DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

A PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVE

Vasudha Pharma Chem Limited
An Indian company having its registered office at
78/A, Vengalrao Nagar,
Hyderabad – 500038,
Telangana
India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed:
A PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVE
FIELD OF THE INVENTION
The present application relates to a process for the preparation of benzimidazole derivative of formula II, which is an intermediate of Dabigatran etexilate and further relates to a process for the preparation of Dabigatran etexilate.
BACKGROUND OF THE INVENTION
Dabigatran etexilate is chemically described as Ethyl 3-[[[4-[[[(hexyloxyl)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino] propanoate and is structurally represented by Formula I:

It was first disclosed in U.S. Patent US 6,087,380. Processes for preparing dabigatran etexilate are also known from US 7,202,368 and US 7,459,566.
The benzimidazole derivative compound of formula II, having the following structure:

is of central importance in the synthesis of dabigatran etexilate as an intermediate product. The aim of the present invention is to provide a process which allows for an improved large-scale industrial synthesis of the compound of formula II.
The process of the present application has advantages of improved yield, simple, easy handling which afford a significantly greater yield.
SUMMARY OF THE INVENTION
In the first embodiment the present application provides a process for the preparation of compound of formula II, comprising: reacting a compound of formula III with a compound of formula IV in the presence of Pyridine salts.

DETAILED DESCRIPTION OF THE INVENTION
In the aspects of the first embodiment, the present application provides a process for the preparation of compound of formula II, comprising: reacting a compound of formula III with a compound of formula IV in the presence of Pyridine salts.

In aspects, the pyridine salts include acid addition salts of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; and those with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid. Preferably inorganic acid salts are used. Most preferably hydrobromic acid salt is used.
In aspects, the reaction of compound of formula III with compound of formula IV may be performed in the presence of a suitable coupling reagent. The coupling reagent is preferably selected from N,N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole (CDI), ethyl-(N’,N’-dimethylamino)propylcarbodiimide hydrochloride (EDC), carbonyl-di-(1,2,4-triazole), dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide. While N,N'-carbonyldiimidazole and carbonyl-di-(1,2,4-triazole), preferably N,N'-carbonyldiimidazole, are of particular is importance according to the present application.
In aspects, the reaction of compound of formula III with compound of formula IV may be performed in a suitable solvent. The solvents includes but not limited to water, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, dioxane and mixtures thereof. Specifically, the solvent is a mixture of methylene chloride and tetrahydrofuran.
In aspects, the reaction of compound of formula III with compound of formula IV may be carried out for about 30 minutes to about 24 hours at about 0 °C to about 120 oC. Specifically, reaction may be carried out for about 1 hour to about 12 hours at about 60 °C to about 75 °C.
In aspects, the preparation of compound of formula II may be performed in the presence of an acid. The acids includes but not limited to inorganic and organic acids. The acid may be selected from hydrochloric acid, sulphuric acid, polyphosphoric acid, orthophosphoric acid, formic acid, acetic acid, propionic acid, trifluoroaceticacid, methanesulphonic acid, ethanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid or mixture(s) thereof. Specifically, the acid may be an organic acid. More specifically, the acid may be acetic acid.
In aspects, compound of formula II may be converted to Dabigatran etexilate by any known methods in the literature.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, "generally," and the like are to be construed as modifying a term or value such that it is not an absolute. 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.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.
The isolation of the product may be accomplished by, among other things, extraction, concentration, precipitation, crystallization, filtration or centrifugation.
Suitable temperatures for isolation may be less than about 120 °C, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 °C, less than about 20 °C, less than about 10 °C, less than about 0 °C, less than about -10 °C, less than about -40 °C or any other suitable temperatures.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
EXAMPLES
Example 1: Preparation of ethyl 3-(2-((4-cyanophenylamino) methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d] imidazole-5-carboxamido) propionate
Dichloromethane (600 ml) and tetrahydrofuran (60 ml) were charged into a round bottom flask at room temperature and stirred for 5 minutes. To this N,N'-carbonyldiimidazole (56.8 gm) was added and stirred for 15 minutes. To the reaction mass 2-(4-cyanophenylamino) acetic acid (54 gm) was added and stirred for 1 hour. Pyridine-hydrobromide (23.3 gm) and ethyl 3-((3-amino-4-(methylamino) benzoyl) (pyridin-2-yl) amino) propionate (100 gm) were added and stirred for 5 hours at the same temperature. Dichloromethane and tetrahydrofuran were distilled out from the reaction mass and acetic acid (100 ml) was added to the flask at 50 oC. The temperature of the reaction mass was raised to 100 oC and maintained for 1 hour and then cooled to room temperature. Now water (300 ml) and dichloromethane (450 ml) were charged into the flask and pH of the reaction mass was adjusted to 9.0 using liquid ammonia (180 ml). The layers were separated and organic layer was taken into a round bottom flask and pH was adjusted to 9.0 using liquid ammonia (5 ml) and layers were separated. Both the aqueous layers were combined and extracted with dichloromethane (200 ml). The organic layers were combined and dichloromethane was distilled out maintaining 200 ml in the flask. Now the reaction mass was washed with ethanol twice (400 ml and 100 ml) and cooled to 6 oC and filtered. The solid was washed with ethanol twice (100 ml and 100 ml) and dried under vacuum at 50 oC to give the titled compound (112 gm).
Yield: 80%
Example 2: Preparation of ethyl 3-(2-((4-cyanophenylamino) methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d] imidazole-5-carboxamido) propionate
Dichloromethane (1200 ml) and tetrahydrofuran (120 ml) were charged into a round bottom flask at room temperature and stirred for 5 minutes. To this N,N'-carbonyldiimidazole (113.6 gm) was added and stirred for 15 minutes. To the reaction mass 2-(4-cyanophenylamino) acetic acid (108 gm) was added and stirred for 1 hour. Pyridine-hydrobromide (46.6 gm) and ethyl 3-((3-amino-4-(methylamino) benzoyl) (pyridin-2-yl) amino) propionate (200 gm) were added and stirred for 5 hours at the same temperature. Dichloromethane and tetrahydrofuran were distilled out from the reaction mass and acetic acid (200 ml) was added to the flask at 50 oC. The temperature of the reaction mass was raised to 100 oC and maintained for 1 hour and then cooled to room temperature. Now water (600 ml) and dichloromethane (900 ml) were charged into the flask and pH of the reaction mass was adjusted to 9.0 using liquid ammonia (390 ml). The layers were separated and organic layer was taken into a round bottom flask and pH was adjusted to 9.0 using liquid ammonia (6 ml) and layers were separated. Both the aqueous layers were combined and extracted with dichloromethane (400 ml). The organic layers were combined and dichloromethane was distilled out maintaining 200 ml in the flask. Now the reaction mass was washed with ethanol twice (800 ml and 200 ml) and cooled to 6 oC and filtered. The solid was washed with ethanol twice (200 ml and 200 ml) and dried under vacuum at 50 oC to give the titled compound (229 gm).
Yield: 81.7%
Example 3: Preparation of ethyl 3-(2-((4-cyanophenylamino) methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d] imidazole-5-carboxamido) propionate
Dichloromethane (1500 ml) and tetrahydrofuran (150 ml) were charged into a round bottom flask at room temperature and stirred for 5 minutes. To this N,N'-carbonyldiimidazole (142 gm) was added and stirred for 15 minutes. To the reaction mass 2-(4-cyanophenylamino) acetic acid (135 gm) was added and stirred for 1 hour. Pyridine-hydrobromide (58.4 gm) and ethyl 3-((3-amino-4-(methylamino) benzoyl) (pyridin-2-yl) amino) propionate (250 gm) were added and stirred for 5 hours at the same temperature. Dichloromethane and tetrahydrofuran were distilled out from the reaction mass and acetic acid (250 ml) was added to the flask at 50 oC. The temperature of the reaction mass was raised to 100 oC and maintained for 1 hour and then cooled to room temperature. Now water (750 ml) and dichloromethane (1125 ml) were charged into the flask and pH of the reaction mass was adjusted to 9.0 using liquid ammonia (485 ml). The layers were separated and organic layer was taken into a round bottom flask and pH was adjusted to 9.0 using liquid ammonia (8 ml) and layers were separated. Both the aqueous layers were combined and extracted with dichloromethane (500 ml). The organic layers were combined and dichloromethane was distilled out maintaining 200 ml in the flask. Now the reaction mass was washed with ethanol twice (1000 ml and 250 ml) and cooled to 6 oC and filtered. The solid was washed with ethanol twice (250 ml and 250 ml) and dried under vacuum at 50 oC to give the titled compound (281 gm).
Yield: 80.2% ,CLAIMS:We Claim:
1) A process for the preparation of compound of formula II, comprising: reacting a compound of formula III with a compound of formula IV in the presence of Pyridine salts.

2) The process according to claim 1, wherein the Pyridine salts are acid addition salts of Pyridine.
3) The process according to claim 2, wherein the acid addition salts of Pyridine are selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid.
4) The process according to claim 3, wherein the acid addition salt of Pyridine is hydrobromic acid salt of Pyridine.
5) The process according to claim 1), wherein the reaction of compound of formula III with compound of formula IV, is carried out in the presence of a coupling reagent.
6) The process according to claim 5), wherein the coupling reagent is selected from N,N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole (CDI), ethyl-(N’,N’-dimethylamino)propylcarbodiimide hydrochloride (EDC), carbonyl-di-(1,2,4-triazole), dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide.

7) The process according to claim 6), wherein coupling reagent is N,N'-carbonyldiimidazole.