DESC:Field of the invention

The present invention relates to an improved method for the preparation of Dabigatran etexilate of formula-I and salt thereof.

Background of the Invention

Dabigatran etexilate is a direct thrombin inhibitor and is used for the treatment of deep venous thrombosis and pulmonary embolism. Dabigatran and its acyl glucuronides are thrombin inhibitors and prevent the development of a thrombus.

Dabigatran etexilate and a process for the preparation of Dabigatran etexilate was first described in U.S. Patent No. 6,087,380.

Various processes for the preparation of Dabigatran and Dabigatran etexilate have been disclosed in patent applications EP 2262771 A1, WO 2006/000353, WO 2010/045900, WO 2014/012880, etc. Each of these references is incorporated herein by reference in its entirety.

However, the processes disclosed in the references yield Dabigatran etexilate that requires further purifications in order to make it suitable for use in the pharmaceutical composition. Hence, there is a need to develop alternative method suitable for the industrial scale production of Dabigatran etexilate.

It is found that the present invention meets this objective and thus provides a method for the production of Dabigatran etexilate that is industrially advantageous.

Objects of the Invention

The main objective of the present invention is to provide an improved method, which allows large-scale industrial production of Dabigatran etexilate and salt thereof.

Another objective of the present invention is to provide a method for the preparation of a substantially pure form of Dabigatran etexilate with high yield.

Summary of the Invention

In one aspect, the present invention is directed to a method for the preparation of Dabigatran etexilate of formula-I and salt thereof, comprising the steps of:
a) contacting [(4-cyanophenyl) amino] acetic acid of formula-II,

and ethyl 3-{[3-amino-4(methyl amino) benzoyl] (pyridin-2-yl) amino} propanoate of formula-III,

in presence of one or more catalysts to obtain compound of formula-IV;

b) cyclizing compound of formula-IV using suitable cyclizing agent to obtain compound of formula-V;

c) converting compound of formula-V into Dabigatran of formula-VI;

d) reacting Dabigatran of formula-VI with 1-hexylchloroformate of formula-VII

in suitable solvents to obtain Dabigatran etexilate of formula-I; and
e) optionally, converting said Dabigatran etexilate into its salt.

In another aspect, the present invention is directed to a process for the preparation of Dabigatran etexilate of formula-I, comprising the step of contacting Dabigatran of formula-VI,

and 1-hexylchloroformate of formula-VII,

in presence of base in a bi-phasic solvent to obtain Dabigatran etexilate of formula-I.

In one more aspect, the present invention is directed to a process for the preparation of Dabigatran etexilate and salt thereof, comprising the steps of:
a) contacting [(4-cyanophenyl) amino] acetic acid of formula-II

and ethyl 3-{[3-amino-4(methyl amino) benzoyl] (pyridin-2-yl)amino}propanoate of formula-III

in presence of one or more catalysts and one or more coupling agents to obtain compound of formula-IV;

b) cyclizing compound of formula-IV using suitable cyclizing agent to obtain compound of formula-V;

c) converting compound of formula-V into Dabigatran of formula-VI;

d) reacting compound of formula-VI with 1-hexylchloroformate of formula-VII

in presence of base in a bi-phasic solvent to obtain Dabigatran etexilate of formula-I; and
e) optionally, converting said Dabigatran etexilate into its salt.

Detailed Description of the Invention

The present invention relates to an improved method for the preparation of Dabigatran etexilate, which allows large-scale industrial production of Dabigatran etexilate and salt thereof.

In one aspect, the present invention is directed to a method for the preparation of Dabigatran etexilate and salt thereof, comprising the steps of:
a) contacting [(4-cyanophenyl) amino] acetic acid of formula-II

and ethyl 3-{[3-amino-4(methyl amino) benzoyl] (pyridin-2-yl)amino}propanoate of formula-III

in presence of one or more catalysts and one or more coupling agents to obtain compound of formula-IV;

b) cyclizing compound of formula-IV using suitable cyclizing agent to obtain compound of formula-V;

c) converting compound of formula-V into Dabigatran of formula-VI;

d) reacting Dabigatran of formula-VI with 1-hexylchloroformate of formula-VII

in presence of base in a bi-phasic solvent to obtain Dabigatran etexilate of formula-I; and
e) optionally, converting said Dabigatran etexilate into its salt.

The compound of formula-II is reacted with compound of formula-III in presence of one or more suitable coupling agents and one or more catalysts in a suitable solvent to prepare compound of formula-IV.

The coupling agent used for this reaction is selected from carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBT), 8-Diazabicyclo [5.4.0] undec-7-ene (DBU) and mixture thereof.

The catalyst is selected from hydrochloric acid, pyridinium hydrobromide, picoline hydrobromide and trimethyl silyl chloride.

The solvent used for reaction of compound of formula-II with compound of formula-III is selected from dichloromethane, tetrahydrofuran, ethyl acetate, toluene, isopropyl acetate, butyl acetate and mixtures thereof.

In one aspect of the present invention, the compound of formula-IV is optionally isolated from the reaction mass.

In one more aspect of the present invention, the compound of formula-IV is reacted with the cyclizing agent to prepare compound of formula-V. The cyclizing agent is selected from acetic acid, phosphoric acid, hydrochloric acid, hydrobromic acid and imidazole.

The obtained compound of formula-V is further converted into Dabigatran of formula-VI by reacting compound formula-V with alcohol in presence of acid, followed by treatment with ammonia source.

The alcohol is selected from methanol, ethanol, n-propanol and preferably ethanol. The acid is selected from organic acid or mineral acid. The mineral acid is selected from hydrochloric acid and sulfuric acid.

The reaction of compound of formula-V with suitable alcohol in presence of acid is carried out in absence or presence of suitable solvent. The suitable solvent is selected from methylene chloride, toluene and mixtures thereof.

The ammonia source is ammonium carbonate, ammonium acetate or ammonia solution prepared in a solvent selected from ethanol, isopropanol, ethanol denatured with toluene, ethanol denatured with hexane and mixtures thereof.

In yet another aspect of the present invention, Dabigatran of formula-VI is reacted by contacting with 1-hexylchloroformate of formula-VII in presence of a base in a bi-phasic solvent system to obtain Dabigatran etexilate of formula-I.

In one embodiment, the bi-phasic solvent system comprises mixture of water with one or more water-immiscible organic solvents selected from methylene chloride, chloroform, toluene, hexane, cyclohexane, chloroform, ethyl acetate, methyl tert-butyl ether and mixture thereof. The base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.

In yet another aspect of the present invention, Dabigatran of formula-VI is reacted with the 1-hexylchloroformate of formula-VII optionally in presence of a phase transfer catalyst. The phase transfer catalyst is selected from triethyl benzyl ammonium chloride (TEBAC), tert-butyl ammonium bromide (TBAB) or tert-butyl ammonium chloride (TBAC).

In one more aspect, Dabigatran etexilate is further converted into its acid addition salt such as mesylate salt by reacting corresponding acid in a suitable solvents.

In one more aspect of the present invention, Dabigatran etexilate or mesylate salt thereof obtained from the method described herein can be used in a pharmaceutical composition.

Present invention is further illustrated with the following non-limiting examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Examples:

Example-1: Preparation of Ethyl 3-(3-(2-((4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate
[(4-Cyanophenyl) amino] acetic acid (1.05 Mole Eq.) was treated N,N-carbonyl diimidazole (CDI) (1.20 Mole Eq.) in a mixture of dichloromethane (6.0 volume) and tetrahydrofuran (0.60 volume) for 1.0 hour and then reacted with ethyl 3-{[3-amino-4(methyl amino) benzoyl] (pyridin-2-yl)amino}propanoate (1.00 Mole Eq.) in presence of pyridinium hydrobromide (0.50 Mole Eq.) for 3 hours to form intermediate ethyl 3-(2-(((4-cyanophenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate. After removal of solvents, water was added to precipitate the solid and this wet mass was heated with acetic acid (6.0 Mole Eq.) to get Ethyl 3-[[[2-[[(4-Cyanophenyl) amino] methyl]-1-methyl-1Hbenzimidazol-5-yl] carbonyl] pyridin-2-ylamino]propionate (DEM-I) after work up and isolation.
Yield: 81.19 %
HPLC purity: 99.62 %.

Example-2: Preparation of Ethyl 3-(3-(2-((4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate
[(4-Cyanophenyl) amino] acetic acid (1.05 Mole Eq.) was treated with N,N’-Carbonyldiimidazole (CDI) (1.20 Mole Eq.) in a mixture of dichloromethane (6.0 volume) and tetrahydrofuran (0.60 volume) for 1.0 hour and then reacted with ethyl 3-{[3-amino-4(methyl amino) benzoyl] (pyridin-2-yl)amino}propanoate (1.00 Mole Eq.) in presence of hydroxy benzotriazole (HOBT) (0.20 Mole Eq.) and trimethyl silyl chloride (TMSC) (1.00 Mole Eq.) to form intermediate species in 5.0 hrs. After removal of solvents water was added to precipitate the intermediate species. The obtained wet mass is then heated with acetic acid (6.0 Mole Eq.) to get title compound after work up and isolation.
Yield: 75.23 %
HPLC purity: 99.25 %.

Example-3 Preparation of Ethyl 3-(3-(2-((4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate
[(4-Cyanophenyl) amino] acetic acid (1.05 Mole Eq.) was treated with N,N-Carbonyl diimidazole (CDI) (1.20 Mole Eq.) in a mixture of dichloromethane (6.0 volume) and tetrahydrofuran (0.60 volume) for 1.0 hour and then reacted with ethyl 3-{[3-amino-4(methyl amino) benzoyl] (pyridin-2-yl)amino}propanoate (1.00 Mole Eq.) in presence of HCl (g) for 5 hours to form intermediate species ethyl 3-(3-(2-((4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate. After removal of solvents, water was added to precipitate the material. The precipitated wet mass was heated with acetic acid (6.0 Mole Eq.) to get title compound after work up and isolation.
Yield: 68.84 %
HPLC purity: 98.44 %.

Example-4: Preparation of Ethyl (3-({2-[(4-Carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5- carbonyl}-pyridin-2-yl-amino)-propionate (Dabigatran)
Ethyl 3-(3-(2-((4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate (1.00 Mole Eq.) was dissolved in dichloromethane and reacted with solution of hydrogen chloride in ethanol, followed by reaction with Ammonia solution in Ethanol at 40-450C for 6 hours. Filtered the solids and distilled off solvent under vacuum from the filtrate. The title compound was precipitated by crystallization with isopropyl alcohol and dried at 45 - 60 °C for 8 hours under vacuum.
Yield: 80.45 %

Example-5: Preparation of N-[2-[4-[N-(Hexyloxycarbonyl) amidino] phenylaminomethyl] -1-methyl-1H-benzimidazol-5-ylcarbonyl]-N-(2-pyridyl)-betaalanine ethyl ester (Dabigatran etexilate)
Ethyl (3-({2-[(4-Carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5- carbonyl}-pyridin-2-yl-amino)-propionate (Dabigatran) (1.00 Mole Eq.) was reacted with 1-hexylchloroformate (0.90 Mole Eq.) in presence of potassium carbonate (2.00 Mole Eq.) in a mixture of dichloromethane (15.0 volume) and water (4.0 volume) at 25- 30°C. The aqueous layer was isolated and the solvent was distilled off and then 2-propanol was added to get pure N-[2-[4-[N-(Hexyloxycarbonyl) amidino] phenylaminomethyl] -1-methyl-1H-benzimidazol-5-ylcarbonyl]-N-(2-pyridyl)-betaalanine ethyl ester.
Yield: 81.19 %
HPLC purity: 99.62 %.

Comparative Example-1: Preparation of Ethyl 3-(3-(2-((4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate
[(4-cyanophenyl) amino] acetic acid (1.05 Mole Eq.) was treated with N,N’-Carbonyldiimidazole (CDI) (1.20 Mole Eq.) in tetrahydrofuran (8.0 volume) and then reacted with ethyl 3-{[3-amino-4(methyl amino) benzoyl] (pyridin-2-yl)amino}propanoate (1.00 Mole Eq.) to form wet mass of ethyl 3-(3-(2-((4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate in 24.0 hrs. The obtained wet mass is heated with acetic acid (60.0 Mole Eq.), to get title compound after work up and isolation.
Yield: 75.94 %
HPLC purity: 98.46 %.

Comparative Example-2: Preparation of N-[2-[4-[N-(Hexyloxycarbonyl) amidino] phenylaminomethyl]-1-methyl-1H-benzimidazol-5-yl carbonyl]-N-(2-pyridyl)-betaalanine ethyl ester
Ethyl (3-({2-[(4-carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionate (1.00 Mole Eq.) was reacted with 1-hexylchloroformate (0.90 Mole Eq.) in presence of potassium carbonate (2.00 Mole Eq.) in a mixture of tetrahydrofuran (15.0 volume) and water (4.0 volume) at 25- 30°C. The aqueous layer was removed, solvent was distill off and then 2-propanol was added to get crude N-[2-[4-[N-(Hexyloxycarbonyl) amidino] phenylaminomethyl] -1-methyl-1H-benzimidazol-5-ylcarbonyl]-N-(2-pyridyl)-betaalanine ethyl ester, which is further purified with 2-propanol to get N-[2-[4-[N-(Hexyloxycarbonyl) amidino] phenylaminomethyl] -1-methyl-1H-benzimidazol-5-ylcarbonyl]-N-(2-pyridyl)-betaalanine ethyl ester.
Yield: 51.19 %
HPLC purity: 97.66 % (Crude)
HPLC purity: 98.59 % (After purification).
,CLAIMS:1. A method for the preparation of Dabigatran etexilate of formula-I or salt thereof, comprising the steps of:
a) contacting [(4-cyanophenyl) amino] acetic acid of formula-II

and ethyl 3-{[3-amino-4(methyl amino) benzoyl] (pyridin-2-yl)amino}propanoate of formula-III

in presence of one or more catalysts and one or more coupling agents, to obtain compound of formula-IV;

b) cyclizing compound of formula-IV using suitable cyclizing agent to obtain compound of formula-V;

c) converting compound of formula-V into Dabigatran of formula-VI;

d) reacting Dabigatran of formula-VI with 1-hexylchloroformate of formula-VII

in presence of base in bi-phasic solvent to obtain Dabigatran etexilate of formula-I; and
e) optionally, converting said Dabigatran etexilate into its salt.

2. The coupling agent according to step a) of the claim-1, comprises carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBT) and 8-Diazabicyclo [5.4.0] undec-7-ene (DBU).

3. The catalyst according to step a) of the claim-1, comprises hydrochloric acid, pyridinium hydrobromide, picoline hydrobromide and trimethyl silyl chloride.

4. The cyclizing agent according to step b) of the claim-1, comprises acetic acid, phosphoric acid, hydrochloric acid, hydrobromic acid and imidazole.

5. The bi-phasic solvent system according to step d) of the claim-1, comprises mixture of water with one or more water-immiscible organic solvents.

6. The base according to step d) of the claim-1, comprises potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.

7. A process for the preparation of Dabigatran etexilate of formula-I,

comprising the step of contacting Dabigatran of formula-VI,

and 1-hexylchloroformate of formula-VII,

in presence of base in a bi-phasic solvent to obtain Dabigatran etexilate of formula-I.

8. The bi-phasic solvent system according to claim-7, comprises mixture of water with one or more water-immiscible organic solvents.

9. The base according to claim-7, comprises potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide.