent to provide alkyl ({4-[imino(methoxy)methyl]phenyl}amino)acetate or salt thereof (III);
(ii) reacting compound of formula (III) or salt thereof with ammonia or any source of ammonia in the presence of a suitable solvent to provide alkyl [(4-carbamimidoylphenyl)amino]acetate (IV);
(iii) treating compound of formula (IV) obtained in step (ii) with n-hexyl chloroformate, a base and a solvent to get an ester derivative methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V);
(iv) deprotection of an acid protecting group of compound (V) to get an acid intermediate [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (VI);

The process as defined above wherein the source of ammonia is required for the preparation of alkyl [(4-carbamimidoylphenyl)amino]acetate (IV) is preferably ammonium carbonate.

wherein,
R can be selected from C1-6 alkyl, aryl or heteroaryl.
R’ can be selected from H, C1-6 alkyl, aryl or heteroaryl.

R’’ can be selected from C1-6 alkyl.
The solvent as defined above can be selected from the group comprising of nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers, amides, dialkylsulfoxides, hydrocarbons, water or the mixtures thereof. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like, preferably acetonitrile. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
Esters as defined above are selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like. Halogenated hydrocarbons are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like. Amides are selected from the group comprising of N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylformamide, N-methylpyrrolidone and the like. Dialkyl sulfoxides can be selected from the group comprising of dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide and the like. Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the like.
A suitable base as defined above can be selected from a group comprising of an organic or inorganic bases. The inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like. Organic base is selected from the group comprising of triethylamine (TEA), N,N-diisopropylethylamine, tributylamine, triisopropylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (4-DMAP), 1,8-bis-(dimethylamino)naphthalene, 1-ethylpiperidine, 1-methylmorpholine, lutidine and mixtures thereof. Carbonates are selected from the group comprising of K2CO3, Cs2CO3 and Na2CO3 etc. Bicarbonates are selected from the group comprising of NaHCO3, KHCO3 etc. Hydroxides are selected from the group comprising of NaOH, KOH, LiOH, CsOH etc.
Coupling agents used for the coupling of [(4-{N-[(Hexyloxy)carbonyl]-carbamimidoyl}phenyl)amino]acetic acid (VI) with ethyl 3-[{[3-amino-4-(methylamino)phenyl]carbonyl}(pyridin-2-yl)amino]propanoate (VII) to obtain dabigatran etexilate (I) with or without additives can be selected from diisopropylcarbodiimide (DIC), N,N’-carbonyldiimidazole (CDI), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1H-benzotriazolium 1-[bis(dimethylamino)methylene]
-5chloro-,hexafluorophosphate (1-),3-oxide (HCTU), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), N,N’-dicyclohexylcarbodimide (DCC), N-(3-dimethylaminopropyl)-N’-ethylcarbonate (EDC) and the like.

The additives used for the preparation of dabigatran etexilate (I) from compound of formula (VI) can be selected from a group comprising of 4-dimethylaminopyridine (4-DMAP), diisopropylethylamine (DIPEA), 2-methylpyridine, 2,6-dimethylpyridine (lutidine), 2,4,6-trimethylpyridine (collidine), 4-(tetrahydropyrrolidinyl)pyridine, imidazole, N-methylimidazole, diazabicycloundecane (DABCO), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt), its aza derivative (HODhat) and the like, preferably 4-dimethylaminopyridine (4-DMAP).

The combination of alcohol and acid (alcohol/acid) such as methanol / ethanol / propanol / butanol etc. and hydrochloric acid can be used as alkylating agent.

A suitable salt as defined above can be selected from an acid salt formed from group comprising of an organic or inorganic acids. Organic acid is selected from the group comprising of methane sulphonic acid, benzene sulphonic acid, acetic acid, tartaric acid, malic acid, maleic acid etc. The inorganic acid is selected from group comprising of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid and the like.

In accordance with another object of the present invention there is provided novel intermediate of formula (V) and (VI).

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of dabigatran etexilate (I) according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of mesylate salt of dabigatran etexilate (Ia) according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.
The details of the process of the invention are provided in the Examples given below, which are provided by way of illustration only and therefore are not intended to limit the scope of the invention.

Examples
Example 1
Preparation of [(4-cyanophenyl)amino]acetic acid.
4-Aminobenzonitrile (100 g) was added to water (1000 ml) at 20-30° C. The reaction was then cooled up to 0-10°C in 1 hr. Ethyl bromoacetate (212 g) was added to the resulting mixture at 0-10°C and the temperature was raised up to 95-100°C and stirred for 10 hr. The reaction mixture was further cooled to 20-30°C and stirred for 3 hr. The product was filtered, washed with water and dried to obtain the title compound. (Yield: 250 g; 87.9%)

Example 2
Preparation of methyl ({4-[imino(methoxy)methyl]phenyl}amino)acetate hydrochloride.
To a solution of dichloromethane (750 ml) and methanol (250 ml), [(4-cyanophenyl)amino]acetic acid (100 g) was added and stirred at 20-30°C. Reaction mass was saturated with hydrogen chloride gas for 6-8 hr at 20-30°C and then stirred the reaction mixture for 40 hr at 20-30°C. The reaction mixture was then cooled to 0-5oC and stirred for 2 hr at 0-5oC. Product was filtered under vacuum and washed with chilled dichloromethane and dried at 50-55oC under vacuum for 20 hr. (Yield: 110.5 g; 69%)

Example 3
Preparation of methyl [(4-carbamimidoylphenyl)amino]acetate.
Methyl ({4-[imino(methoxy)methyl]phenyl}amino)acetate hydrochloride (90 g) and ammonium carbonate (167 g) was stirred with methanol (900 ml) at 20-30°C. The reaction mixture was heated up to 30-35oC for 5-6 hr and filtered under vacuum. Reaction mixture was washed with methanol (180 ml). The solvent was distilled off and the oily mass was treated with dichloromethane (450 ml) at 20-30°C for 30 min and was filtered under vacuum. Reaction mixture was further washed with dichloromethane to obtain a title compound and then dried under vacuum at 35-40°C for 20-25 hr. (Yield: 101.5 g; 110%)

Example 4
Preparation of methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]-acetate.
n-Hexyl chloroformate (55.6 g) in dichloromethane (140 ml) was added to a mixture of methyl [(4-carbamimidoylphenyl)amino]acetate (70 g), triethylamine (85.4 g) in dichloromethane (560 ml) at 0-5oC. The reaction mass stirred at 20-30oC for 3 hr and quenched with water (350 ml). Organic layer was washed three times with water and distilled out the solvent under vacuum. Water was added into the reaction mass and stirred for 1 hr at 20-30oC. Product was filtered, washed with water and dried under vacuum at 45-50oC for 20-25 hr (Yield: 87.4 g; 77.6%).
Melting point- 134.6-137.2oC
MS: m/z 336.1 (M+1)
1H-NMR (400MHz CDCl3 d ppm) : 7.80 (d, 2H, 8.8 Hz); 6.61 (d, 2H, 8.4 Hz); 4.74 (t, 1H, NH, 4.8 Hz); 4.15 (t, 2H, 7.2 Hz); 3.98 (d, 2H, 5.2 Hz); 3.82 (3H, s); 1.74 (m, 2H); 1.43 (m, 2H); 1.39-1.31 (m, 4H) and 0.92 (t, 3H, 6.8 Hz).

Example 5
Purification of methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]-acetate.
A solution of [4-(hexyloxycarbonylaminoiminomethyl)phenyl]carbamic acid methyl ester (1.5 g) in ethyl acetate (7.5 ml) was refluxed at 77°C for 10 min to get a clear solution. Reaction mixture was cooled to room temperature and stirred for 2 hr at 20-30°C. Filtered the solid mass and washed with ethyl acetate, dried the wet solid to obtain 0.9 g of solid. (Fig. 2)

Example 6
Preparation of [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid.
Methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (80 g), 10% aq. solution of lithium hydroxide (110 ml) was stirred in tetrahydrofuran (100 ml) for 3 hr. The solvent was distilled off in vacuum at 45-50oC. Water (400 ml) and ethyl acetate (160 ml) was added to the reaction mixture and the layers were separated and aqueous layer was further washed with ethyl acetate at 20-30oC. Reaction mixture was stirred at 20-30oC for 1 hr and pH of the reaction mixture was adjusted to 5-6 by using 20% aq. citric acid solution (120 ml). Reaction mass was stirred at 20-30oC for 1 hr and filtered under vacuum. Product was washed with water and dried under vacuum at 45-50oC for 20-25 hr (Yield: 66.4 g; 87.3%).
Melting point- 185.6-191.4oC
MS: m/z 322.1 (M+1)
1H-NMR (400MHz (CD3)2SO d ppm): 7.80 (d, 2H, 8.8 Hz); 6.58 (d, 2H, 8.8 Hz); d 3.98 (t, 2H, 6.8 Hz), 3.87 (broad s, 2H); 1.59 (m, 2H); 1.37-1.30 (m, 6H) and 0.88 (t, 3H, 6.4 Hz).
Example 7
Purification of [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid
To a solution of [4-(hexyloxycarbonylaminoiminomethyl)phenyl]carbamic acid (10 g) in water (50 ml) was added lithium hydroxide (1.43 g) at 20-30°C. The reaction mixture was stirred at 20-30°C to get a clear solution and then washed the reaction mixture with ethyl acetate and collected the aqueous layer. pH of the aqueous layer was adjusted to 5-6 with citric acid solution (6 g dissolved in 20 ml of water). Reaction mixture was stirred at room temperature for 1 hr. Solid mass was filtered and washed with water, dried the wet solid to obtain 5.5 g of solid. (Fig. 7)

Example 8
Preparation of dabigatran etexilate (I)
Ethyl 3-[{[3-amino-4-(methylamino)phenyl]carbonyl}(pyridin-2-yl)amino]propanoate (20 g), [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetic acid (56.3 g), N,N’-diisopropylcarbodiimide (11.05 g) and 4-dimethylaminopyridine (0.72 g) in dichloromethane (200 ml) were stirred at 20-30oC for 24 hr. Dichloromethane was distilled under vacuum. To the reaction mixture was added dichloromethane (40 ml) at 20-30oC. Water was added and organic layer was distilled under vacuum at 30-35oC. The residue was taken into acetic acid (100 ml) and heated at 95-100oC for 1 hr. The solvent was distilled off under vacuum and treated with water at 20-30oC. The reaction mass extracted with dichloromethane (100 ml) and organic layer was washed with 10% aqueous sodium carbonate solution and then water. The solvent was distilled out under vacuum. Charged ethyl acetate (200 ml) and heated the reaction mass up to the 80-82oC for 30 min. Cool the reaction mass to 20-30oC, stirred for 3 hr and filtered under vacuum. Wet cake obtained was washed with ethyl acetate and dried in vacuum at 45-50oC for 20-25 hr. (Yield: 18.6 g; 50%)

Example 9
Purification of dabigatran etexilate from isopropyl alcohol
A solution of dabigatran etexilate (5 g) in isopropyl alcohol (35 ml) was refluxed at 82°C for 30 min and cooled to room temperature and stirred for 2 hr. Solid mass was filtered and washed with isopropyl alcohol, dried the wet solid mass under vacuum at 45-50°C for 12 hr to obtain 3.3 g of crystalline solid. (Fig. 12)

Example 10
Purification of dabigatran etexilate from ethylacetate
A solution of dabigatran etexilate (5 g) in ethyl acetate (35 ml) was refluxed at 77°C for 30 min and cooled to room temperature and stirred for 2 hr. Solid mass was filtered and washed with ethyl acetate, dried the wet solid mass under vacuum at 45-50°C for 12 hr to obtain 3.1 g of crystalline solid. (Fig. 13)

Example 11
Preparation of dabigatran etexilate mesylate from dabigatran etexilate
Dabigatran etexilate (5 g) was stirred in acetone (35 ml) at 20-30oC and reaction mass was heated up to 40-46oC. Clear solution formed was filtered through hyflobed and reaction mass was cooled to 30-35oC. Methanesulphonic acid (0.75 g) in acetone (5 ml) was added to reaction mass at 25-35oC in 20-30 min and stirred for 1 hr. After 1 hr reaction mass filtered under vacuum and washed with acetone. Wet solid was dried under vacuum at 45-50oC for 4-5 hr. (Yield: 3.23 g; 72%) (Fig. 14)

Example 12
Purification of dabigatran etexilate mesylate
A solution of dabigatran etexilate mesylate (2.5 g) in acetone (25 ml) was refluxed at 56°C for 30 min, cooled to room temperature and stirred for 2 hr. Solid mass was filtered and washed with acetone, dried the wet solid mass under vacuum at 45-50°C for 4 hr to obtain 2.15 g of white crystalline solid. (Fig. 15).

CLAIMS:WE CLAIM :
1. A process for the preparation of dabigatran etexilate (I) and its salt thereof from compound of formula (V) comprising the steps of:
(i) deprotection of an acid protecting group methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate compound (V) to get an acid intermediate [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino]acetic acid (VI);
(ii) reacting compound of formula (VI) with ethyl 3-[{[3-amino-4-(methylamino)phenyl]carbonyl}(pyridin-2-yl)amino]propanoate (VII) in the presence of the coupling reagent, a solvent and with or without the presence of a additive to get dabigatran etexilate (I);
(iii) optional purification of dabigatran etexilate (I) using a suitable solvent or mixture thereof;
(iv) optionally, converting dabigatran etexilate into to its salt (Ia).
(v) optionally purifying of dabigatran etexilate mesylate (Ia) using a suitable solvent or mixture thereof.
2. A process according to claim 1, wherein compound of formula (V) can be prepared from the compound of formula (II) comprising the steps of:
(i) treating [(4-cyanophenyl)amino]acetic acid (II) with an alkylating agent in presence of a suitable solvent to provide alkyl ({4-[imino(methoxy)methyl]phenyl}amino)acetate or salt thereof (III);
(ii) reacting compound of formula (III) or salt thereof with ammonia or any source of ammonia in the presence of a suitable solvent to provide alkyl [(4-carbamimidoylphenyl)amino]acetate (IV);
(iii) treating compound of formula (IV) obtained in step (ii) with n-hexyl chloroformate, a base and a solvent to get an ester derivative methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate (V);
3. A novel process for the preparation of dabigatran etexilate (I) and its salt thereof comprising the steps of:
(i) treating [(4-cyanophenyl)amino]acetic acid compound of formula (II) with a suitable solvent to provide methyl ({4-[imino(methoxy)methyl]-phenyl}amino)acetate hydrochloride compound of formula (III);
(ii) reacting compound of formula (III) or salt thereof with ammonia or any source of ammonia in the presence of a suitable solvent to provide methyl [(4-carbamimidoylphenyl)amino]acetate compound of formula (IV);
(iii) treating compound of formula (IV) obtained in step (ii) with n-hexyl chloroformate, a base and a solvent to get an ester derivative methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]acetate compound of formula (V);
(iv) deprotection of an acid protecting group compound of formula (V) to get an acid intermediate [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)-amino]acetic acid compound of formula (VI);
(v) coupling compound of formula (VI) with ethyl 3-[{[3-amino-4-(methylamino)phenyl]carbonyl}(pyridin-2-yl)amino]propanoate compound of formula (VII) in the presence of the coupling reagent, a solvent and with or without the presence of a additive to get dabigatran etexilate (I);
(vi) optionally, converting dabigatran etexilate into to its salt (Ia).

4. A process according to any of the preceeding claims, wherein the solvent used is selected from the group comprising of nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers, amides, dialkylsulfoxides, water and mixtures thereof.
5. The process according to claim 4, wherein the solvent is selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylformamide, N-methylpyrrolidone, dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene and xylene.
6. The process according to any of the preceeding claims, wherein the base used is selected from the organic or inorganic bases selected from the group comprising of amines, carbonate, bicarbonate and hydroxides of alkali or alkaline earth metals.
7. The process according to claim 6, wherein the base used is selected from the group comprising of triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), tributylamine, triisopropylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (4-DMAP), 1,8-bis-(dimethylamino)naphthalene), 1-ethylpiperidine, 1-methylmorpholine, lutidine, K2CO3, Cs2CO3 and Na2CO3, NaHCO3, KHCO3, NaOH, KOH, LiOH and CsOH.
8. The process according to any of the preceeding claims, wherein the alkylating agent used is selected from the combination of alcohol and acid wherein, alcohol can be methanol, ethanol, propanol, butanol and the like and acid can be hydrochloric acid.
9. The process according to any of the preceeding claims, wherein the coupling agent used can be with or without additives is selected from the group comprising of diisopropylcarbodiimide (DIC), N,N’-carbonyldiimidazole (CDI), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 1H-benzotriazolium 1-[bis(dimethylamino)methylene]-5chloro-,hexafluorophosphate (1-),3-oxide (HCTU), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), N,N’-dicyclohexylcarbodimide (DCC), N-(3-dimethylaminopropyl)-N’-ethylcarbonate (EDC); more preferably diisopropylcarbodiimide (DIC) and additives can be selected from 4-dimethylaminopyridine (4-DMAP), diisopropylethylamine (DIPEA), 2-methylpyridine, 2,6-dimethylpyridine (lutidine), 2,4,6-trimethylpyridine (collidine), 4-(tetrahydropyrrolidinyl)pyridine, imidazole, N-methylimidazole, diazabicycloundecane (DABCO), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt), its aza derivative (HODhat) and the like.
10. A compound of formula (V)

wherein, R can be C1-6 alkyl, aryl or heteroaryl.

11. A compound of formula (VI)

12. Use of novel intermediate methyl [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino]acetate (Va) as claimed in claim 10 for the preparation of dabigatran etexilate (I) and its salts thereof.
13. Use of novel intermediate [(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino]acetic acid (VI) as claimed in claim 11 for the preparation of dabigatran etexilate (I) and its salt thereof.
14. A pharmaceutical composition comprising dabigatran etexilate (I), or a pharmaceutically acceptable salt thereof prepared by process of present invention and a pharmaceutically acceptable carrier.