WO2013144903A1

WO2013144903A1 - Processes for the preparation of dabigatran etexilate

Info

Publication number: WO2013144903A1
Application number: PCT/IB2013/052500
Authority: WO
Inventors: Vilas Hareshwar Dahanukar; Raghupathi Reddy Anumula; Pranab Haldar; Ravi Ram Chandrashekar ELATI; Ravi Kumar Mylavarapu; Prapulla kumar PALVAI; Anil Kumar PRATAPRAO
Original assignee: Dr. Reddy's Laboratories Limited
Priority date: 2012-03-28
Filing date: 2013-03-28
Publication date: 2013-10-03

Abstract

The present application relates to processes for preparing Dabigatran etexilate, including pharmaceutically acceptable salts or tautomers thereof.

Description

PROCESSES FOR THE PREPARATION OF DABIGATRAN ETEXILATE

INTRODUCTION

Aspects of the present application relate to processes for preparing dabigatran etexilate, including pharmaceutically acceptable salts or tautomers thereof. Particular aspects of the present application relate to processes for preparing dabigatran etexilate mesylate.

The drug compound having the adopted name "dabigatran etexilate mesylate" is a direct thrombin inhibitor and is the active ingredient in the product marketed by Boehringer Ingelheim as PRADAXA^®, for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. A chemical name for dabigatran etexilate is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1 -methyl-1 H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-, ethyl ester. The methanesulfonate salt of dabigatran etexilate mesylate can structurally be represented as formula I.

The synthesis of dabigatran etexilate and the other substituted (4- benzimidazol-2-ylmethylamino) benzamidines was first described in International Patent Application Publication No. WO 98/37075 and another process has been described in WO 2006/000353. However, the synthetic methods described in the prior art are not effective for large scale production because of tedious workup procedures for example, less yield, low purity, separation by column chromatography and this results in excessive production time, which in turn renders the process more costly and less eco-friendly; thus the processes are not suitable for commercial scale up.

There remains a need for an improved, simple, robust, commercially advantageous, eco-friendly, and industrially viable processes for the preparation of dabigatran etexilate, including pharmaceutically acceptable salts and tautomers thereof. SUMMARY

In a first aspect, the present application provides a process for preparing dabigatran etexilate of formula II or pharmaceutically acceptable salts thereof, embodiments comprising:

a) reacting a compound of formula III

with a suitable reagent, to provide an imidate compound of formula IV, or a salt thereof;

b) reacting the compound of formula IV or a salt thereof with a suitable reagent to provide the amidine compound of formula V or a salt thereof;

c) reacting the compound of formula V or salt thereof with a compound of formula VI,

wherein X denotes a nucleofugic leaving group, such as mesyl (CH₃S0₂ ^~), tosyl (4- CH₃C₆H₄S0₂ ^" ), chlorine, bromine or iodine optionally, in the presence of a base to provide compound of formula II or salt thereof; and

d) optionally, converting the compound of formula II or salt thereof into the corresponding salt or free base or tautomer thereof; with the proviso that at least two of the steps a) to d) are carried out in one pot.

In a second aspect, the present application provides a process for preparing amidine compound of formula V, embodiments comprising:

with triethyl orthoformate, to provide imidate compound of formula IV or a salt thereof; and

b) optionally without isolation, reacting the compound of formula IV or a salt thereof with a suitable reagent to provide the amidine of formula V or a salt thereof. 2

In a third aspect, the present application provides a process for preparing dabigatran etexilate of formula II or pharmaceutically acceptable salts thereof, embodiments comprising:

a) reacting a compound of formula III

with triethyl orthoformate, to provide an imidate compound of formula IV, or a salt thereof;

b) optionally without isolation, reacting the compound of formula IV or salt thereof with a suitable reagent to provide the amidine of formula V or a salt thereof;

c) reacting the compound of formula V or salt thereof with a compound of formula VI

v

wherein X denotes a nucleofugic leaving group, such as mesyl (CH₃S0₂-), tosyl (4- CH₃C₆H₄S02- ), chlorine, bromine or iodine optionally, in the presence of a base to provide compound of formula II or salt thereof; and d) optionally, converting the compound of formula II or salt thereof into the corresponding salt or free base or tautomer thereof.

In a fourth aspect, the present application provides dabigatran etexilate of formula II, which is substantially free from process related impurities.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 : Powder X-Ray diffraction pattern of compound of formula V obtained according to example: 12. DETAILED DESCRIPTION

Aspects of the present application relate to processes for preparing dabigatran etexilate or its pharmaceutically acceptable salts thereof.

Inventors of the present application have developed a process for preparing dabigatran etexilate, pharmaceutically acceptable salts or tautomers thereof, comprising performing at least two steps of the said process in one pot. The process of the present application is favorable for large scale production, avoids the need for time-consuming, costly isolation of intermediates and also affords to save time and resources by avoiding purifications between individual steps as desired, minimizes the transfer of material between vessels and thus renders the process more suitable for a commercial scale up.

reacting a compound of formula III

v

wherein X denotes a nucleofugic leaving group, such as mesyl (CH₃S0₂ ), tosyl (4-

CH₃C₆H₄S02^" ), chlorine, bromine or iodine optionally in the presence of a base to provide compound of formula II or salt thereof; and

In embodiments of the present application, the cyano compound of formula III which is used herein for the synthesis of a compound of formula II, may be prepared using methods known to the skilled artisan in organic synthesis, as well as by the methods taught in the art.

In embodiments of the present application, the cyano compound of formula III used in the reaction may include:

i) direct use of a reaction mixture containing formula III compound that is obtained in the course of its synthesis and that comprises a suitable solvent, or by combining a solvent with the reaction mixture; or

ii) dissolving formula III compound in a solvent. In embodiments of step a), suitable reagents used for the reaction include, but are not limited to: alcohols such as methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2-butanol or iso-butyl alcohol.

In embodiments of step a), suitable reagents, alcohols in the reaction may be used directly or generated within the reaction mixture.

In embodiments of step a), the reaction may be carried out optionally in the presence of an acid. Useful acids for the reaction include, but are not limited to: inorganic acids such as hydrofluoric, hydrochloric, hydrobromic, hydroiodic, nitric, perchloric, sulfuric or phosphoric acid; organic acids, such as xinafoic, oxalic, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, 2- or 4- methoxybenzoic, 2- or 4-hydroxybenzoic, 2- or 4-chlorobenzoic, salicylic, succinic, malic, hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, oleic, glutaric acids, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2- hydroxyethanesulphonic, benzenesulfonic, toluene-p-sulfonic, naphthalene-2- sulphonic or camphorsulfonic acids; lewis acids; or any other suitable acid.

In embodiments of step a), use of an aforementioned acid may lead to formation of a corresponding acid addition salt of the imidate of formula IV. The acid addition salt may be a mono-, di- or tri-acid addition salt, such as a monohydrochloride, dihydrochloride, trihydrochloride, monocarboxylate, dicarboxylate or tricarboxylate or the like.

In embodiments of step a), an acid used in the reaction may be gaseous, aqueous, concentrated, or dissolved in a solvent. Examples of solvents for this purpose include, but are not limited to, alcohols, ethers, esters, amides, ketones, aliphatic/aromatic hydrocarbons, halogenated hydrocarbons, and any mixtures of two or more thereof.

In embodiments of step b), a salt of the compound of formula V formed is dependent on the nature of the acid used in step a). The acid addition salt may be a mono-, di- or tri-acid addition salt, such as a di/tri-hydrohalogenic, di/tri-sulfuric, di/tri- phosphoric, or di/tri-organic acid salt. Examples of salts for this purpose include, but are not limited to: hydrochloride, dihydrochloride, trihydrochloride, hydrobromide, hydroiodide, sulfate, acetate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, pamoate (i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3-naphthoate)), oxalate salts or any organic or inorganic salt. In embodiments of step b), suitable reagent is a source of ammonia include, but are not limited to, aqueous, gaseous or liquor ammonia, ammonium carbonate, ammonium formate, ammonium hydroxide, ammonium chloride, ammonium bicarbonate, or any other suitable source of ammonia.

In embodiments of step b), 1 -15 moles of ammonia source, per mole of the compound of formula IV or salt thereof, may be used for the reaction.

In embodiments of step c), the reaction may be carried out optionally in the presence of a base. Bases that are useful for the reaction include, but are not limited to: organic bases such as diisopropylamine, dimethylamine, ethylenediamine, N,N- diisopropylmethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, aniline, pyridine, piperidine, and the like; and inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides and oxides, for example, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide; ammonia, ammonium chloride, and the like.

In embodiments of step d), a salt of the compound of formula II can be converted into a free base in a manner known per se, for example by treating with a suitable base. Salts can be obtained from the latter by reaction with organic or inorganic acids, in particular those which are suitable for forming pharmaceutically acceptable salts. In embodiments of step d), a salt of formula II optionally, can also be converted to a corresponding pharmaceutically acceptable salt, by known methods such as ion exchange. For example, an acetate salt of the formula II compound may be treated with methanesulfonic acid to obtain a mesylate salt of the formula II compound, or vice versa.

In embodiments of step a) to step d), the reaction may be optionally carried out in the presence of a solvent. Examples of solvents for this purpose include, but are not limited to, : water; alcohols, such as methanol, ethanol, 1 -propanol, 2- propanol (isopropyl alcohol), 1 -butanol, 2-butanol or CrC₆ alcohols; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopropylmethyl ether, dioxane, and dimethoxyethane; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, Ν,Ν-dimethylformamide, and N,N- dimethylacetamide; sulfoxides, such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as n-pentane, isopentane, neopentane, n-hexane, isohexane, n- heptane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene; halogenated hydrocarbons such as dichloromethane, 1 ,2- dichloroethane, trichloroethylene, chloroform, carbon tetrachloride; or mixtures of two or more thereof.

In embodiments of step a) to step d), the reaction is carried out at suitable temperatures less than about 200 °C, less than about 150 ^, less than about l OOD, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 ^<€, less than about 20 °C, less than about 10 ^<€, or any other suitable temperatures.

Inventors of the present application have come out with another significantly advantageous, cost effective, simple, robust, time saving and industrially viable process for preparing dabigatran etexilate. The prior art processes are technically inefficient, for example, in application WO 98/37075 large amounts of solvents/reagents were used for preparing the compound of formula V and also it requires complicated purification operations, which burdens the process economy. Inventors of the present application have found that use of triethyl orthoformate for preparing the compound of formula IV and subsequently converting to compound of formula V, followed by compound of formula II, can alleviate the drawbacks of prior art and also can afford a great reduction in cost during the commercial scale up.

a) reacting a compound of formula III

b) optionally without isolation, reacting the compound of formula IV with a suitable reagent to provide the amidine compound of formula V or a salt thereof.

a) reacting a compound of formula III

b) reacting the compound of formula IV or salt thereof with a suitable reagent to provide the amidine compound of formula V or a salt thereof;

v

wherein X denotes a nucleofugic leaving group, such as mesyl (CH₃S0₂-), tosyl (4- CH₃C₆H₄S0₂- ), chlorine, bromine or iodine optionally, in the presence of a base to provide compound of formula II or salt thereof; and

d) optionally, converting the compound of formula II or salt thereof into the corresponding salt or free base or tautomer thereof.

In embodiments of step a), use of an aforementioned acid may lead to formation of a corresponding acid addition salt of the imidate of formula IV. The acid addition salt may be a mono-, di- or tri-acid addition salt, such as a monohydrochloride, di-hydrohalogenic, tri-hydrohalogenic, di/tri-sulfuric, di/tri- phosphoric, or di/tri-organic acid salt.

In embodiments of step b), suitable reagent is a source of ammonia include, but are not limited to, aqueous, gaseous or liquor ammonia, ammonium carbonate, ammonium formate, ammonium hydroxide, ammonium chloride, ammonium bicarbonate, or any other suitable source of ammonia.

In embodiments of step b), the reaction includes:

i. direct use of a reaction mixture containing the compound of formula IV that is obtained in step a) that comprises a suitable solvent, or by adding a suitable solvent to the reaction mixture; or

ii. dissolving a previously isolated and purified compound of formula IV that was obtained in step a), in a suitable solvent.

In embodiments of step b), a salt of the compound of formula V formed is dependent on the nature of the acid used in step a). The acid addition salt may be a mono- or di-acid addition salt, such as a di-hydrohalogenic, di-sulfuric, di-phosphoric, or di-organic acid salt. Examples of salts for this purpose include, but are not limited to: hydrochloride, dihydrochloride, hydrobromide, hydroiodide, sulfate, acetate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, pamoate (i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3-naphthoate)), oxalate salts or any organic or inorganic salt.

In embodiments of step c), the reaction includes:

i. direct use of a reaction mixture containing the compound of formula V that is obtained in step b) that comprises a suitable solvent, or by adding a suitable solvent to the reaction mixture; or

ii. dissolving a previously isolated and purified compound of formula V that was obtained in step b), in a suitable solvent.

In embodiments of step d), a salt of the compound of formula II can be converted into a free base in a manner known per se, for example with alkali base. Salts can be obtained from the latter by reaction with organic or inorganic acids, in particular those which are suitable for forming pharmaceutically acceptable salts. In embodiments of step d), a salt of formula II optionally, can also be converted to the corresponding pharmaceutically acceptable salt, by known methods such as ion exchange. For example, an acetate salt of the formula II compound may be treated with methanesulfonic acid to obtain a mesylate salt of the formula II compound, or vice versa.

In embodiments of step a) to step d), the reaction may be optionally carried out in the presence of a solvent. Examples of solvents for this purpose include, but are not limited to, : water; alcohols, such as methanol, ethanol, 1 -propanol, 2- propanol (isopropyl alcohol), 1 -butanol, 2-butanol or C C₆ alcohols; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopropylmethyl ether, dioxane, and dimethoxyethane; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, Ν,Ν-dimethylformamide, and N,N- dimethylacetamide; sulfoxides, such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as n-pentane, isopentane, neopentane, n-hexane, isohexane, n- heptane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene; halogenated hydrocarbons such as dichloromethane, 1 ,2- dichloroethane, trichloroethylene, chloroform, carbon tetrachloride; or mixtures of two or more thereof.

The chemical transformations described throughout the application may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants.

The compounds obtained by the chemical transformations of steps in the second and third aspects of the present application can be used for their following steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt form, or by washing with an organic solvent or with an aqueous solution, eventually adjusting the pH. Compounds at various stages of the processes may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallisation techniques. The suitable recrystallisation techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, removal/partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, or can be subjected to more than one of the purification techniques, until the desired purity is attained.

Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the mixture to higher temperatures, subsequently cooling, and recovering a compound having a higher purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as methanol, ethanol, 1 - propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2-butanol, iso-butyl alcohol, t- butyl alcohol, and CrC₆ alcohols; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopropylmethyl ether, dioxane, and dimethoxyethane; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, Ν,Ν-dimethylformamide, and N,N-dimethylacetamide; sulfoxides, such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons, such as n-pentane, isopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, 2,3-dimethylpentane, 2,4- dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, 3- methylheptane, cyclohexane, methylcyclohexane, cycloheptane, C₅-C₈ aliphatic hydrocarbons, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o- xylene, trimethylbenzene, chlorobenzene, trifluorotoluene, and anisole; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 , 1 ,1 -trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride; water; or mixtures of two or more thereof.

The final compound obtained in the process of the first aspect and the compounds at various stages of the processes of second and third aspect, of the present application may be isolated using conventional techniques known in the art. For example, useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining a solution with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.

In certain aspects of the present application, the isolated solid may optionally be dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 70°C, less than about 60^, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 10 hours, or longer.

A dried product may optionally be subjected to a particle size reduction technique to obtain desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation sifting; milling using mills, such as, for example, ball, roller, or hammer mills, or jet mills, including, for example, air jet mills; or any other conventional technique. The desired particle sizes may also be achieved directly from the reaction mixture by selecting equipment that is able to provide the compound with the desired particle sizes.

In a fourth aspect, the present application provides dabigatran etexilate of formula II or a pharmaceutically acceptable salt thereof, which is substantially free from process related impurities.

In embodiments of present application, dabigatran etexilate of formula II or a pharmaceutically acceptable salt thereof, which is substantially free from the following compounds of formulae VII, VIII, IX and X.

DEFINITIONS

The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise.

The phrase "pharmaceutically acceptable salt" or "salt" as used herein includes those salts of compounds of the application that are safe and effective in human beings and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the application. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, dihydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate, i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3-naphthoate) salts. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "Ci-C₆ alcohols" include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, i- butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, and the like.

An "aliphatic hydrocarbon" is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic." Examples of "C₅-C₈ aliphatic or aromatic hydrocarbons" include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3- dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3- trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, and anisole.

An "ester" is an organic compound containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "C₃-C₆ esters" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like.

An "ether" is an organic compound containing an oxygen atom -O- bonded to two carbon atoms. "C₂-C₆ ethers" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like.

A "halogenated hydrocarbon" is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 , 1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, and the like.

A "ketone" is an organic compound containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "C₃-C₆ ketones" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, and the like.

A "nitrile" is an organic compound containing a cyano -(C≡N) bonded to another carbon atom. "C₂-C₆ nitriles" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, and the like.

Triethyl orthoformate is an orthoester of formic acid and has the chemical structure as given below.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25° C and normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise.

As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. The terms "about," "substantially" and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The terms "optional" and "optionally" mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

The term "compound" as used herein, refers to the compounds of this application, which includes the key starting materials, intermediates and/or the final product. Specifically it refers to the compounds of formulas I, II, III, IV, V and VI, or pharmaceutically acceptable salts or tautomers thereof.

The term "about" as used herein, refers to mean plus or minus 10% of the quantitative value described.

'Tautomer(s)" as used herein refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another. Compounds of formulas I, II and/or salts thereof, may exist in their tautomeric forms and all such tautomeric forms are contemplated herein as part of the present disclosure.

A "one pot" or "one pot process" within the meaning of this invention means that in a multi-step process with defined isolatable intermediates, the products of previous synthetic step is used in the subsequent synthetic step without isolation of the product of said previous synthetic step.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES

Example 1 : Preparation of β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl] phenyl]amino]methyl]-1 -methyl-1 H-benzimidazol-5-yl]carbonyl]-N-2- pyridinyl-, ethyl ester (dabigatran etexilate) in one pot

1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (10 g) and ethanol (100 mL) were charged into a round bottom flask and cooled to about 5°C, dry HCI gas was passed for about 8-10 hours at around 5-10°C. The clear solution obtained was maintained for 14-16 hours at 25-30^QC for the completion of the reaction and the solution was distilled under reduced pressure at below 40 °C. To the crude compound obtained, ethanol (250 mL) and ammonium carbonate (20 g) were charged and the mixture was maintained for 14-16 hours at 25-30^QC. To the above obtained reaction mass, water (100 mL) and tetrahydrofuran (200 mL) were charged and the resulting mixture was concentrated under reduced pressure at below 48^QC. To the crude obtained, tetrahydrofuran (400 mL), potassium carbonate (18.7 g) were charged followed by slow addition of n-hexyl chloroformate (1 1 .75 g) at 25-30^QC and maintained the reaction mass at 25-30^QC for around 3 hours. After completion of the reaction, the organic layer was separated and distilled off under reduced pressure. The crude obtained was dissolved in dichloromethane (400 mL) and washed twice with water (2x100 mL) followed by washing twice with 10% sodium chloride solution (2x100 mL) and the layers were separated. The organic layer was concentrated under reduced pressure at below 40^QC. To the crude obtained, ethyl acetate (80 mL) was charged and the solid was collected by filtration and washed with ethyl acetate (10 mL). The compound was dried in an oven at 50°C for 5 hours to afford the title compound.

Yield: 5.3 g; Purity by HPLC: 97.90%.

Example 2: Preparation of dabigatran etexilate

1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride (10 g) and tetrahydrofuran (400 mL) were charged into a round bottom flask. Water (80 mL was charged followed by potassium carbonate (9.3 g) and stirred for 10-15 minutes, n- Hexyl chloroformate (3.4 g) was added slowly to the reaction mixture at 25-30^QC and maintained for 2 hours at 25-30^QC. The layers were separated and the organic layer was distilled under reduced pressure at below 30^QC to obtain the crude compound. To the crude, dichloromethane (500 mL) was charged and the organic layer was washed twice with 10% sodium chloride (2 x 100 mL). The organic layer was concentrated under reduced pressure at below 40^QC to obtain the crude. The above obtained crude (2 g) and a mixture of ethyl acetate (20 mL) and ethanol (4 ml) were charged into another round bottom flask and maintained at 25-30^QC for 20-30 minutes. The reaction mixture was cooled to 10^QC and the solid was collected by filtration, washed with ethyl acetate (4 mL) and ethanol (4 ml). The wet compound was suction dried and later dried in an oven at 50^QC for 3 hours to afford the title compound.

Yield: 0.9 g; Purity by HPLC: 98.99%.

Example 3: Preparation of dabigatran etexilate

1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride (10 g) and tetrahydrofuran (400 mL) were charged into a round bottom flask. Water (80 mL was charged followed by potassium carbonate (9.3 g) and stirred for 10-15 minutes, n- Hexyl chloroformate (3.4 g) was added slowly to the reaction mixture at 25-30^QC and maintained for 2 hours at 25-30^QC. The layers were separated and the organic layer was distilled under reduced pressure at below 30^QC to obtain the crude compound. To the crude, dichloromethane (500 mL) was charged and the organic layer was washed twice with 10% sodium chloride (2 x 100 mL). The organic layer was concentrated under reduced pressure at below 40^QC to obtain the crude. The above obtained crude (1 .5 g) and a mixture of isopropyl alcohol (15 mL) were charged into another round bottom flask to obtain a clear solution and maintained for 90 minutes at 25-30^QC. The solid was collected by filtration, washed with isopropanol (5 mL), suck dried and later dried in an oven for 2.5 hours at 50^QC to afford the title compound.

Yield: 1 g; Purity by HPLC: 98.13%. Example 4: Preparation of dabigatran etexilate

1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride (10 g) and tetrahydrofuran (400 mL) were charged into a round bottom flask. Water (80 mL) was charged followed by potassium carbonate (9.3 g) and stirred for 10-15 minutes. n-Hexyl chloroformate (3.4 g) was added slowly to the reaction mixture at 25-30^QC and maintained for 2 hours at 25-30^QC. The layers were separated and the organic layer was distilled under reduced pressure at below 30^QC to obtain the crude compound. To the crude, dichloromethane (500 mL) was charged and the organic layer was washed twice with 10% sodium chloride (2 x 100 mL). The organic layer was concentrated under reduced pressure at below 40^QC to obtain the crude. The above obtained crude (1 .5 g) and a mixture of ethanol (20 mL) were charged into another round bottom flask to obtain a clear solution and maintained for 90 minutes at 25-30^QC. The solid was collected by filtration, washed with ethanol (5 mL), suck dried and later dried in an oven for 4 hours at 50^QC to afford the title compound. Yield: 0.3 g; Purity by HPLC: 98.08%.

Example 5: Preparation of dabigatran etexilate

1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide hydrochloride (10 g) and tetrahydrofuran (400 mL) were charged into a round bottom flask. Water (80 mL was charged followed by potassium carbonate (9.3 g) and stirred for 10-15 minutes, n- Hexyl chloroformate (3.4 g) was added slowly to the reaction mixture at 25-30^QC and maintained for 2 hours at 25-30^QC. The layers were separated and the organic layer was distilled under reduced pressure at below 30^QC to obtain the crude compound. To the crude, dichloromethane (500 mL) was charged and the organic layer was washed twice with 10% sodium chloride (2 x 100 mL). The organic layer was concentrated under reduced pressure at below 40^QC to obtain the crude. The above obtained crude (1 .5 g) and a mixture of ethyl acetate (20 mL) were charged into another round bottom flask to obtain a clear solution and maintained for around 2 hours at 25-30^QC. The solid was collected by filtration, washed with ethyl acetate (10 mL), suck dried and later dried in an oven for 2.5 hours at 50^QC to afford the title compound.

Yield: 1 .1 g; Purity by HPLC: 98.27%. Example 6: Preparation of Dabigatran etexilate

1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (20 g), acetone (220 mL) and water (180 mL) were charged into a round bottom flask and maintained until a clear solution was observed. The reaction mixture was cooled to 5-10°C, followed by addition of potassium carbonate (27.6 g) and maintained for about 30 minutes at the same temperature. n-Hexyl chloroformate (1 1 .2 g) in acetone (20 mL) was added slowly to the reaction mixture over a period of 60-90 minutes at 5-10°C and maintained for 1 -2 hours at the same temperature. After completion of reaction, confirmed by using TLC, ammonium chloride (10 g) was added at 5-10°C and mixture was maintained for 30-60 minutes at 5-10°C. The reaction mixture was allowed to attain 25-35 °C and maintained for 1 -2 hours at the same temperature. Then the reaction mixture was heated to 50-55 °C and maintained for 15-30 minutes. The layers were separated and the acetone layer was cooled to 25-35 °C and maintained for 15-30 minutes. Water (240 mL) was added to the separated acetone layer and maintained for 2-3 hours. The obtained reaction mixture was cooled to 5- 10 °C and maintained for 1 -2 hours. The solid obtained was filtered and washed with a (1 :1 ) mixture of pre-cooled acetone and water (20 mL). The resultant solid compound and isopropanol (240 mL) were charged into another round bottom flask and heated to 50-55 °C until a clear solution was obtained. The reaction mixture was cooled to 25-35 °C, followed by addition of seed (0.2 g) and maintained the reaction mixture for 2-3 hours at 25-35 C and further maintained for 1 -2 hours at 0-5^. The solid obtained was collected by filtration, washed with isopropanol (20 mL) and dried at 50-55 °C under vacuum to afford the title compound.

Yield: 17.6 g; Purity by HPLC: 99.75%

Example 7: Preparation of dabigatran etexilate

1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (50 g), acetone (450 mL) and water (450 mL) were charged into a round bottom flask and maintained until a clear solution was observed. The reaction mixture was cooled to 5-10°C, followed by addition of potassium carbonate (73.2 g) and maintained for 15-30 minutes at the same temperature. n-Hexyl chloroformate (41 .2 g) in acetone (50 mL) was added slowly to the reaction mixture over a period of 60-90 minutes at 5-10°C and maintained for the completion of reaction, confirmed by using TLC. The reaction mixture was heated to 50-55 °C to ensure complete dissolution and maintained for 15-30 minutes. The layers were separated and the acetone layer was cooled to 25- 35 °C and maintained for 30-60 minutes. Water (500 mL) was added slowly to the separated acetone layer and maintained for 2-3 hours at 25-35 °C. The obtained reaction mixture was cooled to 0-5 °C and maintained for 1 -2 hours. The solid obtained was filtered off and washed with a (1 :1 ) mixture of pre-cooled acetone and water (100 mL). The wet compound thus obtained was divided into two parts and proceeded further according to the below variants.

Variant- 1 :

The first part of wet compound obtained in the above step and isopropanol (500 mL) were charged into a round bottom flask, heated the reaction mixture to 50- 60 °C to obtain a clear solution and maintained for 15-30 minutes at the same temperature. The reaction mixture was allowed to cool to 25-35 °C followed by addition of seed (0.5 g) and maintained for 2-3 hours at 25-35 °C and further maintained for 1 -2 hours at 0-5 'C. The solid obtained was collected by filtration, washed with isopropanol (50 mL) and dried at 50-55 °C under vacuum to afford the title compound.

Yield: 21 .8 g; Purity by HPLC: 99.52%

Variant-2:

The second part of wet compound and ethyl acetate (500 mL) were charged into a round bottom flask, heated the reaction mixture to 60-70 °C to obtain a clear solution and maintained for 15-30 minutes. The reaction mixture was allowed to cool to 25-35 °C and maintained the reaction mixture for 2-3 hours at the same temperature and further maintained for 1 -2 hours at 0-5°C. The solid obtained was filtered and washed with ethyl acetate (50 mL). To the solid obtained isopropanol (500 mL) was charged and the reaction mixture was heated to 50-60 °C to obtain a clear solution and maintained for 15-30 minutes at the same temperature. The reaction mixture was allowed to cool to 25-35 °C and maintained for 2-3 hours at 25- 35 °C and further maintained for 1 -2 hours at 0-5 °C. The solid thus obtained was collected by filtration, washed with pre-cooled isopropanol (50 mL) and dried at 50- 55 °C to afford the title compound.

Yield: 21 .9 g; Purity by HPLC: 99.63% Example 8: Preparation of dabigatran etexilate

1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (5 g) and ethyl acetate (45 mL) were charged into a round bottom flask. Water (45 mL) was added followed by addition of potassium carbonate (6.9 g) and stirred for 30 minutes. n-Hexyl chloroformate (2.3 g) in ethyl acetate was added slowly to the reaction mixture over a period of about 40 minutes at 25-35 °C and maintained for the completion of reaction, confirmed by using TLC. Ammonium chloride (1 .25 g) in water (5 mL) was added to the reaction mixture, maintained for 15-30 minutes and then heated to 60- 70 °C to obtain a clear solution. The reaction mixture was maintained for 15-30 minutes at 60-70°C and the layers formed were separated under hot condition. The separated ethyl acetate layer was charged into another round bottom flask, cooled to 25-35 °C and maintained for about 1 hour. The reaction mixture was further cooled to 0-5 °C and maintained for 1 -2 hours at the same temperature. The obtained solid was filtered off and washed with pre-cooled ethyl acetate (5 mL). To the solid obtained isopropanol (60 mL) was charged and the reaction mixture was heated to 50-60^ to obtain a clear solution and maintained for 15-30 minutes. The reaction mixture was allowed to cool to 25-35 °C and maintained for 2-3 hours at 25-35 °C and further maintained for 1 -2 hours at 0-5 °C. The solid thus obtained was collected by filtration, washed with pre-cooled isopropanol (5 mL) and dried at 50-55°C under vacuum to afford the title compound.

Yield: 4.1 g; Purity by HPLC: 97.46%

Example 9: Preparation of 1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide- hydrochloride

1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (5.0 g) and toluene (80 mL) were charged in a round bottom flask at 25-35 °C. To the reaction mixture, triethyl orthoformate (7.7 g) was added slowly at 25-30^QC followed by water (0.25 mL). Dry HCI gas was passed into the reaction mass at 20-25 °C for 2-3 hours and maintained the same for 24 hours at 25-30^QC. The solid was collected by filtration and washed with toluene (15 mL). Ammonium carbonate (2.0 g) and methanol (15 ml.) were charged in to another round bottom flask, stirred for 5 minutes at 25-35 °C and the intermediate obtained above (1 .16 g) was added slowly to the reaction mass at 25-35 C, maintained the same for around 2 hours at 25-30^QC. The reaction mass was distilled under reduced pressure at 40-45 °C. Ethyl acetate (10 ml.) was added to the crude obtained and kept under stirring for 1 -2 hours. The solid was collected by filtration, washed with ethyl acetate (3 ml.) and suction dried to afford the title compound. Yield: 1 .09 g; Purity by HPLC: 86.51 %.

Example 10: Preparation of 1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide- hydrochloride

1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (5.0 g) and toluene (80 ml.) were charged in a round bottom flask at 25-35 °C. To the reaction mixture, triethyl orthoformate (7.7 g) was added slowly at 25-30^QC followed by water (0.25 ml_). Dry HCI gas was passed into the reaction mass at 20-25 °C for 2-3 hours and maintained the same for 24 hours at 25-30^QC. The solid was collected by filtration and washed with toluene (15 ml_).

The intermediate obtained above (1.16 g) was dissolved in ethanol (20 ml.) and ammonium carbonate (2 g) was added slowly at 25-35 °C and maintained the same for 6 hours at 25-30^QC. The reaction mass was filtered, washed with ethanol (3 ml.) and the filtrate obtained was distilled under reduced pressure at 40-45°C to afford the title compound.

Yield: 1 .08 g Purity by HPLC: 88.42%.

Example 1 1 : Preparation of 1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.

Triethyl orthoformate (120 ml.) and water (7.8 ml.) were charged into a round bottom flask and cooled the reaction mixture to 0-10°C. Dry HCI gas was purged into the reaction mixture for 4 hours at 0-10°C (until HCI assay in the reaction mixture was more than 25%). 1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5- yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (30 g) was charged to the reaction mixture and temperature of the reaction mass was raised to 25-35^. Dry HCI gas was purged again into the reaction mixture for about 1 hour at 25-35^ and maintained the reaction mixture for about 8 hours at the same temperature. The reaction mixture was cooled to 0-10 °C followed by slow addition of dimethylformamide (150 mL) over a period of 1 hour, then further cooled the reaction mixture to 0-5 °C. Ammonia gas was purged into the reaction mixture for about 4 hours at 0-5 °C (until the pH of the reaction mixture is about 8-9), and then the temperature of reaction mixture was raised to 25-35 °C while continuing the addition of ammonia gas. Ammonia gas purging was further continued for 4 hours at 25- 35 °C. The reaction mass was filtered, the unwanted salts were washed twice with dimethylformamide (60 and 10 mL), collected the obtained filtrate in a flask and heated the filtrate to 50-55 °C. Ethyl acetate (180 mL) was added slowly to the above filtrate over a period of 60-90 minutes at 50-55 °C followed by addition of seed (0.6 g) and then maintained for 30-45 minutes at 50-55 °C. Again, ethyl acetate (420mL) was added slowly to the reaction mixture over a period of about 1 hour at 50-55^ then cooled the reaction mixture to 25-35 °C and maintained for 8-10 hours at 25-35 C. The solid thus obtained was collected by filtration, washed with ethyl acetate (60 mL) and dried at 55-60 °C under vacuum to afford the title compound.

Yield: 24.7 g; Purity by HPLC: 97.4%; Assay by HPLC: 84.6%; Chloride content: 6.4%.

Example 12: Preparation of Preparation of 1 -Methyl-2-[N-(4-amidinophenyl)- aminomethyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)-amide.

Triethyl orthoformate (400 mL) and water (26.1 mL) were charged into a round bottom flask and cooled the reaction mixture to 0-5 °C. Dry HCI gas was purged into the reaction mixture until HCI strength in the reaction mixture was more than 25% (w/w). 1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (100 g) was added to the reaction mixture and raised the reaction mixture temperature to 25-35 ^. Dry HCI gas was purged again into the reaction mixture until HCI strength in the reaction mixture was greater than 25% (w/w) and maintained for about 10 hours at 25-35 °C. The reaction mixture obtained was divided into two portions and further process was proceeded with one portion (275 mL, i.e., equivalent of 50 g batch) The above reaction mixture (275 mL, i.e., equivalent of 50 g batch) was cooled to 0±5°C followed by addition of dimethylformamide (250 mL) over a period of about 30 minutes at ΟΙδ'Ό. Ammonia gas was purged into the reaction mixture at 0±5°C until the pH of reaction mass was greater than 9.0, and then temperature of the reaction mixture was raised to 25-35 °C and maintained for the completion of reaction, confirmed by using TLC. The reaction mass was filtered, the unwanted salts were washed twice with dimethylformamide (100 and 50 mL), collected the obtained filtrate in a flask and degassed for about 1 hour. The temperature of the filtrate was raised to 50-55 °C followed by addition of ethyl acetate (300 mL) to the reaction mixture over a period of about 1 hour at 50-55°C, then seed (1 g) was added to the reaction mixture and maintained for 30 minutes. Again, ethyl acetate (700 mL) was added slowly to the reaction mixture over a period of 1 hour at 50- 55 °C, and then the reaction mixture was cooled to 25-35 °C and maintained for about 8 hours at the same temperature. The obtained solid was filtered and washed with ethyl acetate (100 mL). The wet compound thus obtained was divided into two parts and one part was dried at 60-65 °C and second part was purified as below:

Purification of crude compound:

The second part of crude compound obtained in the above step, ethyl acetate (250 mL) and water (200mL) were charged and the reaction mixture was heated to 50-55 °C to obtain a clear solution. The reaction mixture was maintained for 15-30 minutes at 50-55 °C then cooled to 20-25 °C and maintained for 5-6 hours at the same temperature. The solid thus obtained was collected by filtration, washed with ethyl acetate (50 mL) and dried at 60-65 °C to afford the title compound.

Yield: 20.5 g; Purity by HPLC: 98.79%; Assay by HPLC: 84.9; ammonia content: 0.03%; chloride content: 6.3%.

Purity of crude compound:

Yield: 24.0 g; Purity by HPLC: 97.64%; Assay by HPLC: 74.0%; ammonia content: 1 .7%; chloride content: 10.9%

Example 13: Preparation of 1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.

Triethyl orthoformate (100 mL) and water (6.3 mL) were charged into a round bottom flask and cooled the reaction mixture to 0-5 °C. Dry HCI gas was purged into the reaction mixture until HCI strength in the reaction mixture was more than 25% (w/w). 1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (25 g) was added to the reaction mixture and raised the reaction mixture temperature to 25-35 °C. Dry HCI gas was purged again into the reaction mixture until HCI strength in the reaction mixture was greater than 25% (w/w) and maintained for about 10 hours at 25-35^. The reaction mixture was cooled to 0±5 °C followed by addition of dimethylformamide (125 ml.) over a period of about 30 minutes at OlS ' . Ammonia gas was purged into the reaction mixture at 0±5°C until the pH of reaction mass was greater than 9.0, then temperature of the reaction mixture was raised to 25-35 °C and maintained for the completion of reaction, confirmed by using TLC. The reaction mass was filtered, the unwanted salts were washed twice with dimethylformamide (50 and 25 ml_), collected the obtained filtrate in a flask and degassed for about 1 hour. The temperature of the filtrate was raised to 50-55 ^ followed by addition of ethyl acetate (150 ml.) to the reaction mixture over a period of about 1 hour at 50-55 °C, then seed (0.5 g) was added to the reaction mixture and maintained for 30 minutes. Again, ethyl acetate (350 ml.) was added slowly to the reaction mixture over a period of 1 hour at 50-55^, and then the reaction mixture was cooled to 25-35^ and maintained for about 8 hours at the same temperature. The obtained solid was filtered and washed with ethyl acetate (50 ml_). To the solid, ethyl acetate (250 ml.) and water (200ml_) were charged and the reaction mixture was heated to 50-55^ to obtain a clear solution. The reaction mixture was maintained for 15-30 minutes at 50- 55 ^ then cooled to 15±5^qC and maintained for 10-12 hours at the same temperature. The solid thus obtained was collected by filtration, washed with ethyl acetate (50 ml.) and dried initially at 55-60 °C under vacuum for about 4 hours and then at 60-65 °C to afford the title compound.

Yield: 20.6 g; Purity by HPLC: 98.5%; PXRD is similar to fig.1

Example 14: Preparation of 1 -Methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.

Triethyl orthoformate (400 ml.) and water (26.1 ml.) were charged into a round bottom flask and cooled the reaction mixture to 0-5 °C. Dry HCI gas was purged into the reaction mixture until HCI strength in the reaction mixture was more than 25% (w/w). 1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (100 g) was added to the reaction mixture and raised the reaction mixture temperature to 25-35 °C. Dry HCI gas was purged again into the reaction mixture until HCI strength in the reaction mixture was greater than 25% (w/w) and maintained for about 10 hours at 25-35 °C. The crude compound obtained was divided into portions and the further process was proceeded with one portion (1 10 mL, i.e., equivalent of 20 g batch)

The reaction mixture (1 10 mL, i.e., equivalent of 20 g batch) was cooled to 0±5°C followed by addition of dimethylformamide (100 mL) over a period of about 30 minutes at 0±5°C. Ammonia gas was purged into the reaction mixture at 0±5°C until the pH of reaction mass was greater than 9.0, and then temperature of the reaction mixture was raised to 25-35 'C and maintained for the completion of reaction, confirmed by using TLC. The reaction mass was filtered, the unwanted salts were washed twice with dimethylformamide (40 and 20 mL), collected the obtained filtrate in a flask.

The obtained filtrate was divided into two equal parts (i.e., equivalent of 10 g batch) and degassed for about 1 hour. The temperature of the filtrate was raised to 50-55 'C followed by addition of ethyl acetate (60 mL) to the reaction mixture over a period of about 1 hour at 50-55 'C, then seed (1 g) was added to the reaction mixture and maintained for 30 minutes. Again, ethyl acetate (140 mL) was added slowly to the reaction mixture over a period of 1 hour at 50-55 'C, and then the reaction mixture was cooled to 25-35 'C and maintained for about 8 hours at the same temperature. The obtained solid was filtered and washed with ethyl acetate (20 mL).

The crude compound obtained in the early step, ethyl acetate (100 mL) and water (80mL) were charged and the reaction mixture was heated to 50-55°C to obtain a clear solution. The reaction mixture was maintained for 15-30 minutes at 50- 55 'C then cooled to 20-25 'C and maintained for 5-6 hours at the same temperature. The solid thus obtained was collected by filtration, washed with ethyl acetate (50 mL) and dried at 60-65 'C to afford the title compound.

Yield: 8.0 g; Purity by HPLC: 98.26%; Assay by HPLC: 83.8; ammonia content: 0.04%; chloride content: 6.3%

Example 15: Preparation of dabigatran etexilate mesylate

Dabigatran etexilate (30 g) and acetone (420 mL) were charged into a round bottom flask, heated to 30-36°C to obtain a clear solution and maintained for 15 minutes. A solution of methane sulfonic acid (4.6 g) dissolved in acetone (10 mL) was added slowly to the reaction mixture at 30-36^QC and maintained the same at 26- 33 ^QC for 1 hour. The reaction mass was cooled to around 17-23°C and maintained the same for 1 hour and the solid was collected by filtration and washed with acetone (60 mL). The compound was dried in an oven for 4.5 hours at 55°C to afford the title compound.

Yield: 32.1 g Purity by HPLC: 99.65%.

Claims

We claim:

1 . A process f prising:

a) reacting a compound of formula III

with triethyl orthoformate in the presence of an acid, to provide imidate compound of formula IV or a salt thereof; and

b) reacting the compound of formula IV or a salt thereof with a source of ammonia to provide the amidine of formula V or a salt thereof.

c) isolating the compound of Formula V or a salt thereof.

2. The process according to claim 1 , wherein the acid in step a) is selected from hydrohalic acids, sulfuric acid or phosphoric acid.

3. The process according to claim 2 wherein the acid is hydrochloric acid.

4. The process according to claim 1 , wherein the source of ammonia in step b) is selected from aqueous, gaseous or liquor ammonia, ammonium carbonate, ammonium formate, ammonium hydroxide, ammonium chloride, and ammonium bicarbonate.

5. The process according to claim 1 , wherein step b) is carried in a polar aprotic solvent, a polar protic solvent or a mixture thereof.

6. The process according to claim 5, wherein the solvent is selected from dimethylformamide, dimethyl acetamide, ethanol or a mixture thereof.

7. The process according to claim 1 , wherein the isolation in step c) involves evaporation, addition of anti-solvent, addition to anti-solvent, cooling, or a combination thereof.

8. The process according to claim 7, wherein the anti-solvent is selected from ethyl acetate, methyl tert-butyl ether, methyl isobutyl ketone, isopropyl acetate, toluene.

9. The process according to claim 8, wherein the anti-solvent is added at a temperature between 40 to 60 °C.

10. The process according to claim 1 further comprising purification of compound of formula V or a salt thereof from suitable solvents selected from ethyl acetate, isopropanol, acetone, methyl tert-butyl ether, methyl isobutyl ketone, dimethylformamide, water or mixtures thereof.

1 1 . The process according to claim 1 further comprising:

a. reacting the compound of formula V or salt thereof,

with a compound of formula VI

V

wherein X denotes a nucleofugic leaving group, such as chlorine, bromine, iodine, mesyl (CH₃S0₂-), or tosyl (4-CH₃C₆H₄S02- ) optionally, in the presence of a base to provide compound of formula II or salt thereof; and b. optionally, converting the compound of formula II or salt thereof into the corresponding salt or free base or tautomer thereof.

12. The process according to claim 1 1 , wherein the compound of Formula II is purified from suitable solvents selected from esters, ethers, ketones, alcohols, nitriles, hydrocarbons, water or mixtures thereof.

13. The process according to claim 12, wherein the solvent is selected from isopropanol, acetonitrile, and ethyl acetate.

14. The compound of Formula II or a salt thereof prepared according to claim 1 , which is substantially free from the compounds of formulae VII, VIII. IX and X.