Field of Invention:

The present invention relates to an improved process for the preparation of 1- methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl- carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide represented by the following structural formula-1.

l-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide is commonly known as Dabigatran etexilate. Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors developed by Boehringer Ingelheim and is used for treatment of thrombosis, cardiovascular diseases, and the like. Dabigatran etexilalte mesylate was approved by both in US and Europe and commercially available under the brand name of Pradaxa.

Background of the Invention:

Dabigatran and process for its preparation was first disclosed in US 6087380. The disclosed process involves the reaction of l-methyl-2-[N-[4-amidino phenyl] aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide hydrochloride with n-hexylchloro formate in presence of potassium carbonate in tetrahydrofuran/water provides Dabigatran etexilate.

So far, the known methods for the preparation of Dabigatran etexilate involve the usage of n-hexylchloroformate for the generation of carbamate in the synthesis of Dabigatran etexilate. US 6919471 and US 7696371 disclose processes for the preparation of n-hexylchloro formate. The disclosed processes involve the reaction of n-hexanol with phosgene or triphosgene. Triphosgene decomposes on heating, upon reaction with nucleophiles and even trace moisture leads to the formation of phosgene. As the phosgene is extreme toxic and poisonous gas, hence is difficult to handle in the laboratory and not recommended for commercial scale-up.

The commercially available n-hexylchloroformate was found to contain numerous impurities which are difficult to remove, which in-turn affect the purity and yields of the subsequent stages and that of the final compound. It also may degrade on storage for long periods. Apart from these disadvantages n-hexylchloroformate is expensive and hence not economical.

Hence there is a need in the art to develop an alternate process for the preparation of Dabigatran etexilate which overcomes the disadvantages of the prior art. It should avoid the use of toxic reagents, should be economical, easy to scale up and also provide dabigatran etexilate with high purity.

The present invention mainly emphasizes the in-situ generation of a alternate carbamate inducing agent which does not involve the usage of toxic and poisonous reagents like phosgene, triphosgene e.tc. which produces the final product with high purity.

Advantages of Present Invention:

• Provides the usage of novel carbamate inducing agent in the synthesis of Dabigatran etexilate.

• Provides in-situ preparation of carbamate inducing agent for the preparation of Dabigatran etexilate.

• Provides pure Dabigatran etexilate without using any additional purification steps.

• Avoids toxic and poisonous reagents during the reaction.

• Utilizing a novel technology for carbamate formation in the synthesis of Dabigatran etexilate.

• Provides simple, safer and economic process for the preparation of Dabigatran etexilate.
Brief Description of Invention:

The first embodiment of the present invention is to provide an improved process for the preparation of Dabigatran etexilate compound of formula-1, which comprising of:

a) Reacting n-hexanol compound of formula-2 with N,N-carbonyldiimidazole compound of formula-3 in a suitable solvent to provide hexyl lH-imidazole-1- carboxylate compound of formula-4,

b) reacting the compound of formula-4 with ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo [d] imidazole-5 -carbox amido)propanoate compound of formula-5 or its salts compound of general formula-6 in presence of a base in a suitable solvent to provide Dabigatran etexilate compound of formula-1.

The second embodiment of the present invention is to provide an improved process for the preparation of Dabigatran etexilate compound of formula-1, which comprising of:

a) Reacting n-hexanol compound of formula-2 with N,N-carbonyldiimidazole compound of formula-3 in a suitable solvent to provide hexyl lH-imidazole-1- carboxylate compound of formula-4,

b) reacting the compound of formula-4 in-situ with ethyl 3-(2-((4- carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d] imidazole-5-carboxamido)propanoate compound of formula-5 or its salts compound of general formula-6 in presence of a base in a suitable solvent to provide Dabigatran etexilate compound of formula-1.

Detailed Description of Invention:

The present invention mainly emphasizes the in-situ generation of a carbamate inducing agent in the synthesis of Dabigatran etexilate, which avoids the usage of toxic and poisonous reagents and produces the final product with high purity.

As used herein the present invention, the term "suitable solvents" wherever necessary, is selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethylether, methyl tert-butyl ether;

"hydrocarbon solvents" like toluene, hexane, heptane, pet.ether and cyclohexane; "polar aprotic solvents" like dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, propanone, methyethyl ketone, methyl isobutyl ketone; "alcohol solvents" like methanol, ethanol, n-propanol, isopropanol, n- butanol, diglycol and isobutanol; "chloro solvents" like dichloromethane, chloroform, and dichloroethane; and "polar solvents" like water; and also mixtures thereof.

The term "base" herein the present invention is selected from inorganic bases like alkali metal, and alkaline earth metal alkoxides, hydroxides, carbonates and bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert- butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and organic bases like ammonia, triethylamine, tributyl amine, dimethyl aniline, N-methyl piperidine and N-methyl pyrrolidine, N-methyl morpholine, diisopropyl methylamine, diisopropyl amine, diisopropyl ethylamine, cyclohexyldimethyl amine, piperidine, dimethyl amino pyridine, pyridine and the like.

The term "acid" herein the present invention is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; organic acids such as methane sulfonic acid, p-toluene sulfonic acid, benzene sulfonic acid, ethane disulfonic acid, ethane sulfonic acid, naphthalene disulfonic acid, naphthalene-2-sulfonic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, malic acid, succinic acid, malonic acid, succinic acid, mandelic acid, lactic acid, citric acid, tartaric acid, gentisic acid, cyclamic acid, D-glucuronic acid, glycolic acid, isethionic acid, saccharine, salicylic acid and the like.

The first embodiment of the present invention is to provide an improved process for the preparation of Dabigatran etexilate compound of formula-1, which comprising of a) Reacting n-hexanol compound of formula-2

Formula-2 with N,N-carbonyldiimidazole compound of formula-3 in a suitable solvent to provide n-hexyl 1H-imidazole-l-carboxylate compound of formula-4,

b) reacting the compound of formula-4 with ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate compound of formula-5 or its salts compound of general formula-6 wherein, n is 1 or 2, in presence of a base in a suitable solvent to provide Dabigatran etexilate compound of formula-1.

In a preferred embodiment of the present invention is to provide Dabigatran etexilate compound of formula-1, which comprising of:

a) Reacting n-hexanol compound of formula-2 with N,N-carbonyldiimidazole compound of formula-3 in dichloromethane to provide n-hexyl lH-imidazole-1- carboxylate compound of formula-4,

b) reacting the compound of formula-4 with ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carbox amido)propanoate compound of formula-5 in presence of potassium carbonate in aqueous acetonitrile to provide Dabigatran etexilate compound of formula-1.

In another preferred embodiment of the present invention is to provide Dabigatran etexilate compound of formula-1, which comprising of:

a) Reacting n-hexanol compound of formula-2 with N,N-carbonyldiimidazole compound of formula-3 in dichloromethane to provide n-hexyl lH-imidazole-1- carboxylate compound of formula-4,

b) reacting the compound of formula-4 with ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carbox amido)propanoate oxalate compound of formula-6a
in presence of potassium carbonate in aqueous acetonitrile to provide Dabigatran etexilate compound of formula-1. Wherein, the suitable solvent used, in step-a) is selected from "chlorosolvents" like dichloromethane, chloroform, dichloroethane; "ester solvents" like ethylacetate, methylacetate, isopropylacetate; "ethersolvents" like tetrahydrofuran, diethylether, methyl tert-butyl ether; "ketone solvents" like acetone, methylethylketone, propanone, methylisobutylketone; and "polar aprotic solvents" like dimethylformamide, acetonitrile; and in step-b) is organic solvent selected from "ethersolvents" like tetrahydrofuran, methyl tert-butyl ether, diethylether, "ester solvents" like methyl acetate,

ethylacetate, isopropylacetate; "ketone solvents" like acetone, propanone, methylethyl ketone, methylisobutylketone; "polaraprotic solvents" like dimethylformamide, acetonitrile, or mixtures of water and organic solvent.

The second embodiment of the present invention is to provide an improved process for the preparation of Dabigatran etexilate compound of formula-1, which comprising of:

a) Reacting n-hexanol compound of formula-2 with N,N-carbonyldiimidazole compound of formula-3 in a suitable solvent to provide n-hexyl lH-imidazole-1- carboxylate compound of formula-4,

b) reacting the compound of formula-4 in-situ with ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo [d] imidazole-5-carbox amido)propanoate compound of formula-5 or its salts compound of general formula-6 in presence of a base in a suitable solvent to provide Dabigatran etexilate compound of formula-1.

Wherein, the suitable solvent used, in step-a) is selected from "chlorosolvents" like dichloromethane, chloroform, dichloroethane; "ester solvents" like ethylacetate, methylacetate, isopropylacetate; "ethersolvents" like tetrahydrofuran, diethylether, methyl tert-butyl ether; "ketone solvents" like acetone, methylethylketone, propanone, methylisobutylketone; and "polar aprotic solvents" like dimethylformamide, acetonitrile; and in step-b) is organic solvent selected from "ethersolvents" like tetrahydrofuran, methyl tert-butyl ether, diethylether, "ester solvents" like methyl acetate, ethylacetate, isopropylacetate; "ketone solvents" like acetone, propanone, methylethyl ketone, methylisobutylketone; "polaraprotic solvents" like dimethylformamide, acetonitrile, or mixtures of water and organic solvent.

The step b) in the above aspects is carried out at a temperature between 0-100°C, preferably at a temperature between 5-55°C, more preferably at a temperature between 10-45°C, most preferably at a temperature between 25-35°C for a period of 9-24 hours.

The solvent used in step-a) of the above aspects is in an amount ranging from 2- 10 volumes, preferably from 3-7 volumes, most preferably 5 volumes to compound of formula-5 or compound of general formula-6.

The solvent used in step-b) of the above aspects is in an amount ranging from 5- 50 volumes, preferably from 10-40 volumes, most preferably 20 volumes to compound of formula-5 or compound of general formula-6 and the ratio of organic solvent and water is between 2:8 to 8:2, preferably is 6:4.

The n-hexanol in the present invention employed in the mole proportions between 0.8-6, preferably between 1-3, most preferably 1.5 per one mole of compound of formula-5 or compound of general formula-6

The N,N-carbonyldiimidazole in the present invention employed in the mole proportions between 0.8-6, preferably between 1-3, most preferably 1.75 per one mole of compound of formula-5 or compound of general formula-6.

The base in the present invention employed in the mole proportions between 0.8- 10, preferably between 1-8, most preferably 5 per one mole of compound of formula-5 or compound of general formula-6.

The previously reported technologies for the formation of carbamate in the synthesis of Dabigatran etexilate involve the usage of expensive n-hexylchloroformate. The commercially available n-hexyl chloroformate may degrade on long storage, which may leads to the formation of impure n-hexylchloroformate. The said impure n- hexylchloroformate affects the purity and yield of the final compound. Hence it is better to synthesize such less stable chemical moieties in-situ in the reaction. Even in the in-situ synthesis of n-hexylchloroformate involves the usage of phosgene, which is toxic, dangerous reagent and difficult to handle in the laboratory. Hence it is advisable to synthesize a novel carbamate inducing agent in-situ in the synthesis of dabigatran etexilate by utilizing non-toxic, cheaper and highly pure reagents.

Thus, the present invention provides a substitute for n-hexylchloroformate i.e. hexyl lH-imidazole-l carboxylate, which is prepared by using widely available and highly pure n-hexanol and N,N-carbolyldiimidazole. Moreover these reagents n-hexanol and N,N-carbonyldiimidazole are non-toxic and cheaper reagents. Hence the usage of hexyl 1 H-imidazole-1 -carboxylate compound of formula-4 is more advantageous over n- hexylchloroformate which is used in the prior-art processes.

The present invention provides a simple, safer, robust, economic process for the preparation of hexyl 1 H-imidazole-1-carboxylate compound of formula-4, which is well suited for commercial scale up. Hexyl 1 H-imidazole-1-carboxylate compound may be further isolated as a solid using a suitable solvent.

We, the first inventor found that the usage of hexyl 1 H-imidazole-1-carboxylate compound of formula-4 for carbamate preparation in the synthesis of Dabigatran etexilate, which is well suited for commercial scale up.

US 2010210845 disclosed Dabigatran Etexilate with purity greater than 99%, which requires additional purification steps in obtaining such purity. It is surprisingly found that, when we utilize the hexyl 1 H-imidazole-1-carboxylate compound of formula- 4 for carbamate formation, it results in the formation of Dabigatran etexilate with enhanced purity i.e. greater than 99%, preferably 99.5%, without any additional purification steps.

The 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1H- benzo [d]imidazole-5-carboxamido)propanoate compound of formula-5 used in the present invention is prepared from the any known methods in the prior art and 3-(2-((4- carbamimidoylphenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d] imidazole- 5-carboxamido)propanoate oxalate compound of formula-6a used in the present invention can be prepared by the process disclosed in our Indian priority application IN 1801/CHE/2011.
Dabigatran etexilate obtained by the present invention can be further converted into its mesylate salt. The said Debigatran etexilate mesylate can be further micronized or milled to get the desired particle size. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.

Further, the said Dabigatran etexilate mesylate can be used in the formation of medicament as an active ingredient for the treatment of thrombosis.

The possible impurities may be formed in the synthesis of Dabigatran etexilate are as follows:

All these impurities are formed due to the presence of impure n-hexanol that is present in commercially available n-hexylchloroformate. The present invention controls all these impurities by using pure n-hexanol.

The present invention is schematically represented as follows:

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of hexyl lH-imidazole-l-carboxylate (Formula-4)

A solution of n-hexanol (25.95 g) in dichloromethane (400 ml) was slowly added to solution of N,N-carbonyldiimidazole (48.08 g) in dichloromethane (100 ml) and stirred for 2 1/2 hour at 25-35°C. Water was added to the reaction mixture. Both the dichloromethane layer and aqueous layer were separated and the dichloromethane layer was distilled under reduced pressure to provide title compound. Yield: 60 grams

Example-2: Preparation of Dabigatran etexilate (Formula-1)

Ethyl 3-(2-((4-carbamimidoyl phenyl amino)methyl)-l-methyl-N-(pyridin-2-yl)- lH-benzo[d]imidazole-5-carbox amido)propanoate oxalate compound of formula-6a (100 g) was added to acetonitrile (1200 ml) and water (800 ml) at 25-3 5 °C and then cooled to 12-18°C. Potassium carbonate (117 g) was added to the reaction mixture and stirred for 15 minutes at 12-18°C. A solution of hexyl lH-imidazole-l-carboxylate compound of formula-4 (60 g) in acetonitrile (150 ml) was slowly added to the reaction mixture over a period of 25 minutes at 12-18°C and stirred for 14 hours at 15-20°C. After completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes. Filtered the solid, washed with acetonitrile followed by aqueous acetonitrile and then dried to get title compound. The obtained compound was further purified by chromatography using dichloromethane:methanol (19:1) as an eluent on silica gel. Yield: 95 g

Example-3: Preparation of Dabigatran etexilate (Formula-1)

Ethyl 3-(2-((4-carbamimidoyl phenyl amino)methyl)-l-methyl-N-(pyridin-2-yl)-lH- benzo[d]imidazole-5-carbox amido)propanoate compound of formula-5 (100 g) was added to acetonitrile (1200 ml) and water (800 ml) at 25-3 5°C and then cooled to 12- 18°C. Potassium carbonate (138 g) was added to the reaction mixture and stirred for 15 minutes at 12-18°C. A solution of hexyl lH-imidazole-l-carboxylate compound of formula-4 (66 g) in acetonitrile (150 ml) was slowly added to the reaction mixture over a
period of 25 minutes at 12-18°C and stirred for 14 hours at 15-20°C. After completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes. Filtered the solid, washed with acetonitrile followed by aqueous acetonitrile and then dried to get title compound. The obtained compound was further purified by chromatography using dichloromethane:methanol (19:1) as an eluent on silica gel. Yield: 114 g

Example-4: Preparation of Dabigatran etexilate (Formula-1)

A solution of n-hexanol (25.95 g) in tetrahydrofuran (400 ml) was slowly added to solution of N,N-carbonyldiimidazole (48.08 g) in tetrahydrofuran (100 ml) and stirred for 2 1/2 hour at 25-35°C to provide hexyl 1 H-imidazole-1-carboxylate compound of formula- 4. Ethyl 3-(2-((4-carbamimidoyl phenyl amino)methyl)-l-methyl-N-(pyridin-2-yl)-lH- benzo[d]imidazole-5-carbox amido)propanoate oxalate compound of formula-6a (100 g), tetrahydrofuran (700 ml), water (800 ml) and potassium carbonate (117 g) were added to the reaction mixture and stirred for 20 hours at 25-30°C. After completion of the reaction, filtered the solid, washed with tetrahydrofuran and then dried to get title compound. The obtained compound was further purified by chromatography using dichloromethane: methanol (19:1) as an eluent on silica gel. Yield: 100 g

Example-5: Preparation of Dabigatran etexilate (Formula-1)

A solution of n-hexanol (30.6 g) in tetrahydrofuran (400 ml) was slowly added to solution of N,N-carbonyldiimidazole (55.08 g) in tetrahydrofuran (100 ml) and stirred for 2 hour at 25-35°C to provide hexyl 1H-imidazole-1-carboxylate compound of formula- 4. Ethyl 3-(2-((4-carbamimidoyl phenyl amino)methyl)-l-methyl-N-(pyridin-2-yl)-lH- benzo[d]imidazole-5-carbox amido)propanoate compound of formula-5 (100 g), tetrahydrofuran (700 ml), water (800 ml) and potassium carbonate (138 g) were added to the reaction mixture and stirred for 20 hours at 25-30°C. After completion of the reaction, filtered the solid, washed with tetrahydrofuran and then dried to get title compound. The obtained compound was further purified by chromatography using dichloromethane:methanol (19:1) as an eluent on silica gel. Yield: 115 g

The crystalline form of Dabigatran etexilate obtained by the present invention is similar to the crystalline form of Dabigatran etexilate obtained in JMC, 2002,45(9),1757- 1766.

We claim:

1. A process for the preparation of Dabigatran etexilate compound of formula-1, comprising of:

a) Reacting n-hexanol compound of formula-2 with N,N-carbonyldiimidazole compound of formula-3 in a suitable solvent to provide hexyl lH-imidazole-1- carboxylate compound of formula-4,

b) reacting the compound of formula-4 with 3-(2-((4-carbamimidoyl phenylamino)methyl)-l-methyl-N-(pyridin-2-yl)-lH-benzo[d]imidazole-5-carbox amido)propanoate compound of formula-5 or its salts compound of general formula-6 in presence of a base in a suitable solvent to provide compound of formula-1.

2. The process according to claim 1, wherein the suitable solvent used in step-a) is selected from "chlorosolvents" like dichloromethane, chloroform, dichloroethane; "ester solvents" like ethylacetate, methylacetate, isopropylacetate; "ethersolvents" like tetrahydrofuran, diethylether, methyl tert-butyl ether; "ketone solvents" like acetone, methylethylketone, propanone, methylisobutylketone; and "polar aprotic solvents" like dimethylformamide, acetonitrile; and

in step-b) the organic solvent is selected from "ethersolvents" like tetrahydrofuran, methyl tert-butyl ether, diethylether, "ester solvents" like methyl acetate, ethylacetate, isopropylacetate; "ketone solvents" like acetone, propanone, methylethyl ketone, methylisobutylketone; "polaraprotic solvents" like dimethylformamide, acetonitrile, or mixtures of water and organic solvent.

3. The process according to preceding claims, wherein the solvent used in step a) in an amount ranging from 2-10 volumes to 1 g of compound of formula-5 (or) compound of general formula-6; and

in step-b) in an amount ranging from 5-50 volumes to 1 g of compound of formula-5 (or) compound of general formula-6 .

4. The process according to claim 3, wherein in step-b) the ratio of water to the organic solvent is in between 2:8 to 8:2.

5. The process according to preceding claims, wherein the mole proportions of base, N,N-carbonyldiimidazole and n-hexanol are in ranging between 0.8-10, 0.8-6 and 0.8-6 respectively, per one mole of compound of formula-5 or compound of general formula-6.

6. The process according to preceding claims, wherein the step-b) is carried at a temperature ranging between 5-55°C for a period of between 9-24 hours.

7. A process for the preparation of Dabigatran etexilate, comprising of:

a) Reacting n-hexanol compound of formula-2 with N,N-carbonyldiimidazole compound of formula-3 in dichloromethane to provide hexyl lH-imidazole-1- carboxylate compound of formula-4,

b) reacting the compound of formula-4 with 3-(2-((4-carbamimidoyl phenylamino) methyl)-1 -methyl-N-(pyridin-2-yl)-1 H-benzo[d]imidazole-5-carboxamido) propanoate compound of formula-5 or 3-(2-((4-carbamimidoylphenylamino)methyl)-1 -methyl-N-(pyridin-2-yl)-1H- benzo[d]imidazole-5-carboxamido) propanoate oxalate salt compound of formula- 6a in presence of potassium carbonate in aqueous acetonitrile to provide compound of formula-1.

8. A process according to claim 1 and 7, the hexyl 1H-imidazole-l-carboxylate compound of formula-4 obtained in step-a) can be used without isolation in step-b).

9. Dabigatran etexilate obtained by the process according to claim 1 and 7, having purity greater than 99% by HPLC.

10. Use of a compound of formula-4 as carbamate inducing agent in the synthesis of Dabigatran etexilate.