WO2016027077A1

WO2016027077A1 - Processes for the preparation of dabigatran etexilate and intermediates thereof

Info

Publication number: WO2016027077A1
Application number: PCT/GB2015/052394
Authority: WO
Inventors: Dharmaraj Ramachandra Rao; Geena Malhotra; Venkata Srinivas Pullela; Vinod Parameshwaran ACHARYA; Sudam Nanabhau Sinare
Original assignee: Cipla Limited; King, Lawrence
Priority date: 2014-08-18
Filing date: 2015-08-18
Publication date: 2016-02-25

Abstract

The present invention relates to a process for the preparation of dabigatran etexilate of Formula (I), or a pharmaceutically acceptable salt thereof, to processes for the preparation of intermediates of dabigatran etexilate, and to dabigatran etexilate in substantially pure form.

Description

PROCESSES FOR THE PREPARATION OF DABIGATRAN ETEXILATE AND INTERMEDIATES

THEREOF

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of dabigatran etexilate or a pharmaceutically acceptable salt thereof. The present invention also relates to processes for the preparation of intermediates of dabigatran etexilate.

BACKGROUND OF THE INVENTION

Dabigatran etexilate (a compound of Formula I) is the international commonly accepted nonproprietary name for ethyl 3-{[(2-{[(4-{(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1 - methyl-1 H- benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate,

(I)

Dabigatran etexilate is the pro-drug of the active substance, dabigatran. The mesylate salt (1 : 1 ) of dabigatran etexilate is known to be therapeutically useful as an oral anticoagulant from the class of the direct thrombin inhibitors and is commercially marketed as oral hard capsules as Pradaxa™ in Australia, Europe and in the United States; as Pradax™ in Canada and as Prazaxa™ in Japan. Additionally, it is also marketed in Europe under the same trade mark for the primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

Dabigatran etexilate was first described in U.S. Patent No. 6,087,380, according to which the synthesis of dabigatran etexilate was carried out in three synthetic steps as depicted in Scheme 1. Scheme 1

1. HCL , EtOH

2. (NH4)2C03, EtOH

Dabigatran etexilate

II. HCI

The process involves the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl] (pyridin-2-yl)amino}propanoate (compound VI) and N-(4-cyanophenyl)glycine (compound VIII) in the presence of Ν,Ν'-carbonyldiimidazole (CDI) in tetrahydrofuran (THF) to give the hydrochloride salt of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5- yl)carbonyl](pyridin-2-yl)amino} propanoate (compound IV), which is subsequently reacted with ethanolic hydrochloric acid, ethanol and ammonium carbonate to give the hydrochloride salt of ethyl 3-{[(2-[{(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5- yl)carbonyl](pyridin-2-yl)amino} propanoate (compound II). Finally, the reaction between compound II and n-hexyl chloroformate (compound IX), in the presence of potassium carbonate, in a mixture of THF and water, affords dabigatran etexilate of Formula (I) after work- up and chromatographic purification. However, no information is given about the purity of the isolated dabigatran etexilate (I) product. Further, the process is not viable industrially as it requires chromatographic purification in several of its steps, thus making it very difficult and costly to implement on an industrial scale.

In order to simplify the process for obtaining dabigatran etexilate described in U.S. Patent No. 6,087,380, several alternative processes have been developed and reported in the art. EP2118090B discloses a process for the preparation of the intermediate compound of Formula (II) by crystallization from a salt with p-toluenesulfonic acid. The amidine salt (ll-pTsOH) is obtained from a compound of formula (IV), which is also isolated in the form of a hydrobromide salt, (IV- HBr).

EP2262771A discloses a process for the preparation of the intermediate compound of Formula (IV), which is obtained in the form of a salt with oxalic acid. This document indicates that the oxalate intermediate of the compound (IV) crystallizes easily and is a good synthesis intermediate to obtain the amidine hydrochloride salt (ll-HCI) with high purity on an industrial scale. The compound (IV) in oxalate salt form is transformed in dabigatran following the process disclosed in WO 98/37075.

WO 2006/000353 describes an alternative process for the synthesis of dabigatran etexilate as depicted in Scheme 2.

Dabigatran etexilate

The process involves condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2- yl)amino}propanoate (compound VI) and 2-[4-(1 ,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (compound Villa) in the presence of a coupling agent such as CDI, propanephosphonic anhydride (PPA), or pivaloyl chloride, to give ethyl 3-{[(2-{[(4-{1 ,2,4-oxadiazol-5-on-3- yl}phenyl)amino]methyl}-1 -methyl-1 H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound IVa), which is subsequently hydrogenated in the presence of a palladium catalyst to give ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1 H-benzimidazol-5- yl)carbonyl](pyridin-2-yl)amino} propanoate (compound II). The compound II is acylated with n- hexyl chloroformate (compound I) to give dabigatran etexilate. Finally, dabigatran etexilate is converted into its mesylate salt. Although the patent describes the HPLC purities of intermediate compounds II, IVa, Villa and VI, no information is given concerning the purity of the isolated dabigatran etexilate or the mesylate salt thereof.

WO 2010/045900 discloses a process to prepare the intermediate amidine hydrochloride compound (ll-HCI) from the oxalate salt of the compound (IV) by reacting with hydrogen chloride in ethanol, followed by reaction with ammonium carbonate to avoid chromatography which is not feasible on an industrial scale.

WO 2014/012880 discloses a process to prepare an intermediate of dabigatran etexilate (compound IV) by reacting carboxylic acid (compound VIII) with diamaine (compound VI) in the presence of the coupling agent CDI, followed by reaction with 6 equivalents of acetic acid at 130°C to obtain compound IV in acetate salt form, having a purity of 94%. The isolated solid is further recrystallized from ethanol to obtain a purity of 99%. The purified (compound IV. acetate) is reacted with hydrogen chloride in the presence of an alcohol, and then with ammonia in an aqueous medium to form the amidine hydrochloride salt (compound ll-HCI) in the presence of water.

The synthesis of intermediate compound II has been reported in the patent literature and known methods require either chromatographic purification or a lengthy purification procedure, such as converting the compound into the HCI salt followed by recrystallization, to obtain 97% pure intermediate compound II. In previously reported methods, the product yield is undesirably less than 50 %.

Similarly, the intermediate compound IV prepared by CDI mediated coupling with glycine derivatives followed by acetic acid mediated cyclization according to known methods results in the formation of highly impure products, which require purification by either column chromatography or by converting the crude reaction mixture to suitable salts. Previously reported methods afford low product yields and purity, which mean that such processes are not suitable for the commercial scale production of dabigatran.

In view of the foregoing, it is of great interest to continue investigating and develop other alternative simplified processes for the large scale industrial production of the active pharmaceutical ingredient dabigatran etexilate or salts thereof, which avoid complicated and costly purification steps in the synthesis of intermediates, while maintaining a high quality of synthesis intermediates and improving the yields of each step of reaction.

OBJECTS OF THE INVENTION

The object of the invention is to provide an alternative and improved process for the preparation of dabigatran etexilate or a pharmaceutically acceptable salt thereof.

Another object of the invention is to provide an alternative and improved process for the preparation of a compound of Formula (II),

II

Another aspect of the invention is to provide an alternative and improved process for preparation of compound of Formula (IV),

Yet another object of the present invention is to provide a process for the preparation of dabigatran etexilate or a pharmaceutically acceptable salt thereof which is simple, economical and suitable for industrial scale-up. SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is provided a process for preparing dabigatran etexilate of Formula (I), or a pharmaceutically acceptable salt thereof,

(I)

comprising the steps of:

(a) reacting 2-(4-cyanophenylamino) acetic acid of Formula (VIII),

Vl!l

with Ν,Ν'-carbonyldiimidazole to obtain a compound of Formula (VII),

DAB Glycine-CDI complex

VII

and isolating the compound of Formula (VII) so formed; and

(b) reacting the isolated compound of Formula (VII) with ethyl 3-(3-amino-4-(methyl amino)-N- (pyridin-2-yl)benzamido)propanoate of Formula (VI),

VI

in presence of a suitable solvent to obtain a compound of Formula (V),

DAB Coupling Intermediate

V

and cyclizing the compound of Formula (V) so formed in a suitable solvent, in the absence of an acid to obtain ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)- IH-benzo[d]- imidazole-5-ca ula (IV),

IV and

either,

(c) reacting the compound of Formula (IV) with an acid in a suitable solvent to obtain a

reaction mixture comprising a compound of Formula (III),

and, optionally without isolation,

(d) treating the compound of Formula (III) with a suitable base to obtain a compound or

Formula (II),

II

or,

(c') reacting the compound of Formula (IV) with N-acetylcysteine in a suitable solvent to obtain a compound of F

Ilia

and, optionally without isolation,

(d') treating the compound of Formula (Ilia) so formed with a suitable base to obtain a compound of Formula (II),

and following steps (c) and (d) or steps (c') and (d'),

(e) reacting the compound of Formula (II) so formed with n- hexyl chloroformate of Formula (IX),

in presence of base, in suitable solvent, to obtain dabigatran etexilate of Formula (I);

and optionally thereafter, (f) converting the dabigatran etexilate so formed into a pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides an improved process for the preparation of ethyl 3- (2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]-imidazole-5-carboxamido) propanoate of Formula (IV),

IV

which comprises the steps of:

(a) reacting 2-(4-cyanophenylamino)acetic acid of Formula (VIII), H

VIII

with Ν,Ν'-carbonyldiimidazole (CDI) to obtain DAB Glycine-CDI complex of Formula (VII); and isolating DAB Glycine-CDI complex

DAB Glycine-CDI complex

VII

and

(b) condensing DAB Glycine-CDI complex of Formula (VII) with ethyl 3-(3-amino-4-(methyl amino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (VI),

VI

in presence of a suitable solvent to obtain DAB coupling intermediate (V),

V

and cyclizing the compound of Formula (V) so formed in a suitable solvent, in the absence of an acid, to obtain ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV).

The prior art processes disclosed in the citations listed above carry out the reaction step (a) without isolation of the DAB Glycine-CDI complex of Formula (VII). The process of the present invention instead involves isolation of the DAB Glycine-CDI complex of Formula (VII). The inventors have surprisingly found that the isolation of the DAB Glycine-CDI complex of Formula (VII) improves the efficiency of the reaction to 85% as compared to 61 % as reported in the prior art. This forms one aspect of the present invention. The coupling reaction described in step (a) is typically carried out in the presence of a suitable solvent. The reaction may be carried out at a temperature ranging from about 0 to about 40°C.

The processes described in the prior art require the addition of an acid, such as acetic acid, for promoting cyclization of the compound of Formula (V) to obtain ethyl 3-(2-((4- cyanophenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV). The prior art process are also performed at high temperatures e.g. > 118-1 19°C. The use of such acids and high temperature reaction conditions makes these processes lengthy, costly and also contributes to environmental pollution. Further, the compound of Formula (IV) is typically either isolated in acetate salt form or converted to another acid addition salt, such as the oxalate or hydrochloride salt, or basified using a base.

It has surprisingly been found that, the cyclization step can be carried out in a solvent without addition of an acid. In accordance with the present invention, the compound of Formula (IV) can be isolated as a base by simple filtration. This advantageously avoids processing steps such as distillation, extraction, basification and thus makes the process of the present invention highly- suitable for industrial scale-up. This forms another aspect of the present invention.

The condensation and cyclization steps may be carried out without isolating the DAB coupling intermediate of Formula (V).

In the context of the present invention, the term "without isolation" means that the product referred to is not isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid. Thus, "without isolation" may mean that the product remains in solution and is then used directly in the next synthetic step, or it may mean that solvent is substantially removed from a solution of the product such that the product is present as a residue, but not as a solid.

Preferably, the condensation and cyclization steps are carried out in the same solvent. The condensation and cyclization steps are preferably carried out at a temperature ranging from about 30°C to about the reflux temperature of the solvent used.

The solid ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N-(pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) may crystallize out of solution after cooling to room temperature and may conveniently be isolated by filtration.

Thus, as compared to the prior art process wherein the compound of Formula (IV) is isolated by a lengthy work up procedure, such as solvent extraction, washing, drying, concentration and isolation, the process of the present invention involves simple work up making this process suitable for industrial scale up. This forms another aspect of the present invention.

The compound of Formula (IV) obtained can, if desired, be purified further, for example by slurring in a suitable solvent, crystallization, extraction or chromatography according to methods known in the art. In another aspect, the present invention provides an improved process for the preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5- carboxamido) propanoate of Formula (II),

II

which comprises the steps of:

(c) reacting ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) with an acid in a suitable organic solvent to obtain DAB imidate ester of Formula (III),

15 and

(d) treating the compound of Formula (III) so formed with a base to obtain ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5- carboxamido)propanoate as a base of Formula (II). In one aspect, the reaction is carried out without isolation of the intermediate compound of Formula (III).

The compound of Formula (II) is an important intermediate in the synthesis of dabigatran etexilate. The prior art processes disclosed in the citations listed above require either a chromatographic purification or a lengthy purification procedure, such as converting into the hydrochloride (HCI) salt or hydrobromide (HBr) salt followed by recrystallization to obtain 97% pure intermediate. In both cases, the yield is undesirably less than 50 %. The process of the present invention to prepare the compound of Formula (II) has an advantage over prior art process as it may be performed in a single solvent. The temperature at which the reaction is carried out typically ranges from -10°C to the reflux temperature of the solvent used. The residual inorganics are typically removed by the filtration. The compound of Formula (II) is preferably obtained as the free base using known techniques such as distillation, precipitation by addition of an anti-solvent and filtration.

In another aspect of the present invention, there is provided a process for preparing ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5- carboxamido)propanoate of Formula (II), which comprises steps of:

(c') reacting ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) with N-acetylcysteine in a suitable organic solvent to obtain an DAB imin -thioether intermediate compound of Formula (Ilia),

Ilia

and

(d') treating the compound of Formula (Ilia) so formed with a suitable base, such as ammonia, to obtain ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH- benzo[d]imidazole-5-carboxamido)propanoate of Formula (II). In one aspect, the reaction is carried out without isolation of DAB imino-thioether intermediate compound (Ilia).

The compound of Formula (II) is an important intermediate in the synthesis of dabigatran etaxilate. Many of the synthetic methods for the preparation of amidines described in the literature involve highly acidic\alkaline or strongly reducing reaction conditions or require high temperatures and are less suitable for the synthesis of the highly functionalized compound of Formula (II). It has surprisingly been found that the use of N-acetylcysteine as a catalyst not only increases the rate of the reaction, in spite of the reduced solubility of ammonia, but also has the function of stabilizing the compound of Formula (II) formed, since the latter decomposes through loss of ammonia in basic media. This forms one aspect of the present invention. Further, N- acetylcysteine is non-toxic and can be recycled after simple separation from the crude product by means of ion exchange chromatography. This forms another aspect of the present invention.

The temperature at which reaction to prepare a compound of Formula (II) proceeds is typically in the range of -10°C to the reflux temperature of the solvent used. The reaction is preferably carried out in an inert solvent. The reaction may be carried out in the presence or absence of an inorganic or organic ammonium salt. The product may be isolated by conventional methods, such as distillation, filtration, centrifugation or extraction. The product obtained can, if desired, be purified further, for example by crystallization, extraction or chromatography according to methods known in the art.

According to yet another aspect of the present invention, there is provided a novel compound "DAB imino-thioether" of For la (Ilia):

Ilia

The compound of Formula (Ilia) may be prepared according to the process described above. According to another aspect of the present invention, there is provided the use of a compound of Formula (Ilia) in the preparation of a compound of Formula (II) and/or in the preparation of dabigatran etexilate or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to use of compound of Formula (IV),

and a compound of Formula (II),

II

for the preparation of dabigatran etaxilate of Formula I, or a pharmaceutically acceptable salt thereof, which comprises further steps of:

(e) reacting 3-(2-((4-carbamimidoylphenylamio)methyl)-l-methyl-N-(pyridin-2-yl)-IH- benzo[d] imidazole-5-carboxamido)propanoate hexyl chloroformate of formula (IX)

in the presence of a base, in suitable organic solvent, to obtain dabigatran etexilate of Formula (I). Optionally, the dabigatran etexilate of Formula (I) so formed may be converted to a pharmaceutically acceptable salt thereof. The dabigatran etexilate of Formula (I) may be crystallized in suitable organic solvent by methods known in the art.

The present invention further provides dabigatran etexilate of Formula (I) containing less than about 0.2 % of 2-pyridyl impurity. The 2-pyridyl impurity associated with dabigatran etexilate can be one of the following compounds of Formula A or B.

Imp A

Imp B In still a further aspect, the invention provides a process for the synthesis of the 2-pyridyl impurities of Formula A and B, and their use as a reference standard in the analysis of dabigatran etexilate or a pharmaceutically acceptable salt thereof, such as by HPLC.

Dabigatran etexilate of Formula (I) obtained by the process of the present invention may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. A particularly preferred acid addition salt of dabigatran etexilate is the mesylate salt.

There is also provided by the present invention dabigatran etexilate or a pharmaceutically acceptable salt thereof prepared by a process of the present invention having a purity of more than about 99% by HPLC.

Dabigatran etexilate or a pharmaceutically acceptable salt thereof obtained by the process of the present invention may be used to reduce the risk of stroke and blood clots in patients with a common type of abnormal heart rhythm called non-valvular atrial fibrillation (AF). It may be combined with at least one pharmaceutically accepted excipient in the preparation of pharmaceutical composition. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of dabigatran etaxilate of Formula (I) or a pharmaceutically acceptable salt thereof which process is economical, fast and which results in a high purity dabigatran etaxilate product.

A process for the preparation of dabigatran etaxilate or a pharmaceutically acceptable salt thereof in accordance with the present invention is depicted in Scheme 3.

Scheme 3

In the above scheme, the brackets indicate intermediate compounds that may, or may not, be isolated in accordance with the process of the present invention. Preferably, said intermediate compounds of Formula (III) and (V) are not isolated in the process of the present invention. The compounds of Formula (II) and (IV) are hitherto reported intermediates useful in the process for the preparation of dabigatran etaxilate or a pharmaceutically acceptable salt thereof as described herein. In one aspect of the invention, the compound of Formula (VIII) is condensed with the coupling agent Ν,Ν'-carbonyldiimidazole (CDI) to obtain a DAB Glycine-CDI complex of Formula (VII).

The condensation reaction is preferably carried out in an inert solvent. The inert solvent used is preferably selected from halogenated solvents, esters, ethers, cyclic ethers, polar solvents, non- polar solvents and the like and mixtures thereof. The condensation reaction is preferably performed at a temperature ranging from about 0 to about 40°C, preferably from about 20 to about 25°C. The solid DAB Glycine-CDI complex of Formula (VII) is isolated from the reaction mixture, preferably by filtration. The DAB Glycine-CDI complex of Formula (VII) is further condensed with ethyl 3-(3-amino-4- (methyl amino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (VI) in the presence of a first suitable solvent to obtain DAB coupling intermediate of Formula (V), which compound is further cyclized to obtain ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV).

The condensation and cyclization steps of the process of the present invention are preferably be carried out without isolating the DAB coupling intermediate of Formula (V).

The solvent used for the condensation and cyclization steps is preferably selected from the group consisting of esters, such as ethyl acetate, isopropyl acetate, butyl acetate; halogenated solvents, such as methylene dichloride, ethylene dichloride, chlorobenzene, chloroform; cyclic ethers such as THF, 2-methyltetrahydrofuran; non polar solvents such as toluene, xylene, cyclohexane; polar solvents such acetonitrile and the like, or mixtures thereof. Preferably, condensation and cyclization steps are carried out in the same solvent. More preferably, the solvent is selected from toluene and xylene.

The condensation and cyclization steps are typically carried out at a temperature ranging from about 30°C to about the reflux temperature of the solvent used. Preferably, the condensation step is carried out at a temperature in the range of from about 40°C to about 80°C. In one aspect, it is carried out at a temperature in the range of from about 40°C to about 60°C.

Preferably, the cyclization step is carried out at a temperature in the range of from about 40°C to about the reflux temperature of the solvent used. In one aspect, it is carried out at a temperature in the range of from about 50°C to about the reflux temperature of the solvent used. Preferably, the cyclization reaction is carried out under reflux temperature of the solvent used.

Preferably, the cyclization step is carried out without the addition of acid.

In one preferred aspect, the process of the present invention comprises the step of condensing a compound of Formula (VI) with the DAB Glycine-CDI complex of Formula (VII) in toluene at a temperature in the range from about 45°C to about 55°C for about 3 hours, and then heating the reaction mixture to a temperature in the range from about 100°C to about 1 10°C for about 3 hours.

In one aspect, the solid ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH- benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) may precipitate out on cooling to room temperature and may be isolated by simple filtration. Alternatively in another aspect, the solid ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) may precipitate out on addition of second solvent and may be isolated by simple filtration. The second solvent acts as a co-solvent and assists in precipitation of the solid. The obtained solid product may be further crystallized in one or more suitable solvents. A co- solvent and a suitable solvent include organic solvents, for example alcohols such as methanol, ethanol, IPA, 1 -octanol; esters, such as ethyl acetate, methyl acetate, butyl acetate; ether such as methyl t-butyl ether(MTBE), diethyl ether; polar aprotic solvents, such as dimethyl sulfoxide (DMSO), DMF, THF, 2-methyltertahydrofuran; non-polar solvents, such as heptane, octane toluene and the like, including mixtures thereof. Preferably, the solid is precipitated out of solution by the addition of an alcohol co-solvent. In one aspect, the isolated solid is further slurried in a solvent such as water. In a preferred aspect, the solid is crystallised from a mixture of solvents, in particular an ester and an alcohol.

The compound ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) obtained by the process of the present invention may be further reacted with an acid to obtain a DAB imidate ester of Formula (III) , which is further reacted with a base to obtain the compound ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5- carboxamido)propanoate of Formula (II).

In one aspect, the intermediate compound DAB imidate ester of Formula (III) is not isolated.

The solvent used for the reaction steps to convert a compound of Formula (IV) to a compound of Formula (II) is preferably selected from the group consisting of C C₅ alcohols; esters, such as ethyl acetate, isopropyl acetate, butyl acetate; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; ketones, such as acetone, methyl ethyl ketone; polar aprotic solvents, such as dimethylfonnamide, dimethylacetamide, N-methylpyrrolidine; polar protic solvents, such as acetonitrile; non polar solvents, such as toluene, xylene, cyclohexane; polar solvents, such as acetonitrile and the like, or mixtures thereof. Preferably, the reaction steps in acid and base are performed in a single solvent, more preferably a C C₅ alcohol. Most preferably, the reaction steps in acid and base are performed in ethanol denatured with toluene.

A suitable acid for reaction with a compound of Formula (IV) is an inorganic or organic acid. The inorganic acid may be a mineral acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid and the like. Organic acids may be carboxylic acids and may be selected from, but not limited to, formic acid, acetic acid, trifluoroacetic acid. Preferably, the acid is hydrochloric acid. The hydrochloric acid used may be aqueous hydrochloric acid, hydrochloric acid gas or a solution of hydrochloric acid in a solvent such as a C1-C5 alcohol, ketone, ester and the like. Preferably, the acid is a solution of hydrochloric acid gas in a C C₅ alcohol. A preferred C C₅ alcohol is ethanol.

A suitable base for reaction with a compound of Formula (III) may be ammonia, ammonium chloride, ammonium bicarbonate or ammonical solution. Typically, the base is added in a solvent, such as a C C₅ alcohol or the like. Preferably, the base is a solution of ammonia in a C C₅ alcohol. A preferred C C₅ alcohol is ethanol.

Preferably, the solvent present is removed from the reaction mixture before the compound of Formula (III) is treated with a base. This ensures removal of traces of any excess acid form the reaction mixture.

The reaction steps to prepare a compound of Formula (II) from a compound of Formula (IV) are typically carried out at a temperature in the range of from about -10°C to the reflux temperature of the solvent used. Preferably, the reaction steps are carried out at a temperature in the range of from about -10°C to about 60°C. In still other aspects, the reaction steps are carried out at a temperature in the range of from about 0°C to about 50°C. Most preferably, the reaction steps are carried out at a temperature in the range from about 10°C to about 40°C. The residual inorganics may be removed by the filtration. The solvent may be removed by known techniques such as distillation and the compound of Formula (II) is preferably obtained as the free base by addition of an anti-solvent, followed by filtration. A suitable anti-solvent used for the isolation step may include one or more of polar protic or aprotic solvents. In an alternative aspect, the compound ethyl 3-(2-((4-carbamimidoyl phenyl amino) methyl)-l- methyl-N-(pyridin-2- yl)-IH-benzo[d]imidazole-5-carboxamido)propanoate of Formula (II) is prepared by reacting ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH- benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) with N-acetylcysteine in a suitable organic solvent to give the corresponding novel intermediate DAB imino-thioether of Formula (Ilia), which compound is treated with ammonia to obtain ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-l-methyl-N-(pyridin-2- yl)-IH-benzo [d] imidazole-5-carboxamido) propanoate as a base of Formula (II) as depicted in Scheme 4.

In one aspect, the DAB imino-thioether intermediate compound of Formula (Ilia) is not isolated.

The reaction is typically performed at a temperature in the range of from about -10°C to the reflux temperature of the solvent used.

The reaction is carried out in an inert solvent, preferably in solvents in which the solubility of ammonia at 0°C is more than 2% by weight. Such solvents include, but are not limited to, C C₅ alcohols, such as methanol and ethanol, or a mixture thereof.

Preferably, the reaction is carried out in the absence of an inorganic or organic ammonium salt. The product compound of Formula (II) is isolated by conventional methods, such as distillation, filtration, centrifugation or extraction. The product obtained can, if desired, be purified further, for example by crystallization, extraction or chromatography using methods known in the art.

The process of the present invention is advantageous as N-acetylcysteine can be recycled after simple separation from the product by means of ion exchange chromatography. Another advantage of the process of the present invention is that undesirable side reactions do not take place and the conversion is quantitative.

The process of the present invention may further comprise reacting 3-(2-((4- carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II) prepared according to Scheme 3 or Scheme 4, with n- hexyl chloroformate of Formula (IX) in presence of a base, in suitable organic solvent, to obtain dabigatran etexilate of Formula (I). Optionally, the dabigatran etexilate so formed may be converted to a pharmaceutically acceptable salt thereof. A suitable base for use in the preparation of dabigatran etexilate from a compound of Formula (II) is an inorganic or organic base. The inorganic base may be selected from the group consisting of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or barium carbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide or barium hydroxide. The organic base may be an aliphatic or aromatic base and may be selected from, but not limited to, triethyl amine, di-isopropyl amine, pyridine, picoline, diethyl amine, piperidine, N,N-diisopropylethylamine. A suitable organic solvent for the reaction may be preferably selected from the group consisting of C C₅ alcohols, ketones, esters, polar aprotic solvents, non-polar solvents, water, or mixtures thereof.

The reaction is typically performed at a temperature in the range of from about -10°C to the reflux temperature of the solvent used. Preferably, the coupling reaction is carried out in the presence of acetone, suitably at a temperature ranging from about 10 to about 50°C, more preferably at a temperature in the range from about 20 to about 30°C.

Dabigatran etexilate of Formula (I) may be further crystallized in a suitable organic solvent by the known methods.

Dabigatran etexilate of Formula (I) obtained by the processes of the present invention is advantageously substantially free of the 2-pyridyl impurities A and B. Dabigatran etexilate is considered to be "substantially free" of a particular impurity if that impurity is present at concentrations no greater than about 0.1 % by weight, as determined by HPLC.

Dabigatran etexilate of Formula (I) obtained by the process of the present invention may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of suitable acids include but not limited to, for example methane sulfonic acid, benzene sulfonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, acetic acid, formic acid, enanthic acid, oxalic acid, adipic acid, succinic acid, lactic acid, citric acid, tartaric acid, caffeic acid, malic acid or maleic acid. A preferred pharmaceutically acceptable salt form is dabigatran etexilate mesylate.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof, prepared by a process as described above, together with one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art. According to another aspect of the present invention, there is provided the use of dabigatran etexilate or a pharmaceutically acceptable salt thereof, prepared by a process as described above, in medicine.

According to another aspect of the present invention, there is provided dabigatran etexilate or a pharmaceutically acceptable salt thereof, prepared by a process as described above, for use to reduce the risk of stroke and blood clots in patients with a common type of abnormal heart rhythm called non-valvular atrial fibrillation (AF).

According to another aspect of the present invention, there is provided the use of dabigatran etexilate or a pharmaceutically acceptable salt thereof, prepared by a process as described above, in the manufacture of a medicament for reducing the risk of stroke and blood clots in patients with a common type of abnormal heart rhythm called non-valvular atrial fibrillation (AF).

According to another aspect of the present invention, there is provided the use of dabigatran etexilate or a pharmaceutically acceptable salt thereof, prepared by a process as described above, in the treatment of reducing the risk of stroke and blood clots in patients with a common type of abnormal heart rhythm called non-valvular atrial fibrillation (AF).

According to another aspect of the present invention, there is provided a method of reducing the risk of stroke and blood clots in patients with a common type of abnormal heart rhythm called non- valvular atrial fibrillation (AF) in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of dabigatran etexilate or a pharmaceutically acceptable salt thereof, prepared by a process as described above. While emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

The details of the invention given in the examples which are provided below are for illustration only and therefore these examples should not be construed to limit the scope of the invention.

Examples:

Example 1. Preparation of DAB Glycin-CDI complex of Formula (VII)

71.02 g (0.438 mol) of CDI was dissolved in 700 ml dichloromethane under nitrogen atmosphere. Added 66.89 g (0.379 mol) of 2-(4-cyanophenylamino)acetic acid of Formula (VIII), under stirring at 20-25°C and stirred for 90-100 minutes. Solid was isolated by filtration under nitrogen atmosphere and washed with 100 ml dichloromethane to yield DAB Glycin-CDI complex.

Example 2. Preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2- yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV)

DAB Glycin-CDI Complex obtained in Example 1 was stirred in 650 ml toluene. Added 100 g (0.292 mol) of ethyl 3-(3-amino-4-(methyl amino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (VI) to the reaction mass and stirred for 3 hours at -45-50°C. The reaction mass was further refluxed for 3 hours. The reaction mass was cooled to 75-80°C, added 50 ml ethanol, further cooled to 20-25°C and stirred for 6 hours. The solid was isolated by filtration and washed with 100 ml toluene.

The wet cake was stirred in 500 ml water at 20-25°C for about 1 hour. The solid was isolated by filtration, washed with 100 ml water and dried in vacuum below 60 °C.

Yield: 120 g

Efficiency: 85%

Example 3. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II) 100 g (0.207 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH- benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was added to 1000 ml EtOH.HCI (32-35%w/w) at 5-10°C under nitrogen atmosphere and stirred for 24 hours at 15-20°C. The solvent was distilled off in vacuum below 40°C. Added 500 ml ethanol and cooled to 0-5°C. The pH of the reaction mass was adjusted to 9.5-10.0 by addition of 400 ml EtOH.NH₃ (10-13%w/w). The temperature of the reaction mass was raised to 20-25°C and stirred for 12 hours. The reaction mass was filtered and the clear filtrate was partially distilled to the half volume below 40°C. The temperature of the reaction mass was raised to 55-60°C. Added 600 ml ethyl acetate at reflux. The reaction mass was cooled to 20-25°C and stirred further for 5 hours. The solid was isolated by filtration and washed with 100 ml-ethyl acetate. The solid was dried in vacuum below 45 °C.

Yield: 72.5 g

Efficiency: 70%

Example 4. Preparation of DAB etexilate of Formula (I)

120 ml acetone, 60 ml water, 16.6 g (0.120 mol) potassium carbonate and 20g (0.040 mol) of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5- carboxamido) propanoate of Formula (II) were stirred at 20-25°C. A solution of 9.88 g (0.060 mol) of hexyl chloroformate of Formula (IX) in 50 ml acetone was added to the reaction mass at 15- 20°C in 1 .5 hours. The reaction mass was further stirred for 2 hours at 15-20°C. The precipitated solid was filtered and washed with 40 ml water.

The wet cake was dissolved in 160 ml acetone at 20-25°C. The insoluble were removed by filtration. Added 160 ml water to the clear filtrate at 20-25°C in 2 hours and the reaction mass was further stirred for 2 hours. The solid was isolated by filtration, washed with mixture of acetone : water (1 : 1), and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 18.85 g

Efficiency: 75%

Purification:

18 g of Dabigatran etaxilate was stirred in mixture of acetone: ethanol: ethyl acetate (1.5:0.5:6 volumes) at 50-55°C and stirred for 20 minutes. The reaction mass was cooled to 20-25°C and further chilled to 15-20 °C for 3 hours. The solid was isolated by filtration, washed with ethyl acetate and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 13.5 g Efficiency: 75%

Example 5. Preparation of DAB etexilate mesylate

10 g (0.02 mol) of dabigatran etexilate was dissolved in 200 ml acetone under nitrogen atmosphere. The temperature of the reaction mass was raised to 50-55°C and treated with a solution of 1.86 g (0.0193 mol) of methane sulfonic acid in 50 ml acetone. The reaction mixture was stirred for 45 minutes, then cooled to 20-25 °C and further stirred for 45 minutes. The solid was isolated by filtration, washed with acetone and dried under vacuum below 45°C to obtain dabigatran etexilate mesylate.

Yield: 10 g

Efficiency: 86%

Example 6. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (ll)using N-acetyl cysteine

10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH- benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was dissolved in 600 ml EtOH.NH₃ (15-18%w/w) and stirred at 25°C. Added 3.38 g (0.020 mol) of N-acetyl cysteine to the reaction mass and stirred for 24 hours at 70-75°C under 2.0-2.3 kg of pressure. The ethanol was distilled under vacuum and residue was purified by column.

Yield: 5.5 g

Efficiency: 53%

Example 7. Preparation of DAB Amidine of Formula (II) using N-acetyl cysteine

10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH- benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) with 3.5 g (0.021 mol) of N- acetyl-(S)cysteine were initially charged in 10 ml of ethanol. The reaction mixture was heated to 60-65°C, and saturated with ammonia. After 4 hours, ethanol was distilled under vacuum to obtain titled compound as a solid.

Yield: 7.0 g

Efficiency: 67%

Example 8. Preparation of 2-pyridyl impurity B Part I: 12.0g (0.016 mol) of dabigatran etexilate was added to the solution of 2.8 g (0.07 mol) sodium hydroxide (in 300 ml water and 150 ml ethanol. The reaction mass was stirred for 5 hours. The solution was concentrated under vacuum and neutralized with aq. solution of citric acid (10%v/v). The solid was separated by filtration and washed with cold water and dried under vacuum to afford the acid as a white crystal.

Yield: 8.50 g

Part 11:10 g ( 0.0166 mol) of DAB-Acid obtained in part I was stirred with 25 ml thionyl chloride under nitrogen The temperature of the reaction mass was raised to 40-45°C and maintained for 1 hour. Thionyl chloride was distilled under vacuum completely The residue was stirred in solution of 100 ml toluene and 10 ml triethyl amine at 5-10°C. Added 3.1 g (0.0329 mol) 2-amino pyridine to the reaction mass at 5-10°C under nitrogen atmosphere. Temperature of the reaction mass was raised to 50-55°C and stirred. Toluene was distilled under vacuum and the residue was dissolved in 150 ml DCM. The organic layer was washed with water, dried on sodium sulfate. The organic layer was distilled under vacuum to obtain t crude 2-Pyridyl impurity which was purified by column chromatography.

Yield: 4.0 g

Example 9. Preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2- yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV)

To a solution of N, N-Carbonyldiimidazole (1.17kg, 7.21 mol) and dichloromethane (1 1.25 L), added 2-(4-cyanophenylamino)acetic acid of Formula (VIII), (1.15Kg,6.52 mol) at 30°C under nitrogen atmosphere. The reaction mixture was stirred for 90-100 min and the resulting solid was filtered under nitrogen atmosphere to obtain form Dab glycine CDI complex of Formula (VII).

Dab glycine CDI complex of Formula (VII) was stirred in toluene (9.0L). Added ethyl 3-(3-amino-4- (methyl amino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (VI) (1.5Kg, 4.38 mol) and maintained the reaction at 45-55°C for 3.0 hrs to form DAB coupling intermediate of Formula (V), which further heated to 90-100°C for 3.0 hrs. The reaction mixture was cooled to 25-30°C and the solid precipitated out was isolated by filtration. The wet cake was stirred in water (9.0L), filtered and dried in vacuum below 60 °C to obtain titled compound.

Yield: 1.80kg

Efficiency: 85 % Example 10. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (II)

A mixture of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) (1.73 kg,3.58mol) was stirred in ethanol denatured with toluene HCI (32-35 % w/w) (20.76 L) at 15- 20°C for 24 hrs. Reaction mass was distilled out completely and the residue was treated with ethanol denatured with toluene. NH₃ (at 10-15% w/w) was added to get the pH 9.0-9.5. The reaction mixture was stirred further for 12.0 hrs. The inorganic was separated by filtration and the filtrate was distilled out and the residue was stirred in ethyl acetate (10 L) . The solid was isolated by filtration and washed with ethyl acetate. The solid was dried in vacuum below 45°C to obtain titled compound.

Yield: 1.70kg

Efficiency: 95 %

Example 11. Preparation of DAB etexilate of Formula (I)

To a solution of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH- benzo[d]imidazole-5-carboxamido) propanoate of Formula (II) (1.61 kg, 3.22mol ), acetone (19.32 L), water( 9.66 L) and potassium carbonate (1.34Kg, 9.69moles ) was added hexyl chloroformate (0.795 kg, 83 moles) slowly at 20-25°C in 2-3 hrs. The reaction mixture was stirred further for 90 min. The solid was filtered and stirred in 7.5 volumes of acetone at 35-40°C. To the clear solution was added dropwise, 7.5 volumes of purified water. The reaction mixture was stirred further for 2 hours at 20-25°C, solid was isolated by filtration and dried at 45°C. The solid was stirred in a mixture of ethanol: ethyl acetate (1 : 10 volume) at 35-40°C to get clear solution, then gradually cooled to 10-15°C and further stirred for 6.0 hours. The solid was isolated by filtration, washed with ethyl acetate and dried under vacuum below 45°C to obtain dabigatran etexilate.

Yield: 1.10 kg

Efficiency: 65%

Example 12. Preparation of DAB etexilate mesylate

Dabigatran etexilate (1.0Kg, 1.59mol) was dissolved in acetone (20.0L) at 50-55°C under nitrogen atmosphere and treated with a solution of methane sulfonic acid (0.15Kg, 1 .56mol) in acetone (1 .5L). The reaction mixture was stirred for 45 minutes, then cooled to 20-25 °C and further stirred for 45 minutes. The solid was isolated by filtration, washed with acetone and dried under vacuum below 45°C to obtain dabigatran etexilate mesylate. Yield: 1.10kg Efficiency: 95 %

Claims

1. A process for preparing dabigatran etexilate of Formula (I), or a pharmaceutically acceptable salt thereof,

(I)

comprising the steps of:

(a) reacting 2-(4-cyanophenylamino) acetic acid of Formula (VIII),

VIII

with Ν,Ν'-carbonyldiimidazole to obtain a compound of Formula (VII),

DAB Glycine-CDI complex

VII

and isolating the compound of Formula (VII) so formed; and

VI

in presence of a suitable solvent to obtain a compound of Formula (V),

DAB Coupling Intermediate

V

and cyclizing the compound of Formula (V) so formed in a suitable solvent in the absence of an acid to obtain ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH- benzo[d]-imidazole-5-carbo (IV),

IV and

either,

reaction mixture comprising a compound of Formula (III),

and, optionally without isolation,

Formula (II),

II

or,

Ilia

and, optionally without isolation,

and following steps (c) and (d) or steps (c') and (d'),

and, optionally thereafter, (f) converting the dabigatran etexilate so formed into a pharmaceutically acceptable salt thereof.

2. A process according to claim 1 , wherein the compound of Formula (V) is not isolated.

3. A process according to claim 1 or claim 2, wherein the compound of Formula (III) or of Formula (Ilia) is not isolated.

4. A process according to any one of claims 1 to 3, wherein step (a) is performed in a solvent selected from the group consisting of halogenated solvents, esters, ethers, cyclic ethers, polar solvents, non-polar solvents, or a mixture thereof.

5. A process according to claim 4, wherein step (a) is performed in dichloromethane.

6. A process according to any one of claims 1 to 5, wherein step (a) is performed at a

temperature ranging from about 0 to about 40°C.

7. A process according to any one of claims 1 to 6, wherein step (b) is performed in a solvent selected from the group consisting of esters, halogenated solvents, cyclic ethers, non-polar solvents, polar solvents, or mixtures thereof.

8. A process according to claim 7, wherein step (b) is performed in toluene.

9. A process according to any one of claims 1 to 8, wherein the reaction between the compound of Formula (VI) and the compound of Formula (VII) in step (b) is performed at a temperature in the range of from about 40°C to about 80°C.

10. A process according to any one of claims 1 to 9, wherein the cyclization reaction of step (b) is performed at a temperature in the range from about 100°C to about 1 10°C.

1 1. A process according to any one of claims 1 to 10, wherein the compound of Formula (IV) is isolated in free base form, optionally by filtration.

12. A process according to any one of claims 1 to 11 , wherein the acid used in step (c) is an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid.

13. A process according to claim 12, wherein the inorganic acid is hydrochloric acid.

14. A process according to any one of claims 1 to 11 , wherein the acid used in step (c) is an organic acid selected from the group consisting of formic acid, acetic acid and trifluoroacetic acid.

15. A process according to any one of claims 1 to 14, wherein the base used in step (d) or (d') is selected from the group consisting of ammonia, ammonium chloride and ammonium bicarbonate.

16. A process according to any one of clams 1 to 15, wherein the solvent used in step (c), (c'),

(d) or (d') is a C C₅ alcohol, optionally ethanol.

17. A process according to any one of claims 1 to 16, wherein step (c) or (c') is performed at a temperature in the range from about 0°C to about 80°C.

18. A process according to any one of claims 1 to 17, wherein step (d') is carried out in the absence of an inorganic or organic ammonium salt.

19. A process according to any one of claims 1 to 18, wherein the base used in step (e) is selected from the group consisting of alkali or alkaline earth metal carbonates and alkali or alkaline earth metal hydroxides.

20. A process according to any one of claims 1 to 19, wherein the base used in step (e) is selected from the group consisting of triethylamine, di-isopropyl amine, pyridine, picoline, diethylamine, piperidine and N,N-diisopropylethylamine.

21. A process according to any one of claims 1 to 20, wherein step (f) comprises converting dabigatran etexilate to dabigatran etexilate mesylate by treatment of dabigatran etexilate with methane sulfonic acid.

22. A process for the preparation of ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-IH-benzo[d]-i noate of Formula (IV),

IV

which comprises the steps of:

(a) reacting 2-(4-cyanophenylamino)acetic acid of Formula (VIII),

VIII

with carbonyldiimidazole (CDI to obtain a compound of Formula (VII),

DAB Glycine-CDI complex

VII

and isolating the compound of Formula (VII) so formed; and

(b) condensing the compound of Formula (VII) with ethyl 3-(3-amino-4-(methyl amino)-N- (pyridin-2-yl)benzamido)propanoate of Formula (VI),

VI

in presence of a suitable solvent to obtain a compound of Formula (V),

V

and cyclizing the compound of Formula (V) so formed in a suitable solvent, in the absence of an acid, to obtain ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)- IH-benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV).

23. A process according to claim 22, wherein the compound of Formula (IV) is isolated in free base form, optionally by filtration.

24. A compound of Formula ( ia),

Ilia

25. Use of a compound of Formula (Ilia), as defined in claim 24, for the preparation of ethyl 3- (2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-IH-benzo[d]imidazole-5- carboxamido) propanoate of Formula (II) and/or dabigatran etexilate, or a pharmaceutically acceptable salt thereof.

26. Dabigatran etexilate or a pharmaceutically acceptable salt thereof containing less than about 0.2 % by weight of a compound of Formula A or B,

Imp A

Imp B

27. Use of a compound of Formula A or Formula B, as defined in claim 26, as a reference

standard in the analysis of dabigatran etexilate or a pharmaceutically acceptable salt thereof.

28. A process for preparing dabigatran etexilate or a pharmaceutically acceptable salt thereof substantially as described herein with reference to the Examples.

29. A pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically

acceptable salt thereof as defined in claim 26 and one more pharmaceutically acceptable excipients.

30. A pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically

acceptable salt thereof prepared according to a process as defined in any one of claims 1 to 21 and one more pharmaceutically acceptable excipients.

31. Use of dabigatran etexilate or a pharmaceutically acceptable salt thereof prepared according to a process as defined in any one of claims 1 to 21 in the manufacture of a medicament for reducing the risk of stroke and blood clots in patients with non-valvular atrial fibrillation.