WO2014192030A2

WO2014192030A2 - An improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof

Info

Publication number: WO2014192030A2
Application number: PCT/IN2014/000364
Authority: WO
Inventors: Ravindra Babu Bollu; Subha Velayudhan NAIR; Prasanta Kumar DALASINGH; Venkata Sunil Kumar Indukuri; Seeta Rama Anjaneyulu GORANTLA; Satyanarayana Chava
Original assignee: Laurus Labs Private Limited
Priority date: 2013-05-29
Filing date: 2014-05-29
Publication date: 2014-12-04
Also published as: WO2014192030A3

Abstract

The present invention provides an improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof, particularly mesylate salt. The present invention also provides novel salts of intermediates of Dabigatran etexilate and their polymorphs.

Description

"AN IMPROVED PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF" PRIORITY

This application claims the benefit under Indian Provisional Application No. 2339/CHE/2013, filed May 29, 2013, the content of each of which is incorporated by reference herein. FILED OF THE INVENTION

The present invention is in general related to an improved process for preparation of Dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof in high product yield and purity.

BACK GROUND OF THE INVENTION Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. There are two types of DTIs, depending on their interaction with the thrombin molecule. Bivalent DTIs (hirudin and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site. The compound Ethyl N-{[2-({[4-((E)-amino{[(hexyloxy)carbonyl]imino}methyl) phenyl] -amino} methyl)- 1 -methyl- 1 H-benzimidazol-5-yl]carbonyl} -N-pyridin-2-yl-P- alaninate (Formula 1) generally named as Dabigatran Etexilate

Formula 1

Dabigatran etexilate is the oral pro-drug of the active moiety Dabigatran of Formula 1A which is a univalent direct thrombin inhibitor that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin.

Formula 1A The dabigatran etexilate pro-drug was developed due to the limited oral availability of dabigatran. Dabigatran etexilate is converted to actual effective compound namely dabigatran in the body. The main category of indication for dabigatran etexilate is the post operative prophylaxis of deep vein thrombosis and the prevention of strokes. Dabigatran etexilate is approved for commercial use as in the form of dabigatran etexilate mesylate salt, is represented by the following structure of Formula:

Dabigatran and dabigatran etexilate together with their analogues were first disclosed in US Patent No. 6,087,380 ("the '380 patent"). According to the '380 patent, dabigatran etexilate was prepared in three steps in accordance with example 25, and in an analogous manner to the process described in example 90. The process disclosed in the '380 patent is schematically represented as follows:

Dabigatran etexilate

In the first step of the '380 patent, compound of Formula 4 reacts with diamine of compound of Formula 2 in presence of 1,1' carbonyl diimidazole (CDI) in THF and subsequent dehydration aided by acetic acid and results intermediate of Formula 3 (in the form of free base or acetate). Though the reaction proceeds smoothly, its isolation proved to be tedious as it requires column chromatography purification and shows significant impact on the yield and purity of intermediate of Formula 3. In the second step of the '380 patent, intermediate of Formula 3 is subjected to Pinner Reaction to yield an amidino of intermediate of Formula 5. While reproducing the procedure as describe in the '380 patent, it has been observed that compound of Formula 5 prepared by this method required subsequent chromatographic purification as it was an oily substance with a relatively high content of impurities.

In the final step of the '380 patent, intermediate of Formula 5 reacts with n- hexylchloroformate and produces dabigatran etexilate of Formula l.The thus-formed dabigatran etexilate base is purified by column chromatography and characterized by thih layer chomatography and mass spectrometry. No information is provided in the description relating to the crystallographic properties of the dabigatran etexilate base.

The same process described in the above patent is disclosed in a publication of Hauel et al. (J Med. Chem. 2002, 45, 1757-1766), wherein the dabigatran etexilate base is characterized by melting point (128- 129 °C) and H-NMR.

However, purity and yield of dabigatran etexilate obtained by the process of the '380 patent or Hauel et al publication is not satisfactory for pharmaceutical use. Since some steps in the synthesis pathway indicated above, in particular the steps of isolating intermediate of Formula 3 and intermediate of Formula 5 require the purification of the obtained compounds by chromatography; thereby these steps are not suitable to be carried out at an industrial level.

Further it is noted that the process disclosed in the '380 patent involves the usage of hydrochloride salt form of intermediate of Formula 5, which degrades to form impurities and results in the formation of dabigatran etexilate with low purity. Hence there is a need to develop improved process of preparing dabigatran etexilate through stable acid addition salts of intermediate of formula 5.

It is evident that by replacement of chromatographic purification with crystallization represents a considerable technological simplification and improves the economy of the entire production process.

Owing to the medical importance of dabigatran etexilate, a number of synthesizes were subsequently published, disclosing improved yields and purity of dabigatran etexilate and its intermediates thereof.

PCT Publication WO2008/095928 describes improved process of preparing dabigatran etexilate which involves, treating compound of Formula 4 with diamine of compound of Formula 2 in presence of carbonyl-di-(l,2,4-triazole), THF and acetic acid and results intermediate of Formula 3, which further isolated as its hydrobromide salt. Later Formula 3 as its hydrobromide salt was hydrolyzed to obtain benzimidazole of Formula 5, which further isolated as its p-TSA salt (represented as Formula 5A) with an improved yield of 80-94%, without involving any chromatography purification; however this application silent about the purity of the thus obtained dabigatran etexilate. Further, the use of carbonyl-di-(l,2,4-triazole) is highly expensive (at least eight fold when compared to CDI), which result an increase in the manufacturing cost.

PCT Publication WO2009/111997 describes isolation of Intermediate of Formula 3 as its oxalic acid salt with an improved yield of 92% (82% purity by HPLC).

PCT Publication WO2010/045900 describes the synthesis of dabigatran etexilate mesylate with the yield of 75% (99.5% purity by HPLC) by following the process exemplified in the Scheme I, which involves Formula 5 as its dihydrochloride or its ethanolate monohydrochloride salt.

Further number of synthesizes were subsequently published through PCT publications WO2012/077136, WO2012/152855, WO2012/04396 and WO2012/004396 disclosing improved yields and purity of dabigatran etexilate and its intermediates thereof.

However, none of the patent/patent applications make it possible to attain dabigatran etexilate with high purity, which is required in the case of a pharmaceutical substance, and in a yield acceptable in the industrial scale. The reason is mainly attributed to the quality of intermediate products, which are moreover produced in forms requiring complicated purification with the use of chromatographic methods.

Hence there is a need in the art to develop an improved process for the preparation of dabigatran etexilate with high product yield and purity to overcome the aforementioned difficulties, in a convenient and cost efficient manner and on a commercial scale.

OBJECT OF THE INVENTION

The main object of the invention is to provide an improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof in high product yield and purity without the formation of undesired impurities and suitable for large scale production.

Another object of the invention is to provide an improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof, wherein the process includes the use of an additive along with a coupling agent during the conversion of diamine of Formula 2 to benzimidazole of Formula 5 thereby substantially reducing the overall reaction time cycle and increasing the product conversion, making the process more cost effective, particularly on large scale operations.

Yet another object of the invention is to provide an improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof includes novel acid addition salts of cyano compound of Formula 3 and benzimidazole of Formula 5, thereby minimizing the process impurities without involving multiple purifications, thereby reducing the overall reaction time cycle and making the process more suitable for commercial applications.

SUMMARY OF THE INVENTION

The present invention encompasses an improved process for the preparation of dabigatran etexilate and its pharmaceutically acceptable acid addition salts thereof in high product yield and purity, wherein the improvements comprise use of an additive along with a coupling agent during the conversion of diamine of Formula 2 to benzimidazole of Formula 5 and purification techniques involving formation of acid addition salts of cyano intermediate of Formula 3 and benzimidazole of Formula 5 to removing undesired process impurities, thereby process more convenient and economical, particularly on commercial scale.

In one embodiment, the present invention provides an improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I,

Formula 1 comprising the steps of:

a) reacting a diamine compound of Formula 2

Formula 2 with a compound of Formula 4

COOH

Formula 4

in presence of a coupling agent and an additive to obtain an intermediate of Formula 3 A,

Formula 3A

cyclizing the compound of Formula 3 A with an acid to obtain cyano compound of Formula 3 or an acid addition salt thereof,

Formula 3

c) reacting the compound of Formula 3 with an acid followed by a base to obtain a benzimidazole compound of Formula 5 or an acid addition salt thereof, and

Formula 5

d) converting the benzimidazole compound of Formula 5 into dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I.

In another embodiment, the present invention provides an improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I, comprising the steps of:

a) reacting a diamine compound of Formula 2 with a compound of Formula 4 in presence of a coupling agent and an additive to obtain an intermediate of Formula 3A,

b) cyclizing the compound of Formula 3 A with an acid to obtain cyano compound of Formula 3 or an acid addition salt thereof, and

c) converting the cyano compound of Formula 3 or an acid addition salt thereof in to dabigatran etexilate of Formula 1.

In another embodiment, the present invention provides acid addition salts of compound of Formula 3, wherein the acid is a suitable acid salt forming agent; provided the acid is not oxalate, hydrochloride or hydrobromide. In another embodiment, the present invention provides acid addition salts of compound of Formula 3, wherein the acid is p-toluene sulfonic acid salt.

In another embodiment, the present invention provides l-Methyl-2- N-(4-cyanophenyl)- amino methyl] -benzimidazol-5-yl -carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of Formula 3 as p-toluene sulfonic acid salt in crystalline form.

a) reacting a diamine compound of Formula 2 with a compound of Formula 4 in presence of a coupling agent and an additive to obtain an intermediate of Formula 3 A,

b) cyclizing the compound of Formula 3 A with an acid to obtain cyano compound of Formula 3 (in the form of free base or acid addition salt thereof),

c) reacting the resulted cyano compound of Formula 3 in presence of an acid followed by a base to obtain a benzimidazole compound of Formula 5 as an acid addition salt thereof, and

d) converting the benzimidazole compound of Formula 5 in to dabigatran etexilate of Formula 1.

Optionally, in another embodiment, the present invention provides an improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I, comprising the steps of:

b) cyclizing the compound of Formula 3 A with an acid to obtain cyano compound of Formula 3,

c) isolating the cyano compound of Formula 3 as p-toluene sulfonate salt, d) reacting the compound of Formula 3 with an acid followed by a base to obtain a benzimidazole compound of Formula 5,

e) isolating the benzimidazole compound of Formula 5 as p-toluene sulfonate salt, f) reacting the compound of Formula 5 with n-hexyl chloroformate in presence of a base in a suitable solvent to provide dabigatran etexilate of Formula 1, g) optionally converting the dabigatran etexilate of Formula 1 in to its pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides an improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable salts thereof, preferably mesylate salt, comprising subjecting the intermediate compound of Formula 3 and/or Formula 5 are isolated as an acid addition salt, preferably p-toluene sulfonate salt; and converting to dabigatran etexilate.

In another embodiment, the present invention provides crystalline forms of dabigatran etexilate of Formula 1 and process for its preparation.

In another embodiment, the present invention provides a pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salts thereof prepared by the process of the invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following, the present invention will be described in more detail by preferred embodiments and examples while referring to the attached drawings, noting, however, that these embodiments, examples and drawings are presented for illustrative purposes only and shall not limit the invention in any way.

Fig. 1 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline p- toluene sulfonate salt of compound of Formula 3.

Fig. 2 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline p- toluene sulfonate salt of benzimidazole compound of Formula 5.

Fig. 3 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline dabigatran etexilate Form LI.

Fig. 4 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline dabigatran etexilate Form LI .

Fig. 5 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline dabigatran etexilate of Formula 1 obtained by example 22.

Fig. 6 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline dabigatran etexilate of Formula 1 obtained by example 22.

DETAILED DESCRIPTION OF THE INVENTION

The inventors achieved an improved and commercially viable process for preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts having desired purity, which ameliorates the problems in the art.

The inventors of the present invention have found that dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof in pure form may be obtained by incorporating the process modifications such as use of an additive along with coupling agent in the reaction between diamine compound of Formula 2 and Formula 4 and isolating the obtained intermediate compounds of Formula 3 and/or Formula 5 as acid addition salts thereof, making the process substantially removing the undesired process impurities at intermediate stage itself, thereby yields and purity of compounds of Formula 3 and/or Formula 5 are substantially increased, which are key intermediates in preparing dabigatran etexilate or its pharmaceutically acceptable acid addition salts.

It has been observed that during the synthesis of dabigatran etexilate, conversion of diamine compound of Formula 2 to benzimidazole compound of Formula 5 has been cumbersome. Most of the reported literatures for the conversion of diamine compound of Formula 2 to benzimidazole compound of Formula 5 have used carbonyl diimidazole (CDI) as coupling agent and tetrahydrofuran (THF) as the solvent in the coupling between diamine compound of Formula 2 and amide compound of Formula 4; low conversion of reactants for amide bond formation (Formula 3A) and for cylization (Formula 3) observed. We envisioned that the poor conversion was due to the less reactive diamine of Formula 2. An attempt was made to improve the Formula 3 A conversion by using relatively more reactive coupling agents such as propanephosphonic acid cyclic anhydride (PPA) and carbonyl di-(l,2,4-traizole), but improvement in conversion was not observed.

The inventors of the present invention have surprisingly found that use of an additive along with coupling agent improved the conversion of Formula 3A upto about 96% within a short period of about 1 hour against about 80% for a period of about 60 hours as reported and relatively better product yields obtained.

Further the inventors of the present invention have surprisingly found that isolation of Formula 3 and/or Formula 5 as suitable acid addition salt may improve purity of the intermediates by removing the process impurities, thereby substantially pure intermediates obtained for the preparation of dabigatran etexilate or pharmaceutically acceptable salts thereof with pharmaceutically acceptable purity.

Thus in one embodiment, the present invention provides an improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula Ϊ,

Formula 1 comprising the steps of: a) reacting a diamine compound of Formula 2

Formula 2 with a compound of Formula 4

in presence of a coupling ermediate of Formula 3 A,

Formula 3A

b) cyclizing the compound of Formula 3 A with an acid to obtain cyano compound of Formula 3 or an acid addition salt thereof,

Formula 3

Formula 5

d) converting the benzimidazole compound of Formula 5 into dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I. The starting materials diamine compound of Formula 2 and compound of Formula 4 used in the present invention are prepared from any known methods in the art.

Step a) of coupling reaction of diamine compound of Formula 2 and Formula 4 involves at least a coupling agent and an additive.

The suitable coupling agent for use herein may be selected from the group comprising carbonyl-diimidazple (CDI), carbonyl-di(l,2,4-triazole), l-ethyl-3-(-3- dimethylaminopropyl) carbodiimide (EDC), dicyclohexylcarbodiimide (DCC) and propanephosphonic acid cyclic anhydride (PPA); preferably carbonyl-diimidazole.

The suitable additives for use herein may be selected from the group comprising hydroxy benzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), 6-chloro-l- hydroxy-lH-benzotriazole (Cl-HOBt), hydroxypyridines (HOPy), Imidazole or its salts, l,8-Diazabicyclo[5.4.0]undec-7-en (DBU); tertiary amines or its hydro halide salts thereof selected from the group consisting of triethyl amine hydrochloride or diisopropylethyl amine hydrochloride or mixtures thereof; preferably Imidazole or hydroxy benzotriazole.

The reaction is advantageously carried out in a solvent. Suitable solvent include, but are not limited to ethers, esters, halogenated hydrocarbons, amides, aromatic solvents or mixtures thereof. The ether includes, but are not limited to tetrahydrofuran, 2-methyl tetrahydrofuran and the like and mixtures thereof; esters include, but are not limited to methyl acetate, ethyl acetate, propyl acetate, butyl acetate and the like and mixtures thereof; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixtures thereof; amides includes, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like and mixtures thereof; aromatic solvents include, but are not limited to toluene, chlorobenzene and the like and mixtures thereof; preferably methylene chloride, tetrahydrofuran, ethyl acetate, dimethyl formamide, N-methyl pyrrolidinone and the like and mixtures thereof.

The reaction temperature should be sufficient to effect coupling reaction. Typically the reaction temperature may be from about ambient temperature to about reflux temperature. Preferably the reaction temperature is about 30°C to about 85°C. The reaction may take from about 0.5 hours to about 12 hours depending upon the coupling agent and additive, solvent and temperature chosen, preferably about 1 hour to 5 hours.

After the coupling reaction, the formed intermediate compound of formula 3A is optionally concentrated under reduced pressure, and subjected to cyclization under suitable conditions to form compound of Form 3. Step b) of the foregoing process involves the cyclization of the compound of Formula 3 A obtained from step a) with an acid to obtain cyano compound of Formula 3 or an acid addition salt thereof.

It has been observed that the reported methods have used different solvents for amide bond formation (Formula 3 A), for cylization (Formula 3) and for isolation of the Formula 3; this makes the process more complex and uneconomical. The inventors of the present invention have surprisingly found that use of single solvent for both the amide bond formation and for the cyclization to form Formula 3 would give same or better results as compared to multisolvent methods.

The suitable acid for use herein may be any acid suitable for dehydration of formula 3 A to form compound of Formula 3. The suitable acid includes, but are not limited to acetic acid, p-toluene sulfonic acid, methane sulfonic acid, chloroacetic acid and the like and mixtures thereof.

The cyclization step may be carried out at a temperature of about 50° to about 95°, particularly at about 65°C to about 85°C and over a period of about 0.5 hour to about 5 hours.

The resultant compound of Formula 3 can be isolated by conventional techniques such as by distillation under reduced pressure, solvent crystallization, solvent precipitation and the like; preferably by distillation under reduced pressure; wherein distillation of solvent from the reaction mass is carried out at a temperature of about 40°C to about 65°C to obtain compound of Formula 3 as residue.

The resultant compound of Formula 3 residue can be purified by solvent crystallization. Solvent crystallization step includes dissolving compound of Formula 3 residue obtained as above in an organic solvent, optionally cooling the solution and filtering the solid crystals so formed. The organic solvent includes, but is not limited to esters, ethers, nitriles, ketones and the like and mixtures thereof. The esters include, but are not limited to ethyl acetate, propyl acetate, butyl acetate and the like; ethers include, but are not limited to diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone and the like.

The repetition of '380 patent, which involves Coupling reaction of diamine of Formula 2 and compound of Formula 4 in presence of coupling agent (CDI) and THF as solvent and acetic acid for the cyclization results compound of Formula 3 with 64% yield (in the form of free base or acetate). The decline in yield of intermediate of Formula 3 is because of poor conversion using a coupling agent in the amide bond formation step. In contrast the present invention utilizes an additive along with coupling agent increases the conversion of amide bond formation, thereby resulting a compound of Formula 3 with about 86% yield.

Alternatively, the resultant compound of Formula 3 can be isolated by acid addition salt thereof. - The present inventors have surprisingly found that, isolation of compound of Formula 3 as its acid addition salt thereof enhances purity by removing the impurities formed during the preparation.

In another embodiment, the present invention provides an improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I, comprising: treating cyano compound of Formula 3 obtained by the processes described above with an acid in a solvent, wherein the acid is a suitable acid salt forming agent; provided the acid is not oxalate, hydrochloride or hydrobromide; and isolating the compound of Formula 3 as corresponding acid salt.

In a preferred embodiment, wherein the acid is selected from the group consisting of p- toluene sulfonic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, methanesulfonic acid, maleic acid, malic acid, glutamic acid, aspartic acid, 2,5-dihydroxy benzoic acid, benzene sulfonic acid, ethane sulfonic acid, ethane disulfonic acid, glycolic acid, mandelic acid, cinnamic acid, camphor suflonic acid, adipic acid, stearic acid and the like; preferably the compound of Formula 3 isolated as its p-toluene sulfonic acid salt.

The acid additions salts of compound of Formula 3 can also be prepared in the similar manner as described above, by replacing acetic acid with corresponding acid addition salt as mentioned just as above.

Preferably p-toluene sulfonic acid salt of Formula 3 can be prepared in accordance with the procedure as described above, by replacing acetic acid with p-toluene sulfonic acid in the cyclization step b) of afore mentioned.

The present invention provides compound of Formula 3 or acid addition salts thereof, preferably p-toluene sulfonic acid salt is found to be substantially pure, having purity by HPLC greater than or equal to 95%, preferably having a purity by HPLC greater than or equal to 97%, more preferably having purity by HPLC greater than or equal to 98%, even more preferably having purity by HPLC greater than or equal to 99%.

In another embodiment, the present invention provides novel acid addition salts of 1- Methyl-2-[N-(4-cyanophenyl)-amino methyl]-benzimidazol-5-yl -carboxylic acid-N-(2- pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide (compound of Formula 3); preferably novel p-Toluene sulfonic acid salt of compound of Formula 3.

Formula 3. PTSA

In another embodiment, the present invention provides crystalline compound of Formula 3 as p-toluene sulfonic acid salt or hydrate or solvate thereof.

In another embodiment, the present invention provides crystalline compound of Formula 3 as p-toluene sulfonic acid salt, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 1.

In another embodiment, the present invention provides an improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I, comprising providing a compound of Formula 3 as free base or pharmaceutically acceptable salts thereof, preferably p-toluene sulfonic acid salt as obtained by the process described above, as a starting material or as an intermediate, and which may be converted into benzimidazole compound of Formula 5 or pharmaceutically acceptable salts thereof, where the yield and the purity of the pharmaceutically acceptable salts thereof, preferably mesylate salt may have a purity equal to or greater than about 99.8% as determined by HPLC.

Step c) of the foregoing process involves the reaction of compound of Formula 3 as free base or an acid addition salt thereof, with an acid in alcohol followed by a base to obtain a benzimidazole compound of Formula 5.

The present inventors found an improvement in the yield and purity of intermediate of Formula 5 and subsequently yield and purity of dabigatran etexilate or its pharmaceutically acceptable salts thereof, by utilizing pure intermediate of Formula 3 as free base or an acid addition salts thereof preferably p-toluene sulfonic acid salt.

The suitable acid for step c) use herein may be includes, but is not limited to hydrochloric acid, hydrobromic acid and the like; where the acid may be in the form anhydrous or gas form, for example hydrochloride gas or solvent containing hydrochloric acid, preferably a solvent containing hydrochloric acid can be used; more preferably ethanolic hydrochloric acid can be used.

The step c) reaction is advantageously carried out in an alcohol or a mixture of alcohol and an organic solvent. The alcohols used include, but are not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol and the like. The suitable organic solvent used herein includes, but are not limited to ethers, esters, ketones or mixtures thereof. The ethers include, but are not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether and the like and mixtures thereof; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and the like and mixtures thereof; ketones include, but are not limited to acetone, methyl ethyl ketone and the like and mixtures thereof. Preferably the step c) is carried out in an alcohol solvent such as ethanol.

The reaction temperature should be sufficient to effect reaction. Typically the reaction temperature may be from about 5°C to about 35°C. Preferably the reaction temperature is about 10°C to about 20°C. The reaction may take from about 2 hours to about 24 hours.

The suitable base used herein may be any ammonium base which includes, but is not limited to ammonia, ammonium carbonate and the like and mixtures thereof; preferably ammonia. The resultant benzimidazole compound of Formula 5 can be isolated by conventional techniques such as by distillation under reduced pressure, solvent crystallization, solvent precipitation and the like; preferably by distillation under reduced pressure; wherein distillation of solvent from the reaction mass is carried out at a temperature of about 40°C to about 65°C to obtain compound of Formula 5 as residue.

The resultant benzimidazole compound of Formula 5 can also be isolated by its acid addition salt thereof.

The present inventors have surprisingly found that, isolation of benzimidazole compound of Formula 5 as its acid addition salt thereof further enhances purity by removing the impurities formed during the preparation.

Preferably, the resultant benzimidazole compound of Formula 5 can be isolated as its acid addition salts thereof. The acid source can be added to the reaction medium either prior to reaction of compound of Formula 3 with acid or after compound of Formula 5 is formed in the reaction.

The acid source for saltification can be selected from the group consisting of p-toluene sulfonic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, methanesulfonic acid, maleic acid, malic acid, glutamic acid, aspartic acid, 2,5-dihydroxy benzoic acid, benzene sulfonic acid, ethane sulfonic acid, ethane disulfonic acid, glycolic acid, mandelic acid, cinnamic acid, camphor suflonic acid, adipic acid, stearic acid, hydrochloric acid, hydrobromic acid and the like; preferably the compound of Formula 5 isolated as its p-toluene sulfonic acid salt or its hydrochloride salt. The present invention provides compound of Formula 5 or acid addition salts thereof, preferably p-toluene sulfonic acid salt is found to be substantially pure, having purity by HPLC greater than or equal to 95%, preferably having a purity by HPLC greater than or equal to 97%, more preferably having purity by HPLC greater than or equal to 98%, even more preferably having purity by HPLC greater than or equal to 99%.

The present invention provides crystalline p-toluene sulfonate salt of benzimidazole compound of Formula 5, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Fig. 2.

In another embodiment, the present invention provides an improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I, comprising providing a compound of Formula 5 or pharmaceutically acceptable salts thereof, preferably p-toluene sulfonic acid salt as obtained by the processes described above, as a starting material or as an intermediate, and which may be converted into dabigartan etexilate or pharmaceutically acceptable salts thereof, preferably mesylate salt, where the yield and the purity of the pharmaceutically acceptable salts thereof, preferably mesylate salt may have a purity equal to or greater than about 99.8% as determined by HPLC.

The step of converting the benzimidazole compound of Formula 5 or an acid addition salt thereof into dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I, comprising:

i) treating benzimidazole compound of Formula 5 or an acid addition salt thereof, preferably p-toluene sulfonic acid salt as obtained by the process described above with a base in an organic solvent at a temperature of about 10°C to about 35°C, ii) stirred for 30 minutes,

iii) adding n-hexyl chloroformate to obtain dabigatran etexilate,

iv) isolating the dabigatran etexilate.

The suitable organic solvent for step i) used herein may be includes, but is not limited to ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether and the like and mixtures thereof; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; water and mixtures thereof.

The suitable base for step i) used herein may be includes, but is not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and the like; preferably potassium carbonate.

The n-hexylchloroformate may be added to the reaction mass optionally in a lot wise at a temperature of about 10°C to 30°C, preferably about 10°C to 20°C. The resultant dabigatran etexilate can be recovered by any conventional technique known in the art e.g. solvent precipitation, solvent extraction, purification and the like; For instance, after completion of the reaction resultant dabigatran etexilate can be recovered by the process which comprises:

a) slurrying the reaction mass with water

b) isolating the precipitate by any conventional technique e.g. by filtration c) washing the precipitate with water (or) mixture of water and an organic solvent d) recovering the resultant dabigatran etexilate by solvent distillation under vacuum e) optionally, recrystallizing the recovered dabigatran etexilate.

Wherein, the organic solvent used in step c) includes, but is not limited to ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether and the like and mixtures thereof; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like and mixtures thereof.

Alternatively, resultant dabigatran etexilate can also be recovered through solvent extraction process which comprises:

a) separating the layers so formed from the reaction and extracting the aqueous layer with an organic solvent,

b) washing the organic layer with water (or) mixture of water and an organic solvent,

c) recovering the resultant dabigatran etexilate by solvent distillation under vacuum

d) Optionally, recrystallizing the recovered dabigatran etexilate. Wherein organic solvent used in step b) and step c) include but is not limited aromatic solvents such as benzene, toluene, xylene, chlorobenzene and the like; nitriles such as acetonitrile, propionitrile and the like; esters such as ethylacetae, isopropyl acetate, n- butyl acetate and the like; and mixtures thereof.

The present inventors have found an enhancement in the purity of dabigatran etexilate, and subsequently in the purity of dabigatran etexilate mesylate, by subjecting the recovered dabigatran etexilate to further recrystallization with one or more organic solvents.

Thus in another embodiment, the present invention provides an improved process for preparation of dabigatran etexilate in high purity via recrystallization of dabigatran etexilate which comprises:

a) providing a solution of dabigatran etexilate obtained just as above in one or more organic solvents;

b) cooling the solution to less than 30°C, c) isolating the precipipated dabigatran etexilate.

In step a) of the forgoing process, providing a solution of dabigatran etexilate by first dissolving the dabigatran etexilate in one or more organic solvents at a suitable temperature ranging from about 35°C to reflux temperature, preferably at reflux temperature.

The suitable solvent used in step a) includes alcohol, esters or mixtures thereof. The alcohols used herein include, but are not limited to methanol, ethanol, isopropanol, n- propanol, n-butanol and the like; the esters include but not limited to ethyl acetate, isopropyl acetate, n-butyl acetate and the like; preferably mixture of isopropanol and ethanol or n-butyl acetate.

In another embodiment, the present invention provides crystalline Form LI of dabigatran etexilate of Formula 1, characterized by a Powder XRD pattern substantially in accordance with Figure- 3

In another embodiment, the crystalline Form LI of dabigatran etexilate of Formula 1 of the present invention, characterized by a Differential scanning calorimetry (DSC) substantially in accordance with Figure-4.

In another embodiment, the present invention provides a process for the preparation of crystalline Form LI of dabigatran etexilate of Formula 1, comprising:

a) providing a solution of dabigatran etexilate in n-butyl acetate; and

b) isolating the crystalline Form LI of dabigatran etexilate.

In step a) of the forgoing process, providing a solution of dabigatran etexilate by first dissolving the dabigatran etexilate in n-butyl acetate at a suitable temperature ranging from about 35°C to reflux temperature, preferably at reflux temperature.

In step b) of the forgoing process, the isolation of dabigatran etexilate may be carried out by the methods known in the art, for example, cooling the reaction mass at a temperature from about 25°C or less and filtering the crystalline Form LI of dabigatran etexilate.

The resulted pure dabigatran etexilate further converts into its pharmaceutically acceptable acid addition salts preferably dabigatran etexilate mesylate salt in accordance with the procedures reported in the art, preferably treating dabigatran etexilate as obtained by the process described above with methane sulfonic acid in acetone solvent to obtain dabigatran etexilate mesylate.

In an embodiment, the present invention provides dabigatran etexilate or pharmaceutically acceptable salts thereof, particularly dabigatran etexilate mesylate as obtained by the process described above having purity of at least about 98%, as measured by HPLC; preferably at least about 99%, as measured by HPLC; and more preferably at least about 99.5%, as measured by HPLC.

The present invention provides crystalline compound of Formula 3 as p-toluene sulfonic acid salt and crystalline benzimidazole compound of Formula 5 as p-toluene sulfonic acid salt, obtained by the above process, as analyzed using the X-Ray powder diffraction with the conditions described as follows: an X-ray powder Diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step width=0.020°; and scan speed=2°/minute.

The following examples and drawings are provided by way of illustration only, and are not intended to be limiting of the present invention. Further, the present invention covers all the possible combinations of particular and preferred embodiments indicated herein.

EXAMPLES:

Example- 1:

Preparation of l-Methyl-2-[N-(4-cyanophenyl)-amino methyl]-benzimidazol-5-yl - carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 3

A mixture of N-(4-cyanophenyl) glycine (14.14g), CDI (15.4 g) and imidazole. HC1 (11.4g) in anhydrous THF (250 mL) was stirred for lh at 40°C, under inert atmosphere. Phenylene-1, 2-diamine of formula 2 (25g), dissolved in anhydrous THF (75 mL) was charged to the reaction mass. After stirring for another lh at 50-55°C resulted reaction mass was concentrated under reduced pressure. Glacial acetic acid (300 mL) was added and the temperature of the reaction mass was raised to 85-90°C. After maintaining for another 3h at the same temp, the solvent was removed under reduced pressure and then cooled to ambient temperature. The residue was dissolved in dichloromethane (500 mL) and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum. To the residue obtained was added EtO Ac (125 mL), cooled to 25°C, and slurred for 2h. The precipitate was filtered, washed with EtOAc and dried under vacuum at 55°C, to afford compound of formula 3 as off-white solid material (26.9g, 98.8% HPLC pure).

Example-2:

Preparation of l-Methyl-2-[N-(4-cyanophenyl)-amino methyl]-benzimidazol-5-yl - carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 3. A mixture of N-(4-cyanophenyl) glycine (28.3 g), CDI (30.8 g) and imidazole. HC1 (22.8g) in anhydrous dichloromethane (250 mL), was stirred for lh at 35-40°C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (50g), dissolved in anhydrous dichloromethane (75 mL) was charged to the reaction mass. After stirring for another lh at 35-40°C resulted reaction mass was concentrated under reduced pressure. Glacial acetic acid (200 mL) was added and the temperature of the reaction mass was raised to 85-90°C. After maintaining for an hour at the same temp, the solvent was removed under reduced pressure and then cooled to ambient temperature. The residue was dissolved in dichloromethane (750 mL) and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum. To the residue obtained was added EtOAc (250 mL), cooled to 25°C, and slurred for 3.5h. The precipitate was filtered, washed with EtOAc and dried under vacuum at 55°C for 6h, to afford compound of formula 3 as off-white solid material (58g, 98.4% HPLC pure).

Example-3:

Preparation of l-Methyl-2-[N-(4-cyanophenyl)-amino methyl]-benzimidazol-5-yl - carboxylic acid-N-(2-pyridyi)-N-(2-ethoxy carbonyl ethyl)-amide of formula 3.

A mixture of N-(4-cyanophenyl) glycine (11.3 g), CDI (11.4 g) and imidazole. HC1 (9.1g) in anhydrous dichloromethane (90 mL), was stirred for lh at 35-40°C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (20g), dissolved in anhydrous dichloromethane (40 mL) was charged to the reaction mass. After stirring for another lh at 35-40°C the resulted reaction mass was concentrated under reduced pressure. EtOAc (140 mL) and glacial acetic acid (20 mL) were added and the temperature of the reaction mass was raised to reflux. After maintaining for 4h at reflux the reaction mixture cooled to ambient temp, and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum and then co-evaporated with EtOAc. To the residue obtained was added EtOAc (60 mL) and slurred for 3h at 0-5°C. The precipitate was filtered, washed with EtOAc and dried under vacuum at 55°C, to afford compound of formula 3 as off-white solid material (24.5g, 99.0% HPLC pure).

Example-4:

Preparation of l-Methyl-2-[N-(4-cyanophenyl)-amino methyl]-benzimidazol-5-yl - carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 3.

A mixture of N-(4-cyanophenyl) glycine (11.3 g), CDI (11.4 g) and imidazole. HC1 (9.1g) in anhydrous EtOAc(120 mL), was stirred for lh at 45-50°C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (20g) was, lot- wise, charged to the reaction mass. After stirring for another lh at 45-50°C, Glacial acetic acid (20 mL) was added and the temperature of the reaction mass was raised to reflux. After maintaining for 4h at reflux, the reaction mixture cooled to ambient temp, and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum. To the residue obtained was added EtOAc (60 mL) and slurred for 2h at 0-5°C. The precipitate was filtered, washed with EtOAc and dried under vacuum at 55°C, to afford compound of formula 3 as off-white solid material (22.2g, 99.0% HPLC pure). Example-5:

Preparation of 1 -Methyl -2- [N-(4-cyanophenyl)-amino methyl]-benzimidazol-5-yl - carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 3.

A mixture of N-(4-cyanophenyl) glycine (28.3 g), CDI (30.8 g) and imidazole. HCl (22.8g) in anhydrous dichloromethane (300 mL), was stirred for lh at 35-40°C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (50g), dissolved in anhydrous dichloromethane (100 mL), was charged to the reaction mass. After stirring for another lh at reflux the resulted reaction mass was concentrated under reduced pressure. EtOAc (350 mL) and glacial acetic acid (50 mL) were added and the temperature of the reaction mass was raised to reflux. After maintaining for 4h at reflux, the reaction mixture cooled to ambient temp, and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum, till approx. 3 volumes were left behind. 5% Brine solution (250 mL) was charged and the precipitate obtained was slurred for 3h. The precipitate was filtered, washed with EtOAc and dried under vacuum at 50°C, to afford compound of formula 3 as off-white solid material (60.0g, 98.6% HPLC pure). Example-6:

A mixture of N-(4-cyanophenyl) glycine (56.6 g), CDI (61.6 g) and imidazole*HCl (7.6g) in anhydrous EtOAc (1000 mL), was stirred for lh at 45-50°C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (lOOg) was, lot-wise, charged to the reaction mass. After stirring for another lh at the same temp, Glacial acetic acid (100 mL) was added and the temperature of the reaction mass maintained at reflux for another 6h. The reaction mixture cooled to 45-50°C, and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum, till approx. 3 volumes were left behind. The reaction mass was cooled to room temp and 5% Brine solution (500 mL) was charged and the precipitate obtained was slurred for 3h. The precipitate was filtered, washed with EtOAc and dried under vacuum at 50°C, to afford compound of formula 3 as off-white solid material (125.0g, 98.8% HPLC pure).

Example-7:

Preparation of l-Methyl-2-[N-(4-cyanophenyl)-amino methyl]-benzimidazol-5-yl - carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyi)-amide of formula 3. A mixture of N-(4-cyanophenyl) glycine (56.6 g), CDI (61.6 g) and imidazole*HCl (7.6g) in anhydrous EtOAc (1000 mL), was stirred for lh at 45-50°C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (lOOg) was, lot- wise, charged to the reaction mass. After stirring for another lh at the same temp, Glacial acetic acid (100 mL) was added and the temperature of the reaction mass maintained at reflux for another 6h. The reaction mixture cooled to 45-50°C, and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum, till approx. 3 volumes were left behind. The reaction mass was cooled to room temp and 5% Brine solution (500 mL) was charged and the precipitate obtained was slurred for 3h. The precipitate was filtered, washed with EtOAc and dried under vacuum at 50°C, to afford compound of formula 3 as off-white solid material (127. Og, 98.8% HPLC pure).

Example-8:

A mixture of N-(4-cyanophenyl) glycine (5.7 g), CDI (6.2 g) and imidazole*HCl (4.6g) in anhydrous DMF (40 mL), was stirred for lh at 35-40°C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (lOg) was, lot- wise, charged to the reaction mass. After stirring for another lh at 45-50°C, Glacial acetic acid (10 mL) was added and the temperature of the reaction mass maintained at 85-90°C for another 1 lh. The reaction mixture cooled to room temp and quenched into brine solution (50 mL), maintained at 0- 5°C. The precipitated material was filtered and washed with water. The semi-dried material was dissolved in dichloromethane (50 mL) and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum. To the residue obtained was added EtOAc (30 mL) and slurred for 3h at room temp. The precipitate was filtered, washed with EtOAc and dried under vacuum at 50°C, to afford compound of formula 3 as off-white solid material (13. Og, 97.5% HPLC pure).

Example-9:

A mixture of N-(4-cyanophenyl) glycine (5.6 g), CDI (6.1 g) and imidazole*HCl (4.5g) in anhydrous NMP(50 mL), was stirred for lh at 35-40°C, under inert atmosphere, phenyl ene-l,2-diamine of formula 2 (lOg) was, lot- wise, charged to the reaction mass. After stirring for another lh at 40-45°C, Glacial acetic acid (10 mL) was added and the temperature of the reaction mass maintained at 85-90°C for another 6h. The reaction mixture cooled to room temp and water (80 mL) added. The precipitated material was filtered and washed with water. The semi-dried material was dissolved in EtOAc (100 mL) and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum. To the residue obtained was added EtOAc (30 mL) and slurred for 3h at room temp. The precipitate was filtered, washed with EtOAc and dried under vacuum at 50°C, to afford compound of formula 3 as off-white solid material (12.6g, 97.5% HPLC pure). Example- 10:

Preparation of l-Methyl-2-[N-(4-cyanophenyl)-amino methyl] -benzimidazol-5-yl - carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 3.

A mixture of N-(4-cyanophenyl) glycine (2.82g), CDI (2.83 g) and HOBt (1.97 g) in EtOAc (25 mL), was stirred for lh at 45°C, under inert atmosphere. Phenylene-1, 2- diamine 2 (5 g) was charged to the reaction mass. After stirring for another 2h at the same temperature, analytical HPLC revealed completion of the reaction. Glacial acetic acid (5 mL) was added and the temperature of the reaction mass was raised to reflux. After maintaining for another 4h at reflux, analytical HPLC revealed completion of the reaction. The reaction mass was cooled to room temp and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum, till approximately 3 volumes remained in the flask. Cooled the reaction mass to 10°C and stirred for lh. The precipitate was filtered and dried under vacuum at 55°C, to afford compound of formula 3 as off-white solid material (5g, 98.0% HPLC pure).

Example-11 :

Preparation of p-TSA salt of l-Methyl-2-[N-(4-cyanophenyl)-amino methyl]- benzimidazol-5-yl -carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 3

A mixture of N-(4-cyanophenyl) glycine (5.6 g), CDI (6.1 g) and imidazole*HCl (4.6g) in anhydrous dichloromethane (55 mL), was stirred for lh at 35-40°C, under inert atmosphere, phenyl ene-l ,2-diamine of formula 2 (lOg), dissolved in anhydrous dichloromethane (30 mL), was charged to the reaction mass. After stirring for another lh at reflux the resulted reaction mass was concentrated under reduced pressure. Toluene (60 mL) and para-toluene sulphonic acid monhydrate (16.6 g) were added and the temperature of the reaction mass was raised to 85-90°C. After maintaining for 4h at the same temperature the reaction mixture concentrated under reduced pressure and the residue dissolved in dichloromethane (200 mL) and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum. To the residue obtained was added EtOAc (50 mL) and slurred for 90 min at room temp. The precipitate was filtered, washed with EtOAc and dried under vacuum at 50°C, to afford p-TSA salt of compound of formula 3 as off-white solid material (15.2g, 98.4% HPLC pure). Example- 12:

Preparation of p-TSA salt of l-Methyl-2-[N-(4-cyanophenyl)-amino methyl] - benzimidazol-5-yl -carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 3

A mixture of N-(4-cyanophenyl) glycine (5.6 g), CDI (6.1 g) and imidazole* HQ (4.6g) in anhydrous dichloromethane (40 mL), was stirred for lh at 35-40°C, under inert atmosphere, phenylene-1, 2-diamine of formula 2 (lOg), dissolved in anhydrous dichloromethane (20 mL), was charged to the reaction mass. After stirring for another lh at reflux the resulted reaction mass was concentrated under reduced pressure. n-BuOAc (50 mL) and para-toluene sulphonic acid monohydrate (19.5 g) were added and the temperature of the reaction mass wasraised to 85-90°C. After maintaining for lh at the same temperature. The reaction mixture concentrated under reduced pressure to half of the original volume. The precipitated material was slurred at 40-45 °C for 30 min, filteredand washed with water. The wet material was slurred in water (100 mL) for 30 min at room temp. The precipitate was filtered, washed, successively with water and EtOAc.The material dried under vacuum at 50°C, to afford p-TSA salt of compound of formula 3 as off-white solid material (15.8g, 98.1 % HPLC pure).

Example- 13

Preparation of p-TSA salt of l-Methyl-2-[N-(4-amidinophenyl)-amino methyl]- benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 5

A stirred mixture of p-TSA salt of compound of formula 3 (lOg) in ethanol (100 mL), at -10°C was purged with dry HC1 gas. Purging continued till a concentration of 38% was achieved. The temperature of the reaction mass was raised to~15°C and maintained at 13-17°C for another 18h when analytical HPLC revealed completion of the reaction. Nitrogen gas was purged for 2h. The reaction mixture was diluted with EtOH (30 mL) and then cooled to -5°C. The pH of the reaction mass was adjusted to 9.0-9.4 with cone, ammonia. The temperature of the reaction mass was allowed to gradually rise to 25- 35°C and then maintained at the same temperature for another 3h when analytical HPLC revealed completion of the reaction. The solvent was distilled off, under reduced pressure. Ethanol (70 mL), DM water (100 mL) and 50 % aqueous NaOH solution (1.87 mL) was added and the temperature of the mixture was raised to 55°C. After maintaining for another hour at the same temperature the reaction mass was cooled to ~10°C and maintained for 3 h at 10-15°C. The solid material was filtered and washed with water and dried, under vacuum, at 55°C, to afford p-TSA salt of compound of formula 5 as off-white solid material (9.2 g, >98% HPLC pure). (95%)

Example- 14: Preparation of p-TSA salt of l-Methyl-2-[N-(4-amidinophenyl)-amino methyl] - benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 5

A stirred mixture of compound of formula 3 (25g) and p-TsOH*H₂0 (12.9g) in ethanol (250 mL), at 20°C was purged with dry HC1 gas. After purging for approx. 15 min the reaction mass was cooled to -3°C and purging continued till a concentration of 38% was achieved. The temperature of the reaction mass was raised to~15°C and maintained at 13-17°C for another 18h when analytical HPLC revealed completion of the reaction. Nitrogen gas was purged for 3h. The reaction mixture was diluted with EtOH (75 mL) and then cooled to -8°C.The pH of the reaction mass was adjusted to 9.0-9.4 with cone, ammonia. The temperature of the reaction mass was allowed to gradually rise to 25- 35°C and then maintained at the same temperature for another 3h when analytical HPLC revealed completion of the reaction. The solvent was distilled off, under reduced pressure. Ethanol (175 mL), DM water (250 mL)and 50 % aqueous NaOH solution (4.7 mL) was added and the temperature of the mixture was raised to 55°C. After maintaining for another hour at the same temperature the reaction mass was cooled to ~12°C and maintained for 3 h at 10-15°C. The solid material was filtered and then slurred in water (125 mL).The solid material was filtered, washed with water and dried, under vacuum, at 55°C, to afford p-TSA salt of compound of formula 5 as off-white solid material (26 g, >95% HPLC pure).

Example-15:

Preparation of p-TSA salt of l-Methyl-2-[N-(4-amidinophenyl)-amino methyl] - benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 5

To a mixture of compound of formula 3 (25g) and p-TsOH*H₂0 (12.9g) was added to~36% ethanolic HC1 (250 mL), at 0-5 °C. The temperature of the reaction mass was raised to 13-17°C and maintained for another 18h, when analytical HPLC revealed completion of the reaction. Nitrogen gas was purged for 3h. The reaction mass diluted with EtOH (75 mL) and then cooled to approx. -8°C.The pH of the reaction mass was adjusted to 9.0-9.4 with cone, ammonia. The temperature of the reaction mass was raise to 25-35°C and maintained for another 4h, when analytical HPLC revealed completion of the reaction. The temperature of the mixture was raised to 55°C and maintained for another hour. The reaction mass was concentrated under reduced pressure. EtOH (175 mL), DM water (250 mL) and 50% aqNaOH solution (4.7mL) were sequentially charged, at 55°C and maintained for another hour. The reaction mass cooled to 10-15°C and slurred for 3h. The solid material was filtered and then slurred in water (125 mL). The solid material was filtered, washed with water and dried under vacuum at 55°C, to afford p-TSA salt of compound of formula 5 as off-white solid material (26.2 g, >95% HPLC pure).

Example- 16:

Preparation of HC1 salt of l-Methyl-2-[N-(4-amidinophenyl)-amino methyl] - benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 5

To a mixture of compound of formula 3 (25 g) in EtOH (250 mL) was purged dry HC1 gas, while maintaining temperature below 0°C till HC1 concentration of 37% was achieved. The reaction of the reaction mass was raised to 12-15°C and maintained for 24h, when analytical HPLC revealed completion of the reaction. Nitrogen gas was purged for 2 h and EtOH (75 mL) was added to the reaction mass.The pH of the reaction mass was adjusted to 9.0-9.4 with cone, ammonia. After stirring the reaction mass, at 25- 30°C, for 6h, analytical HPLC revealed completion of the reaction. The temperature of the reaction mass was raised to 55°C and maintained for an hour. The reaction mass was concentrated till approx. 160-180 mL of the solution was left behind in the flask.DM water (238 mL) and 50% aqNaOH solutions (4.7mL) was charged. The reaction mass was maintained at 55°C for another lh, and then cooled to 10-15°C.The precipitated material was slurred for lh, filtered, washed with water and dried under vacuum, at 55°C, to afford HQ salt of compound of formula 5 as off-white solid material (33.5 g, >94% HPLC pure).

Example- 17:

Preparation of HCl salt of l-Methyl-2-[N-(4-amidinophenyl)-amino methyl]- benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide of formula 5

Compound of formula 3 (25g) in -36% ethanolic HCl (250 mL) was stirred for 22h at 10-15°C. After completion of the reaction nitrogen gas was purged for 2h. The reaction mass was diluted with EtOH (125 mL) and then cooled to -15°C. The pH of the reaction mass was adjusted to ~9.7 with cone, ammonia solution. The reaction mass was stirred for 2h at 25-30°C, when analytical HPLC revealed completion of the reaction. The temperature of the reaction mass was raised to 55°C and maintained for an hour. The Reaction mass was concentrated, under reduced pressure, till 160-190 mL of the solution left behind in the flask.DM water (250 mL) and 50% aq NaOH solution (4.7mL) were sequentially charged to the reaction mass, at 55°C. The reaction mass maintained at 55°Cfor an hour, cooled to 10-15°C and slurred for another 3h.The precipitate was filtered, washed with water and dried under vacuum, at 55°C, to afford HCl salt of compound of formula 5, as off-white solid material (32.5 g, >94% HPLC pure). Example-18:

Preparation of Dabigatran Etexilate.

To a stirred suspension of HC1 salt of compound of formula 5 (lOg) in acetone (80 mL), at 15-17°C was charged a solution of potassium carbonate (15.4 g) in DM water (50 mL). After stirring for 30 min, n-hexyl chloroformate (3g) was added and stirred for 30 min. Second lot of n-hexylchloroformate (0.68 g) was charged and the reaction mass stirred for another 2h, when analytical HPLC revealed completion of the reaction.DM water (50mL) was added to the reaction mass and the temperature of the reaction mass was raised to 20-25°C. After stirring for another 15 min at 20-25°C, the precipitated solid was filtered, and washed with a mixture of acetone and water. The product was dried, under vacuum, at 50°C, to afford Dabigatran Etexilate as off-white solid material (13g, >95% HPLC pure).

Example 19

Preparation of Dabigatran Etexilate.

To a stirred suspension of p-TSA salt of compound of formula 5 (20g) in acetone (150 mL), at 25-35°C, was charged a solution of potassium carbonate (24.7 g) -in DM water (50 mL).The reaction mass was cooled to 12-18°C. n-Hexyl chloroformate (4.9g) was added slowly to the reaction mass. The temperature of the reaction mass was raised 19- 25°C and stirred for 30 min. Second lot of n-hexylchloroformate (1.49 g) was charged and the reaction mass stirred for another hour at 19-25°C, when analytical HPLC revealed completion of the reaction. Raised the temperature of reaction mass to 50-56°C and stirred for 10 min. Separated the layers and stored the organic layer at 50-56°C. Back extracted the aqueous layer with toluene (60 mL). Carbon PS-133 was added to the combined organic layer and stirred for 15 min. Filtered the reaction mass and washed with hot toluene (60mL). Washed the organic, layer with DM water at 50- 56°C.Concentated the organic layer under vacuum and charged IPA (20 mL). Distilled the solvent completely under vacuum. Charged IPA (150 mL) and ethanol (15 mL) to the residue, heated up to 50-55°C till a clear solution is obtained. Then cooled to 20- 25°C and stirred for 12hr, at 20-25°C. The precipitated product was filtered, washed with IPA and dried under vacuum, at 50°C, to afford pure Dabigatran Etexilate as off- white solid material ( 15 g, >99.5% HPLC pure).

Example-20:

Preparation of Dabigatran Etexilate

To a stirred suspension of p-TSA salt of compound of formula 5 (lOg) in acetone (80 mL), at 27°C, was charged a solution of potassium carbonate (12.3 g) in DM water (50 mL).The reaction mass was stirred for 30 min, and then cooled to 12-15°C.n-Hexyl chloroformate (2.4g) was added and stirred for 30 min. The temperature of the reaction mass was raised 18°C. Second lot of n-hexylchloroformate (0.5 g) was charged and the reaction mass stirred for another hour at 16-20°C, when analytical HPLC revealed completion of the reaction. DM water (50mL) was added and the reaction mass slurred for 15 min. The precipitate was filtered, washed with a mixture of acetone and water, dried under vacuum, at 50°C, to afford Dabigatran Etexilate as off-white solid material (10g, >94% HPLC pure).

Example-21:

Preparation of Dabigatran Etexilate

To a stirred suspension of p-TSA salt of compound of formula 5 (20g) in acetonitrile (80 mL), at 27°C, was charged a solution of potassium carbonate (24.7 g) in DM water (50 mL).The reaction mass was stirred for 30 min, and then cooled to 12-15°C. n-Hexyl chloroformate (4.9g) was added and stirred for 30 min. The temperature of the reaction mass was raised 17°C and stirred for 30 min. Second lot of n-hexylchloroformate (1.49 g) was charged and the reaction mass stirred for another hour at 16-20°C, when analytical HPLC revealed completion of the reaction. DM water (50mL) was added and the reaction mass slurred for 15 min at 30°C. The precipitate was filtered, washed with water, dried under vacuum, at 50°C, to afford Dabigatran Etexilate as off-white solid material (16.4g, >96% hplc pure).

A solution of crude Dabigatran Etexilate (15g) in IPA (45 mL) and ethanol (45 mL), heated up to 50-55°C till a clear solution is obtained. Then cooled to 20-25°C and stirred for 12hr, at 20-25°C. The precipitated product was filtered, washed with IPA and dried under vacuum, at 50°C, to afford pure Dabigatran Etexilate as off-white solid material (12.5 g, >99.5% HPLC pure).

Example-22:

Preparation of Dabigatran Etexilate.

To a stirred suspension of p-TSA salt of compound of formula 5 (20g) in acetonitrile (80 mL), at 27°C, was charged a solution of potassium carbonate (24.7 g) in DM water (50 mL).The reaction mass was stirred for 30 min, and then cooled to 12-15°C.n-Hexyl chloroformate (4.9g) was added and stirred for 30 min. The temperature of the reaction mass was raised 17°C and stirred for 30 min. Second lot of n-hexylchloroformate (1.49 g) was charged and the reaction mass stirred for another hour at 16-20°C, when analytical HPLC revealed completion of the reaction. DM water (50mL) was added, raised the temperature of the reaction mass to 30°Cand then slurred for 30 min. The precipitate was filtered, and then slurred in DM water (100 mL). The solid material was filtered, and dried under vacuum, at 50°C, to afford off-white solid material (16.4g, >96% hplc pure). The dried material was dissolved in acetone (100 mL), at 45°C. Carbon (PS-133, lg) was added and the reaction mass was stirred for 15 min at 45°C. The insoluble material was filtered through a short bed of Hyflo and washed with acetone. The filtrated was cooled to 30°C and DM water (240 mL) was added, drop wise. The reaction mass was slurred for 3h. The precipitated material was washed with water, dried under vacuum, at 50°C, to afford Dabigatran Etexilate as a pale yellow solid material ( 15 g, >98% HPLC pure).

A solution of crude Dabigatran Etexilate (15g) in IPA (150 mL) and ethanol (15 mL), heated up to 50-55°C till a clear solution is obtained. Then cooled to 20-25°C and stirred for 12hr, at 20-25°C. The precipitated product was filtered, washed with IPA and dried under vacuum, at 50°C, to afford pure Dabigatran Etexilate as off-white solid material (14 g, >99.5% hplc pure).

Example 23

Preparation of Dabigatran Etexilate.

To a stirred suspension of p-TSA salt of compound of formula 5 (25g) in acetone (200 mL), at 25-35°C, was charged a solution of potassium carbonate (32.2 g) in DM water (125 mL).The reaction mass was cooled to 12-18°C. n-Hexyl chloroformate (6.4g) was added slowly to the reaction mass. The temperature of the reaction mass was raised 19- 25°C and stirred for 30 min. Second lot of n-hexylchloroformate (1.9 g) was charged and the reaction mass stirred for another hour at 19-25°C, when analytical HPLC revealed completion of the reaction. Raised the temperature of reaction mass to 50-56°C and stirred for 10 min. Separated the layers and stored the organic layer at 50-56°C. Back extracted the aqueous layer with toluene (75 mL). Carbon PS-133 was added to the combined organic layer and stirred for 15 min. Filtered the reaction mass and washed with hot toluene (75 mL).Washed the organic layer with DM water at 50- 56°C. Concentrated the organic layer under vacuum and charged isopropyl acetate (25 mL). Distilled off the solvent, completely, under vacuum. Charged isopropyl acetate (250 mL) to the residue, heated up to 60-65°C till a clear solution is obtained. Then cooled to 20-25°C and stirred for 9hr, at 20-25°C. The precipitated product was filtered, washed with isopropyl acetate and dried under vacuum, at 50°C, to afford pure Dabigatran Etexilate as off-white solid material (17.5 g, >99.5% HPLC pure).

Example 24

Preparation of Dabigatran Etexilate

To a stirred suspension of p-TSA salt of compound of formula 5 (200g) in acetone (1600 mL), at 25-35°C, was charged a solution of potassium carbonate (247.2 g) in DM water (1000 mL).The reaction mass was cooled to 12-18°C. n-Hexyl chloroformate (49g) was added slowly to the reaction mass. The temperature of the reaction mass was raised 19- 25°C and stirred for 30 min. Second lot of n-hexylchloroformate (14.6 g) was charged and the reaction mass stirred for another hour at 19-25°C, when analytical HPLC revealed completion of the reaction. Raised the temperature of reaction mass to 50-56°C and stirred for 10 min. Separated the layers and stored the organic layer at 50-56°C. Back extracted the aqueous layer with toluene (600 mL). Carbon PS- 133 was added to the combined organic layer and stirred for 15 min. Filtered the reaction mass and washed with hot toluene (300mL x 2). Washed the organic layer with DM water at 50- 56°C.Concentated the organic layer under vacuum and charged IPA (200 mL). Distilled the solvent completely under vacuum.Charged IPA (2000 mL) and ethanol (200 mL) to the residue, heated up to 50-55°C till a clear solution is obtained. Then cooled to 20- 25°C and stirred for 12hr, at 20-25°C. The precipitated product was filtered, washed with IPA and dried under vacuum, at 50°C, for 8 hrs. The dried material (lOg) was added n-butyl acetate (100 mL) and the temperature of the mixture was raised to 82°C, when the material completely dissolved. The solution was gradually cooled to 20-25 °C and further maintained for 2h. The precipitated material was filtered, washed with n- butyl acetate (10 mL)and dried under vacuum, at 50°C, to afford pure Dabigatran Etexilate as off-white solid material (8.8 g, >99.5% HPLC pure).

Example 25

Preparation of Dabigatran Etexilate

To a stirred suspension of p-TSA salt of compound of formula 5 (20g) in acetone (150 mL), at 25-35°C, was charged a solution of potassium carbonate (25.2 g) in DM water (100 mL).The reaction mass was cooled to 19-25°C and n-Hexyl chloroformate (5.4g) was added. The reaction mass stirred for another hour at 19-25°C, when analytical HPLC revealed completion of the reaction. Raised the temperature of reaction mass to 50-56°C and stirred for 10 min. Separated the layers and stored the organic layer at 50- 56°C. Back extracted the aqueous layer with n-butyl acetate (100 mL). The mixture washed with DM water (50 mL x 2). The organic layer was concentrated under vacuum while maintaining temp at 60°C. n-Butyl acetate (50 mL) was added to the residue at 60°C and maintained till the residue dissolved. Then solution was cooled to 30-55°C, stirred for 2hr, further cooled to 0-5 °C and maintained for another 2h. The precipitated product was filtered, washed with n-butylacetate and dried under vacuum, at 50°C, to afford pure Dabigatran Etexilate as off-white solid material (14.8 g, >99.5% HPLC pure). Example-26:

Preparation of Dabigatran Etexilate Mesylate.

A solution of Dabigatran Etexilate (23g) in acetone (184 mL), at 39-45°C was filtered and then cooled to 30°C. Pre-cooled solution of methanesulphonic acid (3.24g) in acetone (23 mL) was, slowly, added to the reaction mass and then stirred for lh, at 28- 32°C. The reaction mass was cooled to 19-23°C and slurred for another hour. The precipitated product was filtered, washed with acetone and dried, under vacuum, at 50°C, to afford mesylate salt of Dabigatran Etexilate as pale yellow colored solid material (24 g, >99% HPLC pure).

Example-27:

Preparation of Dabigatran Etexilate Mesylate.

A solution of Dabigatran Etexilate (23g) in acetone (184 mL), at 39-45°C was filtered and then cooled to 30°C. Pre-cooled solution of methanesulphonic acid (3.24g) in acetone (23 mL) was, slowly, added to the reaction mass and then stirred for lh, at 28- 32°C. The reaction mass was cooled to 19-23°C and slurred for another hour. The precipitated product was filtered, washed with acetone and dried. The semi-dried product was slurred in acetone, filtered, and dried under vacuum, at 50°C, to afford mesylate salt of Dabigatran Etexilate as pale yellow colored solid material (23.8g, >99% HPLC pure).

Claims

WE CLAIM

Claim 1: An improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I,

Formula 1

comprising the steps of:

a) reacting a diamine compound of Formula 2

Formula 2

with a compound of Formula 4

Formula 4

in presence of a coupling agent and an additive to obtain an intermediate of Formula 3A,

Formula 3A

Formula 3

Formula 5 d) converting the benzimidazole compound of Formula 5 into dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I.

Claim 2: The process according to claim 1, wherein the coupling agent is selected from the group consisting of carbonyl-diimidazole (CDI), carbonyl-di(l,2,4-triazole), 1- ethyl-3-(-3-dimethylaminopropyl) carbodiimide (EDC), dicyclohexylcarbodiimide (DCC) and propanephosphonic acid cyclic anhydride (PPA).

Claim 3: The process according to claim 1, wherein the additive is selected from the group consisting of hydroxy benzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HO At), 6-chloro-l -hydroxy- lH-benzotriazole (Cl-HOBt), hydroxypyridines (HOPy), Imidazole or its salts, l,8-Diazabicyclo[5.4.0]undec-7-en (DBU); tertiary amines or its hydro halide salts thereof selected from the group consisting of triethyl amine hydrochloride or diisopropylethyl amine hydrochloride or mixtures thereof.

Claim 4: The process according to claim 1, wherein the step a) is carried out in a suitable solvent.

Claim 5: The process according to claim 4, wherein the suitable solvent is selected from the group comprising ethers, esters, halogenated hydrocarbons, amides, aromatic solvents or mixtures thereof.

Claim 6: The process according to claim 5, wherein the suitable solvent is selected from the group consisting of methylene chloride, tetrahydrofuran, ethyl acetate, dimethyl formamide, N-methyl pyrrolidinone and mixtures thereof.

Claim 7: The process according to claim 1, wherein step a) reaction is carried out at a temperature from about ambient temperature to about reflux temperature. Claim 8: The process according to claim 7, wherein the reaction is carried out at a temperature from about 30°C to about 85°C.

Claim 9: The process according to claim 1, wherein in the acid of step b) is selected from the group consisting of acetic acid, p-toluene sulfonic acid, methane sulfonic acid, chloroacetic acid and mixtures thereof.

Claim 10: The process according to claim 9, wherein the acid is acetic acid.

Claim 11: The process according to claim 1, wherein the step b) is carried out at a temperature from about 50°C to about 90°C. Claim 12: The process according to claim 1, wherein in the step a) and step b) are carried out in a same solvent.

Claim 13: The process according to claim 1, wherein in the compound of formula 3 is isolated as its acid addition salt.

Claim 14: The process according to claim 13, wherein the compound of formula 3 is isolated as its p-toluene sulfonic acid salt. Claim 15: The process according to claim 1, wherein in the acid of step c) is selected from hydrobromic acid or hydrochloric acid.

Claim 16: The process according to claim 1, wherein in the base of step c) is ammonium base.

Claim 17: The process according to claim 16, wherein the ammonium base is ammonia, ammonium carbonate or mixtures thereof.

Claim 18: The process according to claim 1, wherein in the step c) is carried out in an alcohol or a mixture of alcohol and an organic solvent.

Claim 19: The process according to claim 1, wherein the organic solvent is selected from the group consisting of ethers, esters, ketones or mixtures thereof. Claim 20: The process according to claim 18, wherein the step c) is carried out in ethanol.

Claim 21 : The process according to claim 1, wherein in the compound of formula 5 is isolated as its acid addition salt.

Claim 22: The process according to claim 26, wherein the compound of formula 5 is isolated as its p-toluene sulfonic acid salt or its hydrochloride salt.

Claim 23: The process according to claim 1, wherein the step c) is carried out at a temperature from about 5°C to about 35°C.

Claim 24: The process according to claim 1, wherein in the compound of formula 5 is converted in to dabigatran etexilate by conventional methods. Claim 25: An acid addition salts of compound of Formula 3 or hydrate or solvate thereof;

Formula 3

wherein the acid is selected from the group consisting of p-toluene sulfonic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, malic acid, glutamic acid, aspartic acid, 2,5-dihydroxy benzoic acid, benzene sulfonic acid, ethane sulfonic acid, ethane disulfonic acid, glycolic acid, mandelic acid, cinnamic acid, camphor suflonic acid, adipic acid and stearic acid.

Claim 26: p-toluene sulfonic acid salt of compound of Formula 3. Claim 27: p-toluene sulfonic acid salt of compound of Formula 3, characterized by a Powder XRD pattern substantially in accordance with Figure- 1.

Claim 28: Crystalline p-toluene sulfonate salt of compound of Formula-5, characterized by a Powder XRD pattern substantially in accordance with Figure-2.

Claim 29: A process for the purification of dabigatran etexilate comprising:

a) providing a solution of dabigatran etexilate in one or more organic solvents; b) cooling the solution to less than 30°C, and

c) isolating the precipitated dabigatran etexilate; wherein the one or more organic solvents selected from alcohols, esters and mixtures thereof.

Claim 30: The process according to claim 29, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol and n-butanol; and the esters is selected from the group consisting of ethyl acetate, isopropyl acetate, n- butyl acetate and mixture thereof.

Claim 31 : The process according to claim 29, wherein the one or more organic solvents is a mixture of isopropanol and ethanol. Claim 32: The process according to claim 29, wherein the one or more organic solvents is n-butyl acetate or isopropyl acetate.

Claim 33: The process according to claim 29, wherein the step a) is carried out at a temperature of about 35°C to reflux temperature.

Claim 34: Crystalline Form LI of dabigatran etexilate of Formula-1, characterized by a Powder XRD pattern substantially in accordance with Figure-3. Claim 35: Crystalline Form LI of dabigatran etexilate of Formula- 1, characterized by a Differential scanning calonmetry (DSC) substantially in accordance with Figure-4.

Claim 36: A process for the preparation of crystalline Form LI of dabigatran etexilate of Formula- 1, comprising:

a) providing a solution of dabigatran etexilate in n-butyl acetate; and

b) isolating the crystalline form of dabigatran etexilate.

Claim 37: An improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I,

Formula 1

comprising the steps of:

a) reacting a diamine compound of Formula 2

Formula 2

with a compound of Formula 4

^-COOH

Formula 4

in presence of a coupling agent and an additive to obtain an intermediate of

Formula 3 A, and

Formula 3 A

b) converting the compound of Formula 3 A into dabigatran etexilate or pharmaceutically acceptable acid addition salts thereof of Formula I.

Claim 38: The process according to claim 37, wherein the coupling agent is selected from the group consisting of carbonyl-diimidazole (CDI), carbonyl-di(l,2,4-triazole), 1- ethyl-3-(-3-dimethylaminopropyl) carbodiimide (EDC), dicyclohexylcarbodiimide (DCC) and propanephosphonic acid cyclic anhydride (PPA). Claim 39: The process according to claim 37, wherein the additive is selected from the group consisting of hydroxy benzotnazole (HOBt), l-hydroxy-7-azabenzotriazole (HO At), 6-chloro-l -hydroxy- IH-benzotriazole (Cl-HOBt), hydroxypyridines (HOPy), Imidazole or its salts, l,8-Diazabicyclo[5.4.0]undec-7-en (DBU); tertiary amines or its hydro halide salts thereof selected from the group consisting of triethyl amine hydrochloride or diisopropylethyl amine hydrochloride or mixtures thereof.

Claim 40: The process according to claim 37, wherein the step a) is carried out in a suitable solvent

Claim 41: The process according to claim 40, wherein the suitable solvent is selected from the group comprising ethers, esters, halogenated hydrocarbons, amides, aromatic solvents or mixtures thereof. Claim 42: The process according to claim 41, wherein the suitable solvent is selected from the group consisting of methylene chloride, tetrahydrofuran, ethyl acetate, dimethyl formamide, N-methyl pyrrolidinone and mixtures thereof.

Claim 43: The process according to claim 37, wherein step a) reaction is carried out at a temperature from about ambient temperature to about reflux temperature.

Claim 44: The process according to claim 43, wherein the reaction is carried out at a temperature from about 30°C to about 85°C. Claim 45: An improved process for the preparation of dabigatran etexilate or pharmaceutically acceptable salts thereof, comprising:

a) using p-toluene sulfonate salt of formula 3 according to claim 26 or crystalline p- toluene sulfonate salt of formula 5 according to claim 28 as intermediate; and b) converting the same into dabigatran etexilate of Formula 1.

Claim 46: A pharmaceutical composition comprising dabigatran etexilate or pharmaceutically acceptable salts thereof prepared by the process according to claims 1 - 45 and at least one pharmaceutically acceptable excipient.