FIELD OF INVENTION
The present invention relates to a N-protected amino acid intermediates of Dabigatran etexilate mesylate, which facilities high pure and effective process for the preparation of Dabigatran etexilate mesylate of formula L
BACKGROUND OF THE INVENTION
Direct thrombin inhibitors are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin. Dabigatran is an oral anticoagulant of the direct thrombin inhibitors.
Dabigatran etexilate mesylate is chemically described as a Ethyl N-{[2-({[4-((E)-amino{[(hexyloxy)carbonyl]imino}methyl)phenyl]amino}methyl)-l-methyl-lH-benzimidazol-5-yl]carbonyl}-N-pyridin-2-yl-P-alaninate methanesulfonate, has the following structure
Its empirical formula is C34H41N7O5. CH4O3S with a molecular weight of 723.86 (Mesylate salt) and 627.75 (free base). Dabigatran etexilate mesyalte is commercially marketed under the trade name of PRADAXA® in USA, Europe, Australia and ' Canada.

Dabigatran and its pharmaceutical^ acceptable acid addition salts are first disclosed in US 6,087,380 (herein after US'380). The patent US'380 discloses a process for the preparation of Dabigatran etexilate in the example 58 and Example 113; said process ' for the preparation of Dabigatran etexilate is depicted in scheme-1.
Specific mesylate salt of Dabigatran etexilate process and its pharmaceutical composition is disclosed in example-3 of US2006183779A1 is depicted in scheme-2
The patent US'380 process for the preparation of Dabigatran etexilate suffers from one or more disadvantages like decrease in yield of final product, carryover

. . impurities, isolation of intermediates as well as API by column chromatography. These isolation methods are not economic on commercial scale. Hence there is a necessary to maintain the purity levels of every intermediate on stage wise to get highly pure Dabigatran etexilate.
■ To overcome the problem associated with US'380, several eco-friendly methods are
developed to get the highly pure Dabigatran etexilate mesylate.
The patent US 8,119,810 discloses the process for the preparation of Dabigatran etexilate mesylate from 3-({2-[(4-cyanophenylamino)-methyl]-l-methyl-lH-benzimidazole-5-carbonyl]-pyridin-2-yl-amino)ethyl propionate hydrobromide as one of the intermediate to overcome the problem of the process depicted in the patent US'380.
The patent application US 8,394,961 discloses a process for the preparation of Dabigatran etexilate mesylate by using 3-[(4-methylamino-3-nitro-benzoyl)-pyridin-2-yI-amino]-propionic acid ethyl ester hydrochloride and 3-({2-[(4-cyanophenylamino)-methyl]-l-methyl-lH-benzimidazole-5-carbonyl]-pyridin-2-yl-amino)ethyl propionate oxalate as one of the intermediate

The patent application US 8,394,962 discloses a process for the preparation of Dabigatran etexilate mesylate from 3-({2-[(4-cyanophenylamino)-methyI]-l-methyl-lH-benzimidazole-5-carbonyl]-pyridin-2-yl-amino)ethyl. propionate oxalate and by using following mentioned intermediates of Dabigatran free base
The patent US 8,981,105 discloses a process for the preparation of Dabigatran etexilate mesylate from 3-({2-[(4-cyanophenyIamino)-methyl]-l-methyl-lH-benzimidazoIe-5-carbonyl]~pyridin-2-yl-amino)ethyl propionate hydrochloride as one of the intermediate as depicted below
The patent US 9,006,448 discloses a process for the preparation of Dabigatran etexilate mesylate by using acid addition salts of Dabigatran, more preferably oxalic acid salt of Dabigatran as depicted below

Presence of impurities in each intermediate stage i.e. cyano Dabigatran, Dabigatran single prodrug, Dabigatran etexilate affects the purity of the final product. In the view of intrinsic fragility, there is a necessity to maintain the purity level in each and every intermediate stage to enhance the purity of the final .compound Dabigatran etexilate mesylate.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is use of N-protected amino acid intermediates, for the preparation of Dabigatran etexilate mesylate compound of Formula I
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of Dabigatran etexilate or pharmaceutical acid addition salts thereof of formula-1
comprising the steps of:
a) reacting a diamine compound of formula-2, with a compound of formula-3

in presence of a coupling agent optionally in presence of base, followed by cyclization in presence of suitable solvent to obtain a reaction mixture b) adding suitable N-protected amino acid to the reaction mixture obtained in the step-(a) to get cyano compound salt of formula-4,
c) basifying the compound of formula-4 prepared in the step (b) to obtain free base cyano compound of formula-4a
* without isolating step (c), is treated with an acid in suitable solvent followed by a
base to obtain a reaction mixture containing imidine of formula 5a.
d) adding suitable N-protected amino acid to the reaction mixture obtained in the
step-(c) to get Dabigatran prodrug compound of formula-5,

, e) basifying the compound of formula-5 prepared in the step (d) to obtain free base Dabigatran single prodrug compound of formuIa-5a,
without isolating step (e), is treated with n-hexyl chloroformate in presence of
<
suitable base and solvent to get Dabigatran etexilate of formula-6.
f) treating the compound of formula-6 with methane sulfonic acid in a suitable solvent to provide the Dabigatran etexilate mesylate of formula-1.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the production of the substantially pure Dabigatran etexilate mesylate of formula-1 by removing the undesired process impurities at intermediate stage, thereby increasing the yield and purity of the desired compound of formula-1.
The present invention is schematically represented as depicted in the following* scheme-3

The process for the preparation of Dabigatran etexilate mesylate of formula-1,
comprising the steps of:
a) reacting a diamine compound of formula-2, with a compound of formula-3
in presence of a coupling agent and optionally in presence of base, followed by' cyclization in presence of acid in a suitable solvent to obtain a reaction mixture b) adding suitable N-protected amino acid to the reaction mixture obtained in the step-(a) to get cyano compound of formula-4
c) basifying the compound of formula-4 prepared in the step (b)5 in a suitable solvent to obtain free base cyano compound of formula-4a

without isolating step (c), is treated with an acid in suitable solvent followed by a base to obtain a reaction mixture containing formula-5a.
d) adding suitable N-protected amino acid to the reaction mixture obtained in the step-(c) to get Dabigatran prodrug compound of formula-5,
e) basifying the compound of formuIa-5 prepared in the step (d) to obtain free base Dabigatran prodrug compound of formula-5a,
without isolating step (e), is treated with n-hexyl chloroformate in presence of suitable base and solvent to get Dabigatran etexilate of formula-6.
f) treating the compound of formula-6 with methane sulfonic acid in a suitable solvent to provide the Dabigatran etexilate mesylate of formula-1.

The term "suitable coupling agent" of the present invention is selected from the group comprising carbonyl-diimidazole (CDI), carbonyl-di(I,2,4-triazole), l-ethyl-3-(-3-dimethylaminopropyl) carbodiimide (EDC), dicyclohexylcarbodiimide (DCC) and polyphosphonic acid (PPA); preferably carbonyl-diimidazole. Optionally in presence of base like hydroxyl benzotriazole (HOBT), l-hydroxy-7-azabenzotriazole (HOAt), DMAP, tertiary amines or its hydrohalide salts such as triethyl amine hydrochloride, diisopropylethyl amine hydrochloride or mixture thereof.
Suitable acid used in cyclization is selected from but not limited to acetic acid, p-toluene sulfonic acid, methane sulfonic acid, chloroacetic acid and the like and mixtures thereof.
Suitable solvent used in stage-1, includes but are not limited to ethers, esters, halogenated hydrocarbons, amides, aromatic solvents, water or mixtures thereof The
ether includes, but are. not limited to tetrahydrofuran, 2-methyl tetrahydrofuran and
*
the like and mixtures thereof; esters include, but are not limited to methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like and mixtures thereof; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixtures thereof; amides includes, but are not limited to dimethyl formamide,. dimethyl acetamide, N-methyl pyrrolidinone and the like and mixtures thereof; aromatic solvents include, but are not limited to toluene, chlorobenzene and the like and mixtures thereof; preferably tetrahydrofuran, ethyl acetate, methylene chloride and the like and mixtures thereof.
Base used in stage-2, 3 and stage-4, includes organic and Inorganic bases. Organic bases selected from the group comprising of triethylamine, isopropyl amine,« diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, DBU, and DABCO; inorganic bases according to

the present invention are selected from the group comprising of alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide; metal alkoxides such as alkoxides of sodium, lithium or potassium, sodium tert-butoxide and like.
Acid used in stage-2a is selected from hydrochloric acid or hydrobromic acid and base is selected from ammonia source such as ammonium carbonate, ammonia, ammonium hydroxide.
Suitable solvent used in stage-2, 2a5 3, 3a and Stage-4 is selected from esters, halogenated hydrocarbons, ketone, alcoholic, aromatic solvents, water or mixtures thereof. The esters include, but are not limited to methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like and mixtures thereof; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixtures thereof; ketone includes but not limited to acetone, methylethyl * ketone, methylisobutyl ketone; alcoholic solvents includes but not limited to methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, tert-butanol etc, aromatic solvents include, but are not limited to toluene, chlorobenzene and the like and mixtures thereof; preferably, ethyl acetate, methylene chloride, acetone, ethanol, isopropanol, water and the like and mixtures thereof.
Base used in the process includes organic and inorganic bases. Organic bases selected from the group comprising of isopropyl amine, diisopropyl amine, diisopropyl ethyl-am ine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, DBU, DABCO and triethylamine; and the inorganic bases according to the present

invention are selected from the group comprising of alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide; metal alkoxides such as alkoxides of sodium, lithium or potassium, sodium tert- butoxide; alkali metal hydrides such as sodium hydride; alkali metal chlorides such as calcium chloride; alkali metal acetates such as acetate of calcium, potassium or lithium; and ammonia source such as ammonium carbonate, ammonia, ammonium hydroxide.
The term "N-protected amino acids" of the present invention includes but not limited to N-protected alkyl, acyl, aryl, arylalkyl, heteroaryl derivatives of Alanine, Phenyalanine, Proline, Cysteine, Lysine, Histidine, phenylalanine, Tyrosine, Glycine, Asparagine, Methionine, Serine, Tryptophan, Leucine, Gutamine, Isoleucine, Threonine etc.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
Example-1 Preparation of N-acetyl-L-phenyl alanine salt of Ethyl 3-(2-(((4-cyanophenyl) amino) methyl)-l-methyl-N-(pyridine-2-yl)-lH-benzo[d]imidazole-5-carboxa- mido)propanoate
Step-(a) To the mixture of 2-((4-cyanophenyl)amino) acetic acid (73 g, 0.4143 moles)
in dichloromethane (800 .mL) was added carbonyl diimidazole (67.2, 0.4144 moles),
stirred for 2 h at 25-30°C.. Ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)
. benzamido) propanoate (100 g, 0.2920 moles) was added lot wise for 1 h at the same

temperature and stirred for 8 h. After completion of reaction TLC, evaporated
*
dichloromethane under reduced pressure and added acetic acid (700 mL), heated to
85°C and stirred for 2 h. Acetic acid was evaporated under reduced pressure and
charged water (500 mL), dichioromethane (500 mL). The resulted solution was
stirred for 20 min, separated the layers and aq. layer was extracted with
dichloromethane (500 mL). The combined dichloromethane layers washed with 5%
sodium bicarbonate solution (500 mL) followed by water (500 mL). The clear
dichloromethane layers evaporated to give ethyl 3-(2-(((4-cyanophenyl)amino)
methyl)-1-methyl-N-(pyridine-2-yl)-lh-benzo[d] imidazole-5-carboxamido)
propanoate as an oily residue (-162 g).
Step-(b) The oily residue (25 g, 0.05181 moles) was dissolved in ethanol (100 ml) at 60-65 °C and N-acetyl-L-phenyl alanine (16.1 g, 0.0776 moles) was added at the t same temperature, stirred for 1 h. Ethanol was removed under reduced pressure. To the residue added ethanol (25 ml) followed by isopropyl acetate (75 ml), stirred for 20 min at 60-65°C. The resulting mixture was cooled to 25-30°C and stirred for 10 h. The solid was filtered and dried at 45-50°C to give title compound (20 g, 56%). Purity: 83.1%.
Example-2 Preparation of N-acetyl-L-phenyl alanine salt of Ethyl 3-(2-(((4-
carbamimidoylphenyl)amino)methyl)-l-methyI-N-(pyridin-2-yl)-lH-benzo[d]
imidazole-5-carboxamido)propanoate
Step-(a) N-Acetyl-L-phenyl alanine salt of ethyl 3-(2-(((4-cyanophenyl) amino) methyl)-l-methyl-N-(pyridine-2-yl)-lH-benzo[d]-imidazole-5-carboxamido)-propanoate (15 g, 0.0217 moles) was added to a solution of water (150 ml ) and dichloromethane (150 ml) at room temperature and stirred for 10 min. To the mixture pH was adjusted to 10-12 with aq. sodium hydroxide solution, stirred for 10 min and separated the layers. Aqueous layer extracted with dichloromethane (75 ml) and combined dichloromethane layers washed with water (75 ml) followed by brine

solution (75 ml). The clear dichloromethane layer was evaporated under reduced pressure and the obtained oily residue (-9.0 g) was dissolved in ethanol (180 ml) and purged dry HC1 gas while maintaining temperature at -5°C to 0°C for 10 h. The reaction mass temperature was raised to 25°C and maintained for 20 h. After, conforming the reaction completion by TLC, concentrated ethanol under reduced pressure at below 50°C and added fresh ethanol (90 ml). To the mixture added ammonium carbonate (19.75 g, 0.2050 moles) at below 20°C, stirred for 20 h 25-30°C. Filtered the undissoloved salts through hyflo. The mother liquor was evaporated to get ethyl 3-(2-(((4-carbamimidoylphenyl)amino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d] imidazole-5-carboxamido) propanoate as an oily residue
(10 g).
Step-(b) The above oily reside (9 g, 0.0167 moles) was dissolved in ethanol (90 mL) and added N-acetyl-L-phenyl alanine (5.2 g, 0.0250 moles, water (3 ml) at 70-75 °C, stirred for 1 h at the same temperature. Ethanol was removed under reduced pressure. To this ethanol (9 ml) was added followed by isopropanol (25 mL) and the mixture' was stirred for 20 min at 70-75°C. The resulting mixture was cooled to 25-30°C, stirred for 17 h. The solid was filtered and dried at 45-50°C to give title compound (5 g, 39.4 %). Purity: 93.2%
Example-3 Preparation of ethyl 3-(2-(((4-(7V-((hexyIoxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)-l-methyl-N-(pyridin-2-yI)-lH-benzo[d]imidazole-5-carboxamido) propanoate
Step-(a) N-Acetyl-L-phenyl alanine salt of ethyl 3-(2-(((4-carbamimidoylphenyl) amino) methyl)-l-methyl-N-(pyridine-2-yl)-lh-benzo[d]imidazole-5-carboxamido) propanoate (4.5 g, 0.0063 moles) was added to a solution of water (50 ml ) and dichloromethane (50 ml) at room temperature and stirred for 10 min. To the mixture pH was adjusted to 10-12 with aq. sodium hydroxide solution, stirred for 10 min and separated the layers. Aqueous layer extracted with dichloromethane (75 ml) and

combined dichloromethane layers washed with water (15 ml) followed by brine solution (15 ml). The clear dichloromethane layer was evaporated under reduced to give ethyl 3-(2-(((4-carbamimidoylphenyl)amino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo [d]imidazole-5-carboxamido) propanoate as an oily residue (-3 g). Step-(b) To a stirred mixture of potassium carbonate (2.3 g, 0.0166), water (6 mL) was added dichloromethane (24 mL) and TBAB (0.06 g, 1.8612), stirred for 5 min. To this mixture added above oily residue (3 g, 0.0060 moles) at 25-30°C and stirred' for 1 h at the same temperature. Cooled the mixture to 10-15°C and added a solution of n-hexyl chloroformate (1 g, 0.0060) in dichloromethane (6 mL) for 1 h. The temperature was slowly raised to 20-25°C and stirred for 1 h. After completion of reaction by TLC charged saturated sodium chloride solution (15 mL), stirred for 10 min and filtered the mass through hyflo. The filtrate was separated; aqueous layer was extracted with dichloromethane (12 mL) and the combine dichloromethane layer was washed with water (2x 15 mL). The clear dichloromethane layer was concentrated under reduced pressure and isolated in ethyl acetate (10 mL) to get the title compound (1.9 g, 50%). Purity: 80.1%.
« Example-4 Ethyl 3-(2-(((4-(N'-((hexyloxy) carbonyl) carbamimidoyl) phenyl)
amino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazoIe-5-carboxamido)
propanoate methanesulfonate (Dabigatran etexilate mesylate)
Ethyl 3-(2-(((4«(N'-((hexyloxy) carbonyl) carbamimidoyl) phenyl) amino) methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido) propanoate from example-3 (1.5 g, 0.0023 moles) was dissolved in acetone (15. mL) at 45°C, filtered through hyflo and washed with acetone (3.7 mL). The mother liquor was cooled to below 30° and added a solution of methane sulfonic acid (0.2 g, 0.0023 moles) in acetone (3.7 mL) for 45 min at below 30°C. The resulting mixture was stirred for 2-3 h at 25-30°C and the separated solid was filtered, washed with acetone (4.5 mL). The

wet solid was dried at 45-50°C under reduced pressure to give title compound (1.5 g, 87%). Purity: 99.5%.
Example-5 Preparation of 7V-vaIeroyl-L-phenyl alanine salt of ethyl 3-(2-(((4-cyanophenyl)-amino)-methyI)-l-methyl-N-(pyridine-2-yl)-lH-benzo[d] imidazoIe-5-carboxamido) propanoate
The oily residue of ethyl 3-(2-(((4-cyanophenyl) amino) methyl)-1 -methy 1-N-(pyridine-2-yl)-lH-benzo[d] imidazole-5-carboxamido) propanoate from example-l (5 g , 0.0103 moles) in ethanol (20 ml ) was added Af-valeroyl-L-phenyl alanine (3.9 g, 0.0156 moles) at 60-65 °C and stirred for 1 h at the same temperature. Ethanol was removed under reduced pressure. To the residue added ethanol (5 ml) followed by isopropyl acetate (15 mL) and stirred for 20 min at 60-65°C. The resulting mixture was cooled to 25-30°C, stirred for 3 hrs. The solid was filtered and dried at 45-50°C to give title compound (3 g, 41.6%). Purity: 80.2%, free base: 89.7%.
Example-6 Preparation of ./V-butyryl-L-phenyl alanine salt of ethyl 3-(2-(((4-cyanophenyl) amino) methyl)-l-methyl-N-(pyridine-2-yl)-lh-benzo[d]imidazole-5-carboxa- mido)propanoate
The oily, residue of ethyl 3-(2-(((4-cyanophenyl) amino) methy 1)-1 -methyl-TV-(pyridine-2-yl)-lh-benzo[d] imidazole-5-carboxamido) propanoate from example-l, ( step-1, (5 g , 0.0103 moles) in ethanol (20 ml ) was added N-butyryl-L-phenyl alanine (4.2 g, 0.0178 moles) at 60-65 °C and stirred for 1 h at the same temperature. Ethanol was removed under reduced pressure. To the residue added ethanol (5 ml) followed by isopropyl acetate (15 mL) and stirred for 20 min at 60-65°C. The . resulting mixture was cooled to 25-30°C, stirred for 3 hrs. The solid was filtered and dried at 45-50°C to give title compound (2.3 g, 31%). Purity: 82.8%, free base: 83.7%.

Example-7 Preparation of N-propionyl-L-phenyl alanine salt of ethyl 3-(2-(((4-cyano phenyl) amino) methyl)-l-methyl-N-(pyridine-2-yl)-lh-benzo [d]imidazo!e-5-carboxamido) propanoate
The oily residue of ethyl 3-(2-(((4-cyanophenyl) amino) methyl)- 1-methyI-N-(pyridine-2-yl)-lh-benzo [d] imidazole-5-carboxamido) propanoate from example-1 (5 g , 0.0103 moles) in ethanol (20 ml) was added N-propionyl-L-phenyl alanine (4.3 g, 0.0193 moles) at 60-65 °C and stirred for 1 h at the same temperature. Ethanol was removed under reduced pressure. To the residue added ethanol (5 ml) followed by isopropyl acetate (15 mL) and stirred for 20 min at 60-65°C. The resulting mixture was cooled to 25-30°C, stirred for 3 hrs. The solid was filtered and dried at 45-50°C to give title compound (6 g, 82.3 %). Purity: 82.2%, Free base: 85.1%.
Example-8 Preparation of N-valeroyl-L-phenyl alanine salt of ethyl 3-(2-(((4-carbamimido- ylphenyl) amino) methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido) propanoate
The oily residue of ethyl 3-(2-(((4-carbamimidoylphenyl)amino)methyl)-l-methyl-N-(pyridine-2-yl)-lH-benzo[d]imidazole-5-carboxamido)propanoate from example-2 (5 g, 0.0093 moles) in ethanol (43 ml) was added N-valeroyl-L-phenyl alanine (3.5 g, 0.0139 moles, water (2 mL) at 50-55 °C and stirred for 1 h at the same temperature. Ethanol was removed under reduced pressure. To the residue added ethanol (5 ml) followed by ethyl acetate. (75 mL) and stirred for 20 min at 45-50 °G. The resulting mixture was cooled to 25-30°C, stirred for 2-3 hrs. The solid was filtered and dried at 45-50°C to give title compound (3.3 g, 45%). Purity: 93.1%, free base: 73%.
ExampIe-9 Preparation of N-butyryl-L-phenyl alanine salt of ethyl 3-(2-(((4-carbamimidoyl phenyl) amino) methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo [d]imidazole-5-carboxamido) propanoate

The oily residue of ethyl 3-(2-(((4-carbamimidoylphenyl) amino) methyl)-1-methy 1-N-(pyridine-2-yl)-lh-benzo [d] imidazole-5-carboxamido) propanoate from example-2 (5 g , 0.0093 moles) in ethanol (43 ml) was added Af-butyryl-L-phenyl alanine (3.8 g, 0.01399 moles)»at 50-55 °C and stirred for 1 h at the same temperature. Ethanol t was removed under reduced pressure. To the residue added ethanol (5 ml) followed by Ethyl acetate (75 mL) and stirred for 20 min at 45-50 °C. The resulting mixture was cooled to 25-30°C, stirred for 15 h. The solid was filtered and dried at 45-50°C to give title compound (3.5 gr, 49.2%). Purity: 90.7%, free base: 78.7%.
Example-10 Preparation of N-propionyl-L-phenyl alanine salt of ethyl 3-(2-(((4-carbamimid- oylphenyl) amino) methyl)-l-methyI-N-(pyridin-2-yl)-lH-benzo [d]imidazole-5-carboxamido) propanoate
The oily residue of ethyl 3-(2-(((4-carbamimidoylphenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-lh-benzo [d] imidazole-5-carboxamido) propanoate from example-2 (5 g , 0.0093 moles) in ethanol (43 ml) was added N-propionyl-L-phenyl alanine • (3.095 g, 0.0139 moles) at 50-55 °C and stirred for 1 h at the same temperature. Ethanol was removed under reduced pressure. To the residue added ethanol (5 ml) followed by isopropanol (30 mL) and stirred for 20 min at 45-50 °C. The resulting mixture was cooled to 25-30°C, stirred for 15 h. The solid was filtered and dried at 45-50°C to give title compound (3.5 g, 52.2%). Purity: 91.3%, free base: 80.4%.
Claims:
1. A process for the preparation of Dabigatran etexilate mesylate of formula-1,
comprising the steps of:
a) reacting'a diamine compound of formula-2, with a compound of formula-3

in presence of a coupling agent and optionally a base, followed by cyclization in* presence of acid in suitable solvent to obtain a reaction mixture, adding suitable N-protected amino acid to the reaction mixture to get cyano compound of formula-4 in salt form
b) basifying the compound of formula-4 prepared in the step a), in a suitable solvent to obtain free base cyano compound of formula-4a
without isolating formula-4a is treated with an acid in suitable solvent followed by a base to obtain a reaction mixture containing imidine of formula 5a, adding suitable N-protected amino acid to the reaction mixture to get Dabigatran prodrug compound of formula-5 in salt form

c) basifying the compound of formula-5 prepared in the step (b) to obtain free base Dabigatran prodrug compound of formula-5a,
without isolating step c, is treated with n-hexyl chloroformate in presence of suitable base and solvent to get Dabigatran etexilate of formula-6
d) treating the compound of formula-6 with methane sulfonic acid in a suitable solvent to provide the Dabigatran etexilate mesylate of formula-1.
2. The process according to claim-1 (a), coupling agent is selected from carbonyl-diimidazole (GDI), carbonyl-di(l,2,4-triazole), l-ethyl-3-(-3- dimethylaminopropyl) carbodiimide (EDC)5 dicyclohexylcarbodiimide (DCC) and propanephosphonic acid

cyclic anhydride (PPA); preferably carbonyl-diimidazole; suitable acid used in cyclization in claim-1 (a), is selected from but not limited to acetic acid, p-toluene sulfonic acid, methane sulfonic acid, chloroacetic acid and the like and mixtures thereof; and base is selected during coupling reaction is selected from hydroxyl benzotriazole (HOBT), l-hydroxy-7-azabenzotriazole (HOAt), 6-chloro-l-hydroxy-lH-benzotriazoIe (Cl-HOBt), hydroxypuridines (HOPy), imidazos hydrohalide salts, l,8-Diazabicyclo[5.4.0]undec-7-en (DBU); tertiary amines or its hydrohalide salts such as triethyl amine hydrochloride, diisopropylethyl amine hydrochloride or mixture thereof.
3. The process according to claim-1 (a) & (b), suitable N-protected amino acid is selected from alanine, phenylalanine, proline, cysteine, lysine, etc; most preferably N-1 protected phenylalanine.
4. The process according to claim-3, N-protected alanine are selected from N-acetyl L-phenylalanine, N-propionyl-L-phenyl alanine, N-butyryl-L-phenyl alanine and N-valeroyl-L-phenyl alanine salts; more preferably N-acetyl L-phenylalanine.
5. The process according to claim-l(b) & (c), base is selected from organic or inorganic base; Organic bases is selected from triethylamine, isoprdpyl amine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, N-methyl piperidine, N-methyl pipcrazine, N-methyl pyridine, DBU, and DABCO most preferably triethylamine: Inorganic base is selected from alkali metals, alkali metal • carbonates, alkali metal carbonates, alkali metal hydroxides, metal alkoxides most preferably alkali metal hydroxides.

.6. The process according to claim-1(b), wherein acid is selected from hydrochloric acid or hydrobromic acid; Base is selected from ammonia source such as ammonium carbonate, ammonia, ammonium hydroxide.
* 7. The process for the preparation of compound of Formula-6, comprising the steps of
i) treating the compound of formula-4 in presence of suitable base and solvent to obtain free base cyano compound of formula-4a
without isolating formula-4a is treated with hydrochloric acid followed by a base like ammonium source in presence of alcoholic solvents to obtain a reaction mixture, adding suitable N-protected amino acid to the reaction mixture to get Dabigatran prodrug compound of formula-5 in salt form

ii) treating the compound of formula-5 in presence of suitable base and solvent to obtain free base of Dabigatran prodrug compound of formula-5a,
without isolating formula-5a is treated with n-hexyl chloroformate in presence of suitable base and solvent to get Dabigatran etexilate of formula-6.
8. The process according to claim-7, suitable base is selected from inorganic base « such as alkali metals, alkali metal carbonates, alkali metal hydroxides, metal alkoxides most preferably alkali metal hydroxides, alkali metal carbonates; suitable solvent is selected from ether, esters, halogenated hydrocarbons, ketone, alcoholic, aromatic solvents, water or mixture thereof.
9. The process according to claim-8, suitable base is selected from alkali metal hydroxides, alkali metal carbonates, suitable solvent is selected from esters, halogenated hydrocarbons, ketones, alcohols, water or mixture thereof.

10. N^prdtected amino acids of 3-(2-((4-cyanophenyl amino)-methyl)-l-methyl-1H-
bbnziim^ propanoate of formula-4 or
6thyi3-(2^4%midinophenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d] imidazole-5-fea^bpxamidb)pTopanoate of formula-5 as an intermediates for the preparation of c^tnjpduhd of formula-1.