Field of the invention

The present invention relates to novel intermediates i.e. isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) and crystalline form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran.

Background of the invention
Preparation of Dabigatran Etexilate was first described in the document no. WO9837075; however, this method brings many technological problems, e.g. very complicated purifying operations, problems with low purity of intermediate products and the resulting low yield and low purity of the final product.
One of the advanced intermediates during the production of Dabigatran Etexilate is the compound of formula (VI)

The compound of formula (VI) is prepared by a reaction of compound of formula (IV) compound of formula (V) with reagent as shown in Scheme 1.

Scheme 1
The procedure described in WO 9837075 produces compound of formula (VII) in the form of its base or acetate. Both these products require chromatographic purification, which is very difficult to apply in the industrial scale. This purification method burdens the process economy very much and has a negative impact on the yield.
In the next stage acidic hydrolysis of the nitrile function of compound of formula (VI) and a reaction with ammonium carbonate is performed to produce the compound of formula (VII). The reaction is shown in Scheme 2.

Scheme 2
The procedure in accordance with WO9837075 produces compound of formula (II) in the mono-hydrochloride form.
When reproducing the procedure of WO9837075 we found out, in line with WO9837075, that compound of formula (VII) prepared by this method required subsequent chromatographic purification as it was an oily substance with a relatively high content of impurities. We did not manage to find a solvent that would enable purification of this substance by crystallization. The compound of formula (VII) in its hydrochloride salts was obtained in its amorphous form with a relatively high content of impurities, this compound subsequent required chromatographic purification
The last stage is a reaction of intermediate (VII) with hexyl chloroformate producing Dabigatran Etexilate and its transformation to a pharmaceutically acceptable salt; in the case of the above mentioned patent application it is the methanesulfonate.
However, the method in accordance with WO9837075 does not make it possible to prepare 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 low purity of the intermediate products, which are moreover produced in forms requiring complicated purification with the use of chromatographic methods.
Several methods for the preparation of Dabigatran Etexilate have been described. Like any synthetic compound, Dabigatran, or a pharmaceutically-acceptable salt thereof can contain process impurities, unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient (“API”) may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis.

While developing a process for the preparation of Dabigatran Etexilate, present inventors serendipitously found an improved process for the preparation of highly pure Dabigatran Etexilate which minimizes process impurity.

Object of the invention

Therefore, it is an object of the present invention to provide novel intermediates i.e. isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran.

Yet another object of the present invention to provide crystalline form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide of formula (VII) an intermediate of Dabigatran.

Yet another object of the present invention to provide novel intermediates i.e. 4-methylamino-3-nitro-benzoic acid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide sulfate salt of formula (IIIa) an intermediate of Dabigatran.

Yet another object of the present invention to provide novel intermediates i.e. 4-methylamino-3-nitro-benzoic acid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide of formula (III) an intermediate of Dabigatran.

Wherein X represent salts of inorganic or organic acids selected form the group of hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, malic acid, glutamic acid or aspartic acid except hydrochloride acid.

Yet another object of the present invention is to provide a process for the preparation isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran
.

Yet another object of the present invention is to provide a process for the preparation crystalline form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran.

Summary of the invention

In one aspect, the present invention to provide novel intermediates i.e. isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran.

In another aspect, the present of the present invention, there is provided a new crystalline polymorphic Form I of isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2? at about 6.7, 9.3, 14.0, 14.6, 16.7, 17.5, 17.9, 19.1, 19.7, 21.8, 23.5, 27.6

The XRD of crystalline polymorphic Form I of isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran characterized is depicted in Fig. 1.

In another aspect, the present invention to provide crystalline form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran.

In another aspect, the present of the present invention, there is provided a new crystalline polymorphic Form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2? at about 6.9, 10.5, 13.7, 16.5, 17.3, 19.8, 20.3, 21.2, 23.5, 28.2, 32.6

The XRD of crystalline polymorphic Form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran characterized is depicted in Fig. 2.

In another aspect, of the present invention to provide novel intermediates i.e. 4-methylamino-3-nitro-benzoic acid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide sulfate salt of formula (IIIa) an intermediate of Dabigatran.

In another aspect, of the present invention to provide novel intermediates i.e. 4-methylamino-3-nitro-benzoic acid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide of formula (III) an intermediate of Dabigatran.

Wherein X represent salts of inorganic or organic acids selected form the group of hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, malic acid, glutamic acid or aspartic acid except hydrochloride acid.

In another aspect, the present invention provides a process for the preparation isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide of formula (VIIa) an intermediate of Dabigatran which comprising step of treating 1-methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide with alcoholic hydrochloride in solvent such as ethanol and dichloromethane and treated with isopropyl ether followed by treatment with ammonical ethanol of residue dissolved in ethanol to obtain 1-methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) –amide of formula (VII), the product is than treated with isopropyl alcohol and acetonitrile.

In another aspect, the present invention provides a process for the preparation crystalline form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide of formula (VII) an intermediate of Dabigatran which comprising step of treating 1-methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide with alcoholic hydrochloride in solvent such as ethanol and dichloromethane and treated with isopropyl ether followed by treatment with ammonical ethanol of residue dissolved in ethanol to obtain 1-methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) –amide of formula (VII), the product is than treated with Ethyl acetate.
.

In another aspect, the present invention provides a process for the purification of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) –amide hydrochloride of formula (VII) an intermediate of Dabigatran which comprising step of
a) dissolving 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) –amide hydrochloride of formula (VII) in solvent selected form the group are ethanol, methanol, Isopropyl alcohol , ethyl acetate solvent or acetonitrile and mixtures there off;
b) isolating pure 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) –amide hydrochloride.

In another aspect, the present invention provides a method for preparing Dabigatran Etexilate salt, comprising the steps of:
a) treating chloride of compound of formula (I) reacts with compound of formula (II) in tetrahydrofuran in the presence of a base to obtain compound of formula (III);
b) reduction of the nitro group to the amino group compound of formula (III);
c) compound of formula (IV) reacts with the compound of formula (V) producing the compound of formula (VI);
d) treating compound of formula (VI) with alcoholic hydrochloride in mixture of solvents of alcohol and chlorinated solvent and ammonia to obtain compound of formula (VII);
e) treating compound of formula (VII) with isopropyl alcohol , acetonitrile or ethyl acetate or mixture of solvent to obtain compound of formula (VIIa) or compound or formula (VII); and
f) treating intermediate of compound of formula (VIIa) or compound or formula (VII) to obtain Dabigatran Etexilate.

Brief description of the drawing

Fig. 1 shows the X-ray powder diffraction pattern of new polymorph Form I of isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran.

FIG. 2 shows the X-ray powder diffraction pattern of new polymorph Form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran.

FIG. 3 shows the X-ray powder diffraction pattern of prior art polymorph amorphous form of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula an intermediate of Dabigatran.

Details description of the invention

In one embodiment, the present invention to provide novel intermediates i.e. isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran.

In another embodiment,, the present of the present invention, there is provided a new crystalline polymorphic Form I of isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride an intermediate of Dabigatran characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2? at about 9.3, 16.7, 17.5, 17.9, 19.1, 19.7, 21.8, 23.5, 27.6

The crystalline polymorphic Form I of isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) –amide hydrochloride is furthere characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2? at about 6.7, 8.5, 9.3, 10.6, 11.3, 14.0, 14.6, 15.3, 15.5, 16.7, 17.5, 17.9, 19.1, 19.7, 21.1, 21.3, 21.8, 22.3, 23.5, 23.9, 24.6, 25.4, 27.6, 28.3, 28.8.

The XRD of crystalline polymorphic Form I of isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran characterized is depicted in Fig. 1.

In another embodiment, the present invention to provide novel crystalline form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIb) an intermediate of Dabigatran.

In another embodiment, the present of the present invention, there is provided a new crystalline polymorphic Form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride an intermediate of Dabigatran characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2? at about 10.5, 13.7, 16.5, 17.3, 19.8, 20.3, 21.2, 23.5, 28.2, 32.6

The crystalline polymorphic Form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) –amide hydrochloride is furthere characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at 2? at about 6.9, 10.5, 11.5, 12.2, 13.7, 15.1, 15.6, 16.5, 17.3, 19.0, 19.8, 20.3, 21.2, 21.7, 22.9, 23.2, 25.3, 28.2.

The XRD of crystalline polymorphic Form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride an intermediate of Dabigatran characterized is depicted in Fig. 2.

In another embodiment, of the present invention to provide novel intermediates i.e. 4-methylamino-3-nitro-benzoic acid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide sulfate salt of formula (IIIa) an intermediate of Dabigatran.

In another embodiment, of the present invention to provide novel intermediates i.e. 4-methylamino-3-nitro-benzoic acid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide of formula (III) an intermediate of Dabigatran.

Wherein X represent salts of inorganic or organic acids selected form the group of hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, malic acid, glutamic acid or aspartic acid except hydrochloride acid.

Here the term “crystallizing” means crystallizing compounds using methods known in the art. For example either reducing the volume of the solvent with respect to solute or decreasing the temperature of the solution or using both so as to crystallize the compound.

The term “treating” as used hereinabove refers to suspending, dissolving or mixing and contacting or reacting of product with solvent or reagents followed by isolating Teriflunomide by removal of reagents and solvents.

The term “triturating” as used hereinabove refers to suspending product in solvent and stirring for period of time sufficient for surface contact of solid with solvent and then filtering the compound from the mixture.

In another embodiment, the present invention provides a process for the preparation isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) an intermediate of Dabigatran which comprising step of treating 1-methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride with alcoholic hydrochloride in solvent such as alcohol and chlorinated solvent and treated with ether solvent and decant is dried and washed with hydrocarbon solvent followed by treatment with ammonical ethanol of residue dissolved in alcoholic solvent to obtain 1-methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) –amide hydrochloride of formula (VIIa), the product is than treated with ethanol and ethyl acetate and followed by purification.
.

In another embodiment, the present invention provides a process for the purification of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) –amide hydrochloride of formula (VII) an intermediate of Dabigatran which comprising step of
a) dissolving 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) in solvent selected form the group are ethanol, methanol, Isopropyl alcohol , ethyl acetate solvent or acetonitrile and mixtures there off;
b) isolating pure 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) –amide hydrochloride and.

In another embodiment, the present invention provides a method for preparing Dabigatran Etexilate salt, comprising the steps of:
a) treating chloride of compound of formula (I) reacts with compound of formula (II) in tetrahydrofuran in the presence of a base to obtain compound of formula (III);
b) reduction of the nitro group to the amino group compound of formula (III);
c) compound of formula (IV) reacts with the compound of formula (V) producing the compound of formula (VI);
d) treating compound of formula (VI) with alcoholic hydrochloride in mixture of solvents of ethanol and dichloromethane and ammonia to obtain compound of formula (VII);
e) treating compound of formula (VII) with isopropyl alcohol , acetonitrile or ethyl acetate or mixture of solvent to obtain compound of formula (VIIa) or compound or formula (VII); and
f) treating intermediate of compound of formula (VIIa) or compound or formula (VII) to obtain Dabigatran Etexilate.

Procedure as described in the present invitation:

Procedure for the preparation of Dabigatran Etexilate according to the present invention In the first stage the chloride of compound of formula (I) reacts with compound of formula (II) in tetrahydrofuran in the presence of a base. The base used is selected from amines, alcoholates, hydroxides, phosphates and carbonates. Triethylamine appears to be the most suitable base to obtain compound of formula (III). The next production stage is reduction of the nitro group to the amino group compound of formula (III).

Reduction of compound of formula (III)

Wherein X represent salts of inorganic or organic acids selected form the group of hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, malic acid, glutamic acid or aspartic acid except hydrochloride acid.

was conducted by using reducing agent such as metal catalyst selected from Platinum, Ruthenium, Osmium, Iridium, and especially Palladium, Raney-nickel, and sodium dithionite along with a suitable solvent chosen from water, alcohol having C1-C4 alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof. Preferably the reaction can favorably be conducted in the presence of palladium, charcoal and ethyl acetate. The procedure according to the present invention is also performed in a solvent mixture of ethanol and water and sodium dithionite as reagent this process is less costly and more advantageous. The compound of formula (III) reacts in its salt form other than its hydrochloride salt form, which has a positive influence on the course of the reaction and purity of the product. Using the combination of changing the quality and composition of the starting compound and of the method of reduction of the nitro group it is possible to obtain compound of formula (IV) with a minimum content of impurities.

The above reactions can be carried out advantageously in the presence of solvent. Any solvent which can dissolve both starting materials may be employed so far as it does not disturb the reaction, and more preferably one is exemplified by alcohols such as methanol, ethanol, propanol, the like, ketones such as acetone, methyl ethyl ketone, the like, ethers such as ether, tetrahydrofuran, dioxane, ethyl acetate the like, or mixture thereof.

In next stage compound of formula (IV) reacts with the compound of formula (V) producing the compound of formula (VI). The next stage acidic hydrolysis of the nitrile function of compound of formula (VI) and a reaction with alcoholic hydrochloride in solvent mixture of alcohol and dichloromethane and treated with isopropyl ether followed by treatment with ammonical ethanol to the residue dissolved in alcoholic solvent to obtain 1-methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) –amide hydrochloride of formula (VII), the product is than treated with ethanol and ethyl acetate and followed by treatment with isopropanol, acetonitrile or ethyl acetate producing the compound of formula (VIIa) or compound of formula (VII) .

The last stage is a reaction of intermediate compound of formula (VIIa) or compound of formula (VII) with hexyl chloro formate producing Dabigatran Etexilate. The procedure in accordance with the present invention enables production of a high-quality product with a low content of impurities and a relatively high yield. The production of intermediate compound of formula (VIIa) or compound of formula (VII) significantly simplifies the purifying operations during the manufacture of dabigatran etexilate the chromatographic purification mentioned in WO9837075 cannot be used in the industrial scale. This procedure will considerably increase the yield of the process. The purification of the compound formula (VII) with high demands on technology and material represents a substantial simplification and will positively influence the economy of the whole process.

Dated this 12h day of August 2011

Abstract

The present invention relates to novel intermediates i.e. isopropanolate solvate of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VIIa) and crystalline form II of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) an intermediate of Dabigatran.

Applicant: Alembic Pharmaceuticals Ltd Sheet 1
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Fig. 1

Dated this 12h day of August 2011

Applicant: Alembic Pharmaceuticals Ltd Sheet 2
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Fig. 2
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Applicant: Alembic Pharmaceuticals Ltd Sheet 3
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Fig. 3

Dated this 12h day of August 2011