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Publication numberWO2013024384 A1
Publication typeApplication
Application numberPCT/IB2012/053886
Publication dateFeb 21, 2013
Filing dateJul 30, 2012
Priority dateAug 12, 2011
Publication numberPCT/2012/53886, PCT/IB/12/053886, PCT/IB/12/53886, PCT/IB/2012/053886, PCT/IB/2012/53886, PCT/IB12/053886, PCT/IB12/53886, PCT/IB12053886, PCT/IB1253886, PCT/IB2012/053886, PCT/IB2012/53886, PCT/IB2012053886, PCT/IB201253886, WO 2013/024384 A1, WO 2013024384 A1, WO 2013024384A1, WO-A1-2013024384, WO2013/024384A1, WO2013024384 A1, WO2013024384A1
InventorsVenkatraman JAYARAMAN, Samir Patel, Samir Mistry, Mukesh Timbadiya, Bhupendra Parmar, Parimal TAMBOLI
ApplicantAlembic Pharmaceuticals Limited
Export CitationBiBTeX, EndNote, RefMan
External Links: Patentscope, Espacenet
Improved process for preparation of dabigatran etexilate and its novel intermediate
WO 2013024384 A1
Abstract
Provided are intermediates for preparing dabigatran etexilate i.e. isopropanol solvate of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride of formula (Vila) and crystalline form II of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride of formula (VII).
Claims(9)
  1. [1] 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride Isopropanolate solvate of formula (VIIa)
  2. [2] According to claim-1 the 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride Isopropanolate solvate of formula (VIIa) is a crystalline solid.
  3. [3] A crystalline Form I of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride Isopropanolate solvate of formula (VIIa) as claimed in claim 2 characterized by X-ray powder diffraction (XRD) pattern having peaks expressed at degrees two theta 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 +0.2 degrees two theta.
  4. [4] A 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) characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at degrees two theta at about 6.9, 10.5, 13.7, 16.5, 17.3, 19.8, 20.3, 21.2, 23.5, 28.2, 32.6 +0.2 degrees two theta.
  5. [5] Acid addition salt of 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.
  6. [6] 4-methylamino-3-nitro-benzoic acid- N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide hemisulfate salt of formula (IIIa)
  7. [7] 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)
    comprising steps of :
    (a) reacting 1-methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide with alcoholic hydrochloride in mixture of solvents ethanol and dichloromethane and washing with isopropyl ether;
    (b) reacting the compound of step(a) with ammonical ethanol in a solvent 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);
    (c) treating 1-methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide of formula (VII) with mixture of solvents isopropyl alcohol and acetonitrile;
    (d) isolating 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).
  8. [8] 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)
    comprising steps of :
    (a) reacting 1-methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide with alcoholic hydrochloride in a mixture of solvents ethanol and dichloromethane and washing with isopropyl ether;
    (b) reacting the compound of step(a) with ammonical ethanol in a solvent 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);
    (c) isolating the solid obtained in step (b) and washing with ethyl acetate.
  9. [9] 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 triethylamine 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 dichloromethane and washing with isopropyl ether;
    (e) reacting the compound of step(d) with ammonical ethanol in ethanol to obtain compound of formula (VII);
    (f) washing compound of formula (VII) with ethyl acetate; and
    (g) treating intermediate compound of formula (VII) with hexyl chloro formate to obtain Dabigatran Etexilate
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE AND ITS NOVEL INTERMEDIATE

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) (Dabigatran).

BACKGROUND OF THE INVENTION

Preparation of Dabigatran Etexilate was first described in the document no. WO9837075; however, this method brings many technological challenges, e.g. very tricky purifying operations, issues with purity of intermediate products which leads to less yield and less purity of the final product.

One of the advanced intermediates as per reported process for the preparation of Dabigatran Etexilate is compound of formula (VI).

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

As per the reported processes, the 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.

The procedure in accordance with WO9837075 produces compound of formula (VII) in the mono-hydrochloride form. When reproducing the procedure as describe in WO9837075, it has been observed 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.

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 attributed to the quality of the intermediate products, which are moreover produced in forms requiring complicated purification with the use of chromatographic methods.

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 is 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) (isopropanolate solvate of Dabigatran).

Yet another object of the present invention is 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) (Dabigatran).

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) (isopropanolate solvate 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 (VII) (Dabigatran).

Yet another object of the present invention is 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 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.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides 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) (isopropanolate solvate of Dabigatran).

In another aspect of the present invention provides 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) (isopropanolate solvate of Dabigatran) characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at degrees two theta 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 +0.2 degrees two theta.

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) (isopropanolate solvate of Dabigatran) characterized is depicted in Fig. I.

In another aspect of the present invention provides 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) (Dabigatran).

In another aspect of the present invention provides 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) (Dabigatran) characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at degrees two theta at about 6.9, 10.5, 13.7, 16.5, 17.3, 19.8, 20.3, 21.2, 23.5, 28.2, 32.6 +0.2 degrees two theta.

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) (Dabigatran) characterized is depicted in Fig. II.

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

In another aspect of 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) (isopropanolate solvate of Dabigatran) comprising steps of :

  1. reacting 1-methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide with alcoholic hydrochloride in mixture of solvents ethanol and dichloromethane;
  2. washing compound obtained in step (a) with isopropyl ether;
  3. reacting the compound obtained in step (b) with ammonical ethanol 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);
  4. treating 1-methyl -2- [N-(4-amidinophenyl) -aminomethyl] benzimidazol -5-yl- carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy-carbonyl ethyl) -amide of formula (VII) with mixture of solvents isopropyl alcohol and acetonitrile;
  5. isolating 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).

In another aspect of 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) (Dabigatran) comprising steps of:

  1. reacting 1-methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide with alcoholic hydrochloride in a mixture of solvents ethanol and dichloromethane;
  2. washing compound obtained in step(a) with isopropyl ether;
  3. reacting the compound obtained in step (b) with ammonical ethanol 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);
  4. isolating the solid obtained in step (c) and washing with ethyl acetate.

In another aspect of the present invention provides a method for preparing Dabigatran Etexilate salt, comprising the steps of:

  1. 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);
  2. reduction of the nitro group to the amino group compound of formula (III);
  3. compound of formula (IV) reacts with the compound of formula (V) producing the compound of formula (VI);
  4. treating compound of formula (VI) with alcoholic hydrochloride in mixture of solvents of alcohol and dichloromethane;
  5. washing compound obtained in step(d) with isopropyl ether;
  6. reacting the compound obtained in step (e) with ammonical ethanol in ethanol to obtain compound of formula (VII);
  7. washing compound of formula (VII) with ethyl acetate; and
  8. treating intermediate compound of formula (VII) with hexyl chloro formate to obtain Dabigatran Etexilate.

BRIEF DESCRIPTION OF THE DRAWING

Figure - I 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) (isopropanolate solvate of Dabigatran).

Figure - II 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) (Dabigatran).

Figure - III shows the X-ray powder diffraction pattern of prior art 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 (VII) (Dabigatran) which is obtained by following the process disclosed in WO9837075.

DETAILS DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides 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) (isopropanolate solvate of Dabigatran).

In another embodiment the present invention provides 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 (isopropanolate solvate of Dabigatran) characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at degrees two theta at about 9.3, 16.7, 17.5, 17.9, 19.1, 19.7, 21.8, 23.5, 27.6 +0.2 degrees two theta.

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 further characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at degrees two theta 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 +0.2 degrees two theta.

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) (isopropanolate solvate of Dabigatran) characterized is depicted in Fig. I.

In another embodiment the present invention provides 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 (VII) (Dabigatran).

In another embodiment the present invention provides 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 (Dabigatran) characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at degrees two theta at about 10.5, 13.7, 16.5, 17.3, 19.8, 20.3, 21.2, 23.5, 28.2, 32.6 +0.2 degrees two theta.

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 further characterized by an X-ray powder diffraction (XRD) pattern having peaks expressed at degrees two theta 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 +0.2 degrees two theta.

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 (Dabigatran) characterized is depicted in Fig. II.

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

For the purpose of this specification 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 herein refers to suspending, dissolving or mixing and contacting or reacting of product with solvent or reagents followed by isolating product by removal of reagents and solvents.

The term 'triturating' as used herein 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.

Procedure for the preparation of Dabigatran Etexilate according to the present invention is describes as follows.

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 step is reduction of the nitro group to the amino group 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.

Reduction of compound of formula (III) 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 palladium, charcoal as catalyst 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.

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 washed with ethanol and ethyl acetate and followed by hexane. Solid was precipitated and dried at 50C. This solid residue was dissolved in isopropanol, acetonitrile or ethyl acetate producing the compound of formula (VIIa) or compound of formula (VII).

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) (Dabigatran) comprising steps of reacting 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 a mixture of solvents such as alcohol and dichloromethane and treated with isopropyl ether and decant is dried and washed with isopropyl ether 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 method for preparing Dabigatran Etexilate salt, comprising the steps of:

  1. 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);
  2. reduction of the nitro group to the amino group compound of formula (III);
  3. compound of formula (IV) reacts with the compound of formula (V) producing the compound of formula (VI);
  4. treating compound of formula (VI) with alcoholic hydrochloride in mixture of solvents of alcohol and dichloromethane;
  5. washing compound obtained in step(d) with isopropyl ether;
  6. reacting the compound obtained in step (e) with ammonical ethanol in ethanol to obtain compound of formula (VII);
  7. washing compound of formula (VII) with ethyl acetate; and
  8. treating intermediate compound of formula (VII) with hexyl chloro formate to obtain Dabigatran Etexilate.

The general reaction scheme is as follow:

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 since chromatographic purification is not required. 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.

The present invention is described by the following Example, which are for illustrative purpose only and should not be construed so as to limit the scope of the invention in any manner.

Example 1 - Preparation of ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2-yl)amino]propanoate hydrochloride hemisulfate

In the mixture of thionyl chloride and THF were added to 100 g of 4-(methylamino)-3-nitrobenzoic acid compound of formula (I) under inert atmosphere. The mixture was brought to boil. During that 4-(methylamino)-3-nitrobenzoic acid got dissolved in several minutes and produced a dark brown solution. Then, the solution was refluxed for another 40-45 minutes. After that, excessive thionyl chloride was distilled off. To the brown residue toluene were added under inert atmosphere and the toluene was removed by distillation. This operation was repeated once again. The obtained brown crystalline residue was dissolved in dry THF at an increased temperature.

After cooling of the solution of acid chloride of formula (I) to the temperature of 40 C. dry triethylamine was added. To this solution a solution of ethyl 3-(pyridin-2-ylamino)propanoate in dichloromethane was added dropwise. Then, the reaction mixture was stirred without heating for 2 hours. After sucking off triethylamine hydrochloride dichloromethane was evaporated. The evaporation residue was dissolved in chloroform and shaken with water. The separated organic layer was shaken with 2 M HCl and then with water. The organic layer was dried with sodium sulphate.

The crude product was dissolved in dichloromethane. Solutions of sulfuric acid were added slowly to the solution dropwise under intensive stirring. During the stirring a yellow precipitate separates. After cooling in a fridge it was filtered off and dried.

EXAMPLE 2 - Preparation of ethyl 3-[[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino]-propanoate (IV)

The product ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2-yl)amino]propanoate hydrochloride hemisulfate was dissolved in ethanol-water mixture 1:1 and heated up to 50 C. To the solution of ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2-yl)amino]propanoate hydrochloride hemisulfate was reduced with palladium, charcoal and passing hydrogen gas in autoclave. After the completion of reaction the reaction mixture was concentrated in a vacuum evaporator. After separation of oil the concentration was completed and the product was extracted with ethyl acetate. After its drying with sodium sulphate the solvent is evaporated. The product is obtained as a brown, very viscous liquid.

EXAMPLE 3 - Preparation of 3-([2-[(4-cyanophenyl amino)-methyl]-1-methyl-1H-benzimidazole-5-carbonyl]-pyridin-2-yl-amino)ethyl propionate (VI)

[(4-cyanophenyl)amino]acetic acid and 1,1′-carbonyldiimidazole are put into a flask blown with an inert gas. THF are added and the mixture is boiled under a reflux condenser with a calcium-chloride tube for 40 minutes. After 40 minutes a solution of ethyl 3-[[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino]-propanoate in of THF is added to the mixture and the mixture is boiled for another 7 hours. After expiration of this time period the reaction mixture is slightly cooled and THF is removed by distillation in vacuum.

Glacial acetic acid are added to the residue and the resulting solution is boiled for 3 hour. The acid is distilled off and the produced residue is dissolved in dichloromethane and shaken with water. The separated organic layer is dried with sodium sulphate and the solvent is evaporated. A dark brown honey-like residue is obtained.

EXAMPLE 4 - Process for the preparation of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride

To the previously prepared saturated solution of HCl in Ethanol (The solution is prepared by passing dry HCl gas to the absolute alcohol at ~10-20C), was added a solution of 1-methyl -2-[N-(4-cyanophenyl)-aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide in a mixture of Ethanol and Dichloromethane at 15-30C. After completion of addition, reaction mixture was allowed to stir at 20-30C for about 6h. After that the reaction was terminated and taken for work up. Isopropyl ether was added to the above reaction mass, stirred it for 5-10min. Ethanol was added to the residue to give clear solution. To this solution, was added previously prepared ammonical ethanol (Ammonia gas passed into ethanol) at 15-30C. The reaction mixture was allowed to stir at r. t. for about 20-24h. The reaction mass was filtered and washed with ethanol. To this filtered was added equal amount of ethyl acetate and allowed to stir it for 3-4h. Filtered the product and washed with ethyl acetate followed by Hexane. Collected solid was dried at 50C.

EXAMPLE 5 - Preparation of the 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) (Form I)

The crude 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride is dissolved in isopropyl alcohol and acetonitrile and heated the solution to 80-85C for 1h. The solution is cooled to room temperature and filtered. The crystals are sucked off, washed with Isopropyl alcohol and dried.

EXAMPLE 6 - Crystallization of the Crude 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride of formula (VII) (Form II)

The crude 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride product are dissolved in ethyl acetate under boiling. The solution is cooled in a water bath under simultaneous stirring. The crystal suspension is cooled in a fridge and are sucked off and dried.

EXAMPLE 7 - Preparation of Dabigatran etexilate:

1-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol -5-yl-carboxylicacid -N- (2-pyridyl) -N- (2-ethoxy carbonyl ethyl) -amide hydrochloride was dissolved in acetonitrile and water. Hexyl chloroformate and triethylamine was added to it at a temperature of about 15 C. After the end of the reaction, the precipitated product is filtered off and washed with acetone/water. Dissolved the obtained solid in ethyl acetate under heating and then filtered. The title product was crystallized by the addition of water. The isolated substance is dried under reduced pressure at 45 C.

EXAMPLE 8 - Preparation of dabigatran etexilate mesylate:

l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl] amino methyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide was dissolved acetone under heating. A solution of methane sulfonic acid in acetone was added to the reaction mixture. The solution is filtered and after the addition of acetone cooled to approximately 20 C. The precipitated product was filtered and washed with acetone then dried at 50 C under reduced pressure.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
WO2009111997A1 *Mar 10, 2009Sep 17, 2009Zentiva, K.S.A method for the preparation of dabigatran
WO2010045900A1 *Oct 26, 2009Apr 29, 2010Zentiva, K.S.A method for the preparation of dabigatran and its intermediates
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
WO2014012880A1 *Jul 15, 2013Jan 23, 2014Interquim, S.A.Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates
WO2015132794A1 *Mar 6, 2014Sep 11, 2015Symed Labs LimitedImproved processes for the preparation of dabigatran etexilate using novel intermediates
EP2835370A1Aug 8, 2013Feb 11, 2015Medichem, S.A.New crystals of dabigatran etexilate mesylate
Classifications
International ClassificationC07D213/74, C07D401/12
Cooperative ClassificationC07D213/74, C07D401/12
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