MPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATE OF DABIGATRAN

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate, compound of formula (I), an intermediate of Dabigatran.

BACKGROUND OF THE INVENTION

Direct thrombin inhibitors are a class of medication that act as anticoagulants by directly inhibiting the enzyme thrombin. Dabigatran is an oral anticoagulant from the class of the direct thrombin inhibitors.

The chemical name of Dabigatran etexilate mesylate is (E)-ethyl 3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate methanesulfonate and is structurally represented its empirical formula is C34H41N7O5.CH4O3S with a molecular weight of 723.86 (mesylate salt) and 627.75 (free base). Dabigatran etexilate is commercially marketed under the trade name of PRADAXA® in United States, Europe, Australia and Canada and under the trade name of PRAZAXA® in Japan.

The active compound, Dabigatran and Dabigatran etexilate has been disclosed in US6087380 and WO9837075 (Hauel et al, 1998). '380 discloses the process for the preparation of Dabigatran from ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate. The process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate from 4-methylamino-3-nitro-benzoic acid chloride and N-(2-ethoxy-carbonylethyl)-aniline has been disclosed in the patent. The preparation of compound 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester requires column purification in this patent, which is not industrially viable.

Similarly, the process for preparation of Dabigatran and Dabigatran etexilate has been disclosed in J.Med. Chem. 2002, 45, 1757-1766. The process for preparing the intermediate, ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate, used in the preparation of Dabigatran has also been disclosed in the journal article, from 4-methylamino-3-nitro-benzoic acid.

WO2009111997 (Jirman et al, 2009) relates to a method for the manufacture of Dabigatran, in which the intermediate, ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate, is prepared by reaction of 4-ethylamino-3-nitrobenzoic acid chloride with ethyl-3-(pyridine-2-ylamino)propanoate, is converted to the hydrochloride and the nitro group is reduced by means of sodium dithionite. The preparation of the pure compound of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester requires a number of isolation steps which increases the cost of production. The use of sodium dithionate in this invention leads to liberation of sulphur dioxide gas, which is hazardous and the reduced product obtained is a thick oily residue, which is difficult to handle on commercial scale.
WO2009153214 (Hedesheimer et al, 2009) relates to a process for the synthesis of diamine, 4-ethylamino-3-nitrobenzoic acid chloride with ethyl-3-(pyridine-2-ylamino)propanoate by catalytic hydrogenation of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate in presence of a tertiary amine.

The use of organic bases like tertiary amine such as Triethyl amine, trimethyl amine, and disopropylethyl amine and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) for reduction of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and use of an autoclave leads to high production cost.

WO2012004397 (Segade et al, 2011) describes the process for preparing Dabigatran etexilate or its salt by catalytic hydrogenation of compound of formula (VII) in the presence of an inorganic base and within a solvent to obtain ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate. The compound of formula (VII) is obtained from its HBr salt. The disadvantages of this process are the use of an autoclave and special equipments such as Halar coated centrifuge and glass line reactor used for preparation of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester HBr salt, which increases the production cost in commercial scale.

The inventors have achieved a cost-effective, simple and improved alternate process for preparing ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate, an intermediate of high quality, used in the process for preparing Dabigatran.

OBJECT OF THE INVENTION

One object of the present invention is to provide alternate process for preparing ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate, an intermediate used in the process for preparing Dabigatran.

Another object of the present invention is to provide a cost effective process for preparing ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate of high quality.

Another object of the present invention is to provide an efficient process for preparing the diamine intermediate of Dabigatran by using commercially easily available compounds.

Yet another object of the present invention is to provide industrially feasible and environmental friendly process without the use of hazardous chemical reagents.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of compound of formula (I) comprising reduction of compound of formula (V) in polar solvent in presence of reducing agents such as Zinc dust in aq ammonium chloride at a temperature range of 40-80 °C, preferably 60-65 °C.
According to another aspect, the present invention provides an improved process for preparing compound of formula (I) comprising a) condensing compound of formula (II) in polar solvent with compound of formula (III)
in presence of tertiary amine, organic acid, such as oxalic acid at room temperature to give compound of formula (IV);
b) hydrolysis of compound of formula (IV) in an organic solvent in presence of a base to give compound of formula (V) and
c) reduction of compound of formula (V) in polar solvent in presence of reducing agents such as Zinc dust in aq ammonium chloride at a temperature range of 40-80 °C, preferably 60-65 °C to give compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present patent application relates to an improved process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate, compound of formula (I), an intermediate used in the process for preparing Dabigatran.

An embodiment of the present invention, provides an alternate process for preparing ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate, compound of formula (I)

In an embodiment of the present invention, provides a process for preparing 4-(methylamino)-3-nitrobenzoyl chloride hydrochloride, compound of formula (II) by reacting 4-methylamino-3-nitrobenzoic acid with halogenating agent in an organic solvent. The halogenating agent could be selected from thionyl chloride, phosphorus trichloride and the like, preferably thionyl chloride. The organic solvent can be selected from organic solvent such as toluene in presence of a catalyst such as Dimethylformamide.

Another embodiment of the present invention, provides a process for preparing compound of formula (IV) by condensing compound of formula (II) in polar solvent with compound of formula (III) in presence of tertiary amine, followed by addition of organic acid, such as oxalic acid at room temperature. The polar solvent can be selected from dichloromethane, ethyl acetate and the like, preferably ethyl acetate. The tertiary amine can be selected from triethylamine, trimethylamine, preferably triethylamine.

In yet another embodiment, the present invention provides a process for the preparation of compound of formula (V) by hydrolysis of compound of formula (IV) in organic solvents and in presence of a base. The polar solvents can be selected from ethyl acetate, dichloromethane, water and the like, preferably ethyl acetate and water. The base can be selected from alkali metal salts, such as alkali metal carbonates of potassium carbonate, sodium carbonate, preferably sodium carbonate.

In another embodiment, the present invention provides a process for the preparation of compound of formula (I) by reduction of compound of formula (V) in polar solvent in presence of reducing agents such as Zinc dust in aq ammonium chloride at a temperature range of 40-80 °C, preferably 60-65 °C and crystallized the compound of formula (I) from an organic solvent. The polar solvent can be selected from ethyl acetate, dichloromethane, Acetonitrile, methanol, tetrahydrofuran, preferably ethyl acetate. The organic solvent used for crystallization can be selected from Isopropanol, toluene, preferably toluene or IPA.

The process for the preparation of compound of formula (I) can be illustrated in the following scheme:

Advantages of the present invention:
1) It is simple and operation friendly that does not require special equipments like high pressure autoclave.
2) Avoids use of costly catalysts like Palladium on charcoal for reduction and relies on easily available zinc metal that makes the process cost effective.
3) The preparation of oxalate salt of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester, its conversion to free base, followed by reduction with Zinc dust in Aq ammonium chloride gives the desired intermediate of ICH quality.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of 4-Methylamino-3-nitro-benzoyl chloride hydrochloride To toluene (400 ml) and Dimethyl formamide (10 ml), 4-Methylamino-3-nitro-benzoic acid (100 g, 0.509 moles) was added, followed by slow addition of thionyl chloride (100 g, 0.84 moles) at ambient temperature. After addition, the reaction temperature was raised to 50-55°C and maintained till completion of the reaction as checked by TLC. The reaction mass was cooled to ambient temperature, the solid obtained was filtered, washed with toluene (100 ml) and dried to get title compound [140 g, (wet)].

Example 2: Preparation of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester oxalate 4-Methylamino-3-nitro-benzoyl chloride hydrochloride (100 g, 0.4 moles) was added to ethyl acetate (300 ml) at ambient temperature and cooled to 0-5°C. To this reaction mixture, triethylamine (120 ml, 1.64 moles) and 3-(Pyridin-2-ylamino)-propionic acid ethyl ester (100 g ,0.51 moles) were added at the same temperature, the temperature was raised to 25-30°C and maintained till completion of reaction as checked by TLC. Purified water (300 ml) was added to the reaction mixture, stirred and the layers were separated. The solvent was evaporated under reduced pressure below 55°C. The reaction mass was cooled to ambient temperature, methanol (300 ml) was added to it and stirred till a clear solution was formed. To this clear solution, oxalic acid (50 g, 0.55 moles) was added of at ambient temperature. Purified water (300 ml) was added to the reaction mixture, stirred for 60 min, filtered the solid obtained, washed with purified water and dried the solid in vacuum oven at 50-55°C to obtain title compound (150 g,81%)

Example 3: Preparation of 3-[(4-Methylamino-3-nitro-benzoyI)-pyridin-2-yl-amino]-propionic acid ethyl ester (Free base Solid)
To a suspension of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester Oxalate salt (150 g, 0.32 moles), water (400 ml) and ethyl acetate (600 ml) was added and the pH was adjusted to 9-10 by using 10% sodium carbonate solution at ambient temperature. The layers were separated and the solvent was evaporated completely under reduced pressure below 60°C. Isopropanol (150 ml) was added to the reaction mixture, cooled to ambient temperature, stirred the reaction mixture for 1 h at same temperature and filtered the solid obtained to give title compound (100 g,83%).

Example 4: Preparation of 3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
To a solution of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester free base (100 g,0.268 moles) and ethyl acetate (700 ml), Zinc dust (100 g) was added at 25-30°C. The suspension obtained was heated to 60-65°C, -30% of aqueous ammonium chloride solution (430 ml) was slowly added to the reaction mixture at the same temperature in 60-90 min. The reaction mixture was stirred for 2-3 hours at 60-65°C. The completion of the reaction was checked by TLC. The reaction mixture was cooled to 25-30°C; purified water (400 ml) was added to it and basified to pH 9-10 with aqueous ammonia solution. The organic layer was separated and distilled out under reduced pressure completely. Toluene (200 ml) was added to the residue and the reaction mixture was heated to 65-70°C to get a clear solution. The clear solution was cooled to 20-30°C and stirred for 30 min. The solid obtained was filtered, washed with toluene (25 ml) and dried under reduced pressure at 50-55°C to obtain the title compound (83 g, 95%).

Example 5: Preparation of 3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
To a solution of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester free base (100 g,0.268 moles) and methanol (1200 ml), Zinc dust (100 g) was added at 25-30°C. The suspension was heated to 60-65°C and -30% of aqueous ammonium chloride solution (430 ml) was slowly added to the reaction mixture at same temperature in 60-90 min and stirred for 2-3 hours at 60-65°C. The completion of the reaction was checked by TLC. The reaction mixture was cooled to 25-30°C, purified water (800 ml) was added to reaction mixture and basified to pH 9-10 with aqueous ammonia solution. The solid obtained was filtered, washed with water (500 ml) and isopropyl alcohol (200 ml) was added to reaction mixture and heated to 65-70°C to get a clear solution. The clear solution was cooled to 0-5°C and stirred for 30 min.

The solid obtained was filtered, washed with isopropyl alcohol (25 ml) and dried under reduced pressure at 50-55°C to obtain the title compound (81 g, 94%).

Example 6: Preparation of 3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
To a solution of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester free base (50 g,0.134 moles) and dichloromethane (1200 ml),Zinc dust (50 g) was added at 25-30°C. The suspension was heated to 40-45°C and -30% of aqueous ammonium chloride solution (215 ml) was slowly added to the reaction mixture at the same temperature in 60-90 min and stirred for 8-10 hours at 60-65°C. The completion of the reaction was checked by TLC. The reaction mixture was cooled to 25-30°C, purified water (300 ml) was added to it and basified to pH 9-10 with aqueous ammonia solution. The organic layer was separated and distilled out under reduced pressure completely. Toluene (100 ml) was added to the solid obtained and the reaction mixture was heated to 65-70°C to get a clear solution. The clear solution was cooled to 20-30°C, stirred for 30 min, filtered the obtained solid and washed with toluene (15 ml). The solid was dried under reduced pressure at 50-55°C to obtain the title compound (40 g, 93%).

Example 7: Preparation of 3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
To a solution of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester free base (75 g, 0.201 moles) and Acetonitrile (1000 ml), Zinc dust (75 g) was added at 25-30°C. The suspension was heated to 60-65°C and -30% of aqueous ammonium chloride solution (430 ml) was slowly added to the reaction mixture at same temperature in 60-90 min and stirred for 2-3 hours at 60-65°C. The completion of the reaction was checked by TLC. The reaction mixture was cooled to 25-30°C, purified water (800 ml) was added to it and basified to pH 9-10 with aqueous ammonia solution. The solid obtained was filtered and washed with water (500 ml). Toluene (150 ml) was added to the solid obtained and heated to 65-70°C to get a clear solution. The clear solution was cooled to 20-30°C, stirred for 30 min, the solid obtained was filtered, washed with toluene (25 ml) and dried under reduced pressure at 50-55°C to obtain the title compound (60 g,93%).

Example 8: Preparation of 3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester.
To a solution of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester free base (30 g,0.080 moles) and Tetrahydrofuran (200 ml), Zinc dust (30 g) was slowly added at 25-30°C. The suspension was heated to 60-65°C and -30% of aqueous ammonium chloride solution (430 ml) was slowly added to the reaction mixture at same temperature in 60-90 min and stirred for 2-3 hours at 50-55°C. The completion of the reaction was checked by TLC. The reaction mixture was cooled to 25-30°C; purified water (150 ml) was added to it and basified to pH 9-10 with aqueous ammonia solution. The solid obtained was filtered and washed water (500 ml). Isopropyl alcohol (60 ml) was added to solid and the reaction mixture was heated to 65-70°C to get a clear solution. The clear solution was cooled to 0-5 °C and stirred for 30 min. The solid obtained was filtered, washed with Isopropyl alcohol (25 ml) and dried under reduced pressure at 50-55°C to obtain the title compound (24 g, 93%).

Example 9: Preparation of 3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester oxalic acid salt.
To a solution of oxalic acid (20 g,0.212 moles) and water (200 ml), 3-[(3-Amino-4-methylamino-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester (100 g,0.305 moles) was added at 25-30°C. The resultant reaction mixture was stirred for 30 min and cooled to 15-20°C. The slurry obtained was stirred for 30 min at to 15-20°C and filtered, washed with water (25 ml) and dried under reduced pressure to obtain the title compound (100 g).

We claim:

1. An improved process for the preparation of compound of formula (I) comprising reduction of compound of formula (V)
in polar solvent in presence of reducing agents such as Zinc dust in aq ammonium chloride at a temperature range of 60-80 °C, preferably 60-65 °C.

2. The process according to claim 1), wherein the polar solvent is selected from ethyl acetate, dichloromethane, Acetonitrile, methanol, tetrahydrofuran, preferably ethyl acetate.

3. An improved process for preparing compound of formula (I) comprising a) condensing compound of formula (II)
in polar solvent with compound of formula (III)
in presence of tertiary amine, organic acid, such as oxalic acid at room temperature to give compound of formula (IV);
b) hydrolysis of compound of formula (IV) in an organic solvent in presence of a base to give compound of formula (V) and
c) reduction of compound of formula (V) in polar solvent in presence of reducing agents such as Zinc dust in aq ammonium chloride at a temperature range of 40-80 °C, preferably 60-65 °C to give compound of formula (I).

4. The process according to claim 3a), wherein the polar solvent can be selected from dichloromethane, ethyl acetate and the like, preferably ethyl acetate.

5. The process according to claim 3a), wherein the tertiary amine can be selected from triethylamine, trim ethylamine, preferably triethylamine.

6. The process according to claim 3b), wherein the organic solvents can be selected from ethyl acetate, dichloromethane, water and the like, preferably ethyl acetate and water.

7. The process according to claim 3b), wherein the base can be selected from alkali metal carbonates such as potassium carbonate, sodium carbonate, preferably sodium carbonate.

8. The process according to claim 3c), wherein the polar solvent is selected from ethyl acetate, dichloromethane, Acetonitrile, methanol, tetra hydro furan, preferably ethyl acetate.

9. An improved process according to any of the preceding claims substantially as herein described with reference to examples.