CLIAMS:1. A process for the preparation of Dabigatran etexilate, which comprises reaction of salt of Dabigatran etexilate with a base in presence of a solvent to provide substantially pure Dabigatran etexilate.

2. The process of claim 1, wherein the base is selected from inorganic or organic base.

3. The process of claim 1, wherein the base is inorganic base such as sodium bicarbonate.

4. The process of claim 1, wherein the salt of Dabigatran etexilate is mesylate salt of Dabigatran etexilate.

5. The process of claim 1, wherein the solvent is selected from chlorinated solvent such as dichloromethane, dichloroethane and chlorobenzene; hydrocarbon such as hexane, heptane, cyclohexane and cyclopropane; ester such as ethyl acetate, methyl acetate, and t-butyl acetate, and water or any combination thereof.

6. The process of claim 1, wherein the solvent is dichloromethane.

7. The process of claim 1, wherein the Dabigatran extexilate is form I.

8. The purity of Dabigatran etexilate of the claim 1 is about 99.5% by HPLC.
,TagSPECI:Field of Invention

The present invention relates to a process for the preparation of Dabigatran etexilate free base from salt of Dabigatran etexilate.

Background of the invention

Dabigatran etexilate mesylate, chemically known as b-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate, is a direct thrombin inhibitor, represent as Formula I:

Formula 1

The drug is a direct thrombin inhibitor used to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

Various synthetic routes for preparing Dabigatran etexilate, its salts thereof and the intermediates thereof were previously described in European Pat Nos. EP 966 454, Hauel et al., in Journal of Medicinal Chemistry 2002, 45, 1757-1766, PCT application Nos. 2006/000353, 2012/153158, and 2010/045900. However, none of the prior art processes provides pure compound of Dabigatran etexilate and viable process for providing polymorphic form I.

Therefore, there is a need to develop an improved and industrially feasible process for providing pure Dabigatran etexilate free base and its substantially pure polymorphic form I.

Summary of the Invention

The present invention provides a process for the preparation of Dabigatran etexilate and a process for the preparation of its substantially pure Form I.

In an aspect, the present invention provides a process for the preparation of Dabigatran etexilate, which comprises reaction of salt of Dabigatran etexilate with a base in presence of a solvent to provide substantially pure Dabigatran etexilate.

In another aspect, the present invention provides a process for the preparation of Dabigatran etexilate Form I, the process comprises reaction of methane sulfonate salt of Dabigatran etexilate with a base in presence of chlorinated solvent to provide substantially pure Form I of Dabigatran etexilate.

The resultant Dabigatran etexilate of the present invention can be used to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

Drawings of the invention

Figure 1: Illustrates XRPD pattern of crystalline form I of Dabigatran etexilate obtained as per the process of example-1.

Description of the Invention

The term “substantially pure or pure” as used herein, unless otherwise defined, refers to Dabigatran etexilate or its salt that has purity of about 99 % or above.

The advantages of the process of preparation of Dabigatran etiexilate of the present invention:
(i) improves the yield and purity;
(iii) improves the quality of product; and
(iv) commercially and industrially more economical and viable one.

In an aspect, the present invention provides a process for the preparation of Dabigatran etexilate, which comprises reaction of salt of Dabigatran etexilate with a base in presence of a organic solvent to provide substantially pure Dabigatran etexilate.

The salt of Dabigatran etexilate can be hydrochloride, hydrobromide, mesylate, tosylate, acetate, sulfonate, and the like. In an embodiment, the salt is selected from mesylate salt of Dabigatran etexilate.

The conversion of salt of Dabigatran etexilate to Dabigatran etexilate free base is occurred in presence of base. The base may include but are not limited to inorganic base and organic base. The inorganic base includes but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, ammonia and the like. The organic base includes but are not limited to triethyl amine, dimethyl amine, pyridine, N-methyl pyrrolidine and the like.

The base can be used as a solid or a liquid. The liquid can be formed by the dissolution of base in a solvent includes water or an organic solvent such as alcohol.

In an embodiment, the present invention comprises use of sodium bicarbonate for the conversion of salt of Dabigatran etexilate to Dabigatran etexilate.

The reaction may be performed in presence of solvent, for example, chlorinated solvent such as dichloromethane, dichloroethane, chlorobenzene and the like; hydrocarbon such as hexane, heptane, cyclohexane, cyclopropane, and the like; ester such as ethyl acetate, methyl acetate, t-butyl acetate and the like; water or any combination thereof.

Dabigatran etexilate may be prepared at a temperature of about 20 to about 50 °C or more from the salt of Dabigatran etexilate. In an embodiment, the product is prepared at an ambient temperature. The reaction may be stirred for about 30 minutes to 2 hours or more to affect the yield of the product.

The resultant compound may be isolated by using concentration, anti-solvent, crash cooling, recrystallization, or any other commercially known techniques.

The obtained solid may be dried. The drying process may be conducted at a temperature of about 35 to about 50 °C for a period of about 30 minutes to 5 hours or more to provide stable and pure compound having purity greater than about 99.5% determined by HPLC.

In another aspect, the present invention provides a process for the preparation of Dabigatran etexilate Form I, the process comprises reaction of methane sulfonate salt of Dabigatran etexilate with a base in presence of chlorinated solvent, water or mixture thereof to provide substantially pure Form I of Dabigatran etexilate.

The base used for preparing Form I includes but are not limited to inorganic base and organic base. The inorganic base includes but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, ammonia and the like. The organic base includes but are not limited to triethyl amine, dimethyl amine, pyridine, N-methyl pyrrolidine and the like.

The chlorinated solvent includes and are not limited to dichloromethane, dichloroethane, chloroform, chlorobenzene and the like. In an embodiment, the invention utilizes dichloromethane or water or combination thereof.

The suitable temperature for preparing form I of the present invention is about 20 to about 50 °C or more. The process further involves stirring of the reaction mixture for a period of about 30 minutes to about 1 hour.

The resultant Dabigatran etexilate form I is isolated by separation of layers followed by concentration of organic layer completely or crystallization by using suitable known techniques.

Further, Dabigatran etexilate of the present invention may be used for the preparation of pharmaceutical composition along with at least one pharmaceutically acceptable excipient.

In another aspect, the present invention relates to pharmaceutical composition comprising Dabigatran etexilate obtained from the present invention and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example 1: A process for preparation of Dabigatran etexilate

Dabigatran Etexilate Mesylate (70 g, 0.096 mol) was dissolved in dichloromethane (560 mL) and treated with 10 % sodium bicarbonate solution (80 mL). The reaction mixture was stirred at room temperature for 60 minutes. The organic layer was separated, washed with water and recovered dichloromethane under vacuum to give 55.3 g of Dabigatran Etexilate.

1H NMR, dppm (CDCl3-d): 0.85 – 0.89 (3H, t, CH3), 1.18 – 1.21 (3H, t, CH3), 1.29 – 1.39 (6H, m, 3xCH2), 1.68 – 1.72 (2H, m, CH2), 2.77 – 2.80 (2H, t, COCH2), 3.64 (3H, s, CH3), 4.05 – 4.08 (2H, q, OCH2), 4.09 – 4.13 (2H, t, OCH2), 4.39 – 4.42 (4H, m, 2xNCH2), 5.32 (1H, t, NH), 6.58 – 6.60 (2H, d, 2xArH), 6.67 – 6.69 (1H, d, ArH), 6.96 – 7.02 (2H, m, 2xArH), 7.22 – 7.31 (2H, m, 2xArH), 7.65 – 7.72 (3H, m, 3xArH), 8.39 – 8.40 (1H, d, ArH).

13C NMR, dppm (CDCl3-d): 14.01, 14.10, 22.52, 25.63, 28.87, 29.72, 31.52, 33.29, 40.58, 44.67, 60.51, 65.31, 108.80, 111.94, 120.15, 121.06, 122.39, 122.97, 123.61, 129.10, 129.80, 137.18, 137.32, 140.98, 148.89, 150.49, 152.44, 156.04, 167.66, 171.02, 171.65.

HPLC purity: 99.63 %
XRPD: Figure.1.