FIELD OF THE INVENTION:
The present invention relates to improved, safe and industrially applicable process for preparing Dabigatran intermediates.
BACKGROUND OF THE INVENTION:
Dabigatran, chemically known as 3-[[2-[[(4-carbamimid°y|Pneny|)amino]methyl]-K.
methyl-benzoimidazole-S-carbony^-pyridin^-yl-aminoJpr'opa110'0 acid (Formula-1) and
Dabigatran Etexilate Mesylate, chemically known as N-[[2-[[[4-
[[[(hexyloxy)carbonyl]amino]iminomethyl] ppenyl]amino]methyl]-l-methyl-lH-
benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, mrthanesulfonate (Formula-2).

Dabigatran, an anticoagulant, is a direct thrombin inhibits1" and usefuI for the prophylaxis or treatment of venous and arterial thrombotic diseases s^ch & deeP !e§ vein thrombosis, reocclusion after a bypass operation or angioplasty. occl^s'on m peripheral arterial disease, pulmonary embolism, disseminated intravascular coagul^tlon> coronary thrombosis, stroke, and the occlusion of a shunt or stent. It is given orally in the form of prodrug Dabigatran etexilate and markted by Boehringer Ingelheim under the f rand name PRADAXA .
Dabigatran and dabigatran etexilate were first disclosed ir* Patent application WO 98/37075. US 6087380 (herein after US'380) discloses the process for lhe preparation of Dabigatran from ethyl 3-(3-amino-4-(methytamino)-N-(pyridin-2-yl]benzamido)ProPanoate- Moreover the process for the preparation of ethyl 3-(3-amin°-4-(metMarnino)-N-(pyridin-2-yl)benzamido)propanoate from 4-methy!amino-3-nitro-r;enzoic acid chloride and N-(2-ethoxy-carbonylethyO-aniline also disclosed in US'380 . Yhe preparation of compound 3-[(4--MethviamiDO-J-_nitrorbenzovl)-Dvridin-2-vl-aminol-Dropionic _ acid ethyl ester requires chromatographic purification which is not convenient to bC carried out at an industrial level.

J. Med. Chem. 2002, 45, 1757-1766 describes process for preparation of Dabigatran and Dabigatran etexilate as well as intermediate, ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate from 4-methylamino-3-nitro-benzoic acid.
WO2009111997 discloses a method for the manufacture of Dabigatran as well as intermediate ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate, which comprising reaction of 4-ethylamino-3-nitrobenzoic acid chloride with ethyl-3-(pyridine-2-ylamino)propanoate which converted to the hydrochloride and hydrogenation is carried out with sodium dithionite.
This process shows some drawbacks. 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. Moreover the use of sodium dithionate leads to liberation of sulphur dioxide gas and is hazardous. Also the reduced product obtained is a thick oily residue, which is difficult to handle on commercial scale.
WO2012004397 describes the process for preparing Dabigatran etexilate or its salt by catalytic hydrogenation of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester in presence of an inorganic base and within a solvent to obtain ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate which further reacts with hydrobromic * acid to obtain ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate HBr salt. The disadvantage of this process is use of hazardous chemicals like hydrobromic acid. Moreover special equipments such as Halar coated centrifuge and glass line reactor required for preparation of 3-[(4-Methylamino-3-nitro-benzoyl)-pyridin-2-yl-amino]-propionic acid ethyl ester HBr salt, which makes process tedious and costly at industrial scale.
Ethyl N-(3-amino-4-methylaminobenzoyl)-N-(2-pyridyl)-3-aminopropionate of
FormuIa-3 is a key intermediate in the preparation of dabigatran and dabigatran etexilate.

Thus it is required to have improved process which avoids the use of hazardous chemicals, multiple isolation steps and column chromatographic purifications.
The present invention involves easy work up methods, simple isolation process for preparing Ethyl N-(3-amino-4-methylaminobenzoyl)-N-(2-pyridyl)-3-aminopropionate.
SUMMARY OF THE INVENTION:
The present invention relates to simple, safe and advantageous process for preparing ethyl-3-(3-amino-4-(mcthylamino)-N-(pyridinc-2-yl)benzamido)propionate of Formula-3

One embodiment of the present invention provides a process for preparing ethyl 3-(pyridine-2-yIamino)propanoate comprising the steps of;
(a) Reacting 2-Amino Pyridine with Ethyl Acrylate in presence of organic acid at temperature 80-95 °C
(b) Isolating ethyl 3-(pyridine-2-ylamino)propanoate
(c) Purifying ethyl 3-(pyridine-2-ylamino)propanoafe
One embodiment of the present invention provides a process for preparing 4-(methvlamino)-3-nitrobenzoicacid of Formula-9 comprising the steps of;
(a) Reacting 3-Nitro-4-chloro benzoic acid with Mono methylamine
(b) Isolating 4-(methyIamino)-3-nitrobenzoicacid
One embodiment of the present invention provides a process for preparing ethyl 3-(4-
(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate of Formula-U ^
comprising the steps of;
(a) Reacting 4-(methylamino)-3-nitrobenzoicacid with halogenating agent in presence of solvent to get 4-(methylamino)-3-nitrobenzoyl chloride of Formula-10 ■ (b) CoRdensjng formula-10 ..with eth^l^3-(pxri,^ine-2-yl_arnjno)propanqate in presence of solvent and base

(c) Isolating ethyl 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate One another embodiment of the present invention provides a process for preparing ethyl-3-(3-amino-4-(methylamino)-N-(pyridm-2-yl)benzamido)propionate of Formula-3
comprising the steps of;
(a) Hydrogenating 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate in presence of hydrogenation catalyst, solvent and base
(b) Isolating ethyl-3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propionate
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to improved, safe, economical and industrially applicable process for the preparation of ethyI-3-(3-amino-4-(methylamino)-N-(pyridine-2-yl)benzamido)propionate of Formula-3

One aspect of the present invention provides a process for preparing ethyl 3-(pyridine-2-y!amino)propanoate comprising the steps of;
(a) Reacting 2-Amino Pyridine with Ethyl Acrylate in presence of organic acid at temperature 80-95 °C
(b) Isolating ethyl 3-(pyridine-2-ylamino)propanoate
(c) Purifying ethyl 3-(pyridine-2-y!amino)propanoate
The process for preparation of ethyl 3-(pyridine-2-ylamino)propanoate of Formula-6
given in the below reaction scheme-1

The Organic acid for step (a) is selected from the group consisting of acetic acid, Succinic acid, Oxalic acid.
The solvents use for isolation and purification, step (b) and step (c) respectively, are non-polar solvents and selected from the group consisting of Hexane, Dichloromethane, Cyclohexane, and Toluene.
One aspect of the present invention provides a process for preparing 4-(methylamino)-3-nitrobenzoicacid of Formula-9 comprising the steps of;
(a) Reacting 3-Nitro-4-chloro benzoic acid with Mono methylamine
(b) Isolating 4-(methyIamino)-3-nitrobenzoicacid
The process for preparation of 4-(methylamino)-3-nitrobenzoicacid given in the below reaction scheme-2

Prior art WO2013150545 process describes the process for preparing 4-(methylamino)-3-nitrobenzoicacid in autoclave. However, we have carried out the above said procedure without using autoclave with higher purity and yield. Hence, it reduced the cost for product at industrial scale.
One another aspect of the present invention provides a process for preparing ethyl 3-(4-
(methylamino)-3-nitro-N-(pyridine-2-yI)benzamido)propanoate of Formula-11
comprising the steps of;
(a) Reacting 4-(methylamino)-3-nitrobenzoicacid with halogenating agent in presence of solvent to get 4-(methylamino)-3-nitrobenzoyl chloride of Formula-10
(b) Condensing formula-10 with ethyl 3-(pyridine-2-ylamino)propanoate in presence of solvent and base
(c) Isolating ethyl 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate
Tljf . process for preparation of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridine-2-
yl)benzamido)propanoare given in theBeiowreactien'-scnefme-l


The halogenating agent for step(a) is selected from the group consisting of thionyt chloride,
phosphorous trichloride, phosphorous pentachloride, phosphorus oxychloride.
The solvent for step (a) is Polar aprotic solvents selected from the group consisting of
Dirnethylformamide, Ethyl acetate, Acetonitrile, Dimethyl sulfoxide.
The solvent for condensation step (b) is Non-polar solvents selected from Toluene,
Dichloromethane, Hexane.
The base for condensation step (b) is tertiary amine selected from the group consisting of
triethylamine, trimethylamine.
One another aspect of the present invention provides a process for preparing ethyl-3-(3-amino-4-(mcthylamino)-i\-(pyridin-2-\ l)benzamido)propionate of Formula-3 comprising the steps of;
(a) Hydrogenating 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate
in presence of hydrogenation catalyst, solvent and base
(b) Isolating ethyl-3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propionate
The process for preparation of ethyl-3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propionate given in the below reaction scheme-4


The hydrogenating catalyst for step (a) is selected from the group consisting of Raney nickel,
Palladium, Platinum, Rhodium, Ruthenium, Activated carbon, Alumina, Calcium carbonate,
Barium sulphate or mixture thereof.
The temperature range for hydrogenation is 15°C to 60°C.
The solvent for step (a) is selected from polar protic solvents, polar aprotic solvents such
Ethyl acetate, Dimethylformamide,Acetonttrile. Dimethyl sulfoxide, methanol, isopropyl
alcohol, isopropyl acetate, water, or mixture thereof.
The base for step (a) is selected from the group consisting of dimethylamino pyridine (DMAP),
aq. Ammonia, triethylamine,trirnethylamine, diisopropylethylamine or mixture thereof.
The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Preparation of ethyl 3-(pyridine-2-ylamino)propanoate
Charged 150g Ethyl acrylate, lOOg 2-Aminopyridine, Aceticacid and slowly heated the Reaction mass to 80-95 °C. Maintained the Reaction Mass for 900min. Cooled the reaction mass and charged 105ml water in to the reaction mass. Adjusted pH to 1.0-4.0 with con. hydrochloric acid. Charged 150ml dichloromethane and stirred the reaction mass for 15min. Aqueous and organic layers separated. Charged 200ml n-Hexane and slowly heated the reaction mass to reflux. Slowly cooled the reaction mass and filtered the reaction mass. Washed the wet cake with Chilled 50ml n-Hexane and dried the material to get 51% above compound.
Evampit-2: Preparation of 4-(methylamino)-3-nitrobenzoicacid
Charged lOOg 3-Nitro-4-chloro benzoic acid, 300ml mono methyl amine and heated the mass to 70-95°C. Cooled reaction mass and adjusted pH to 3.0 to 5.0 with con. HCI. Filtered and ^vvashejd with Mteg Dnfe^igeT^t.&ilce to git S.bovi grid [IrdMctS.

Example-3: Preparation of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yI)benzamido)propanoate
Charged 1 lOg 4-(methylamino)-3-nitrobenzoicacid in 500ml toluene and cooled the reaction mass to 20-35°C. Slowly added 5ml dimethyl formamide, 83g thionyl chloride to the reaction mass and heated the mass to 55-80 °C to give acid chloride. Maintained the mass for 360-480mins. Cooled the reaction mass to 20-35°C. Slowly added 88g triethyl amine and stirred for 15 mins. Dissolved lOOg ethyl 3-(pyridine-2-ylamino)propanoate in 200ml toluene and slowly added to acid chloride solution. Stirred mass for 180-240mins. After reaction completion fdter unwanted Salt and wash the toluene layer with 5% sodium bicarbonate solution. Then toluene layer distill off under vacuum completely to get 92.5% above product.
ExampIe-4: Preparation of ethyl-3-(3-amino-4-(methy!amino)-N-(pyridine-2-yl)benzamido)propionate
Charged 500ml Ethyl acetate and 500ml Ethanol to 150g ethyl 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate in an autoclave to reduce the compound to amine in presence of 30g Raney nickel, Aqueous Ammonia, 2g dimethylaminopyridine(DMAP) and Hydrogen at 2-3 kg Pressure and Temperature 40-55°c for 6 hour to give ethyl -3-(3-amino-4-(meyhylamino)-N-(pyridine-2-yl)benzamido)propionate as Crude. Recrystallized crude in Ethyl Acetate to get pure compound. Purity: 97.58%

Claims:
1. A process for preparing ethyl-3-(3-amino-4-(meyhylamino)-N-(pyridine-2-
yl)benzamido)propionate of Formula-3 comprising
H2NYV^N^AO'"CH3
U
Formula-3
(a) Haloginating of 4-(methylamino)-3-nitrobenzoicacid with thionyt chloride in presence of Dimethylformamide to get 4-(methylamino)-3-nitrobenzoyI chloride of Formula-10
(b) Condensing formula-10 with ethyl 3-(pyridine-2-ylamino)propanoate in presence of toluene and triethylamine to get ethyl 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate
(c) Hydrogenating 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate in presence of hydrogenation catalyst, solvent and base

2. The process according to claim 1. wherein the solvent is polar protic solvents, polar aprotic solvents selected from the group consisting of Ethyl acetate. * Dimethylforrnamide,Acetonitrile, Dimethyl sulfoxide, methanol, isopropyl alcohol, isopropyl acetate, water, or mixture thereof.
3. The process according to claim I, wherein the base is selected from the group consisting of dimethylamino pyridine (DMAP), aq. Ammonia, triethylamine,trimethylamine, diisopropylethylamine or mixture thereof.
4. The process according to claim 1. wherein the hydrogentation catalyst is selected from the group consisting of Raney nickel, Palladium, Platinum, Rhodium, Ruthenium, Activated carbon, Alumina, Calcium carbonate, Barium sulphate or mixture thereof.
5. An improved process for preparing ethyl-3-(3-amino-4-(meyhylamino)-N-(pyridine-2-yl)benzamido)propionate of Formula-3 comprising

(c) Hydrogenating 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl)benzamido)propanoate with Raney nickel in ethanol, in presence of dimethylamino pyridine and ethyl acetate
(d) Isolating ethyl-3-(3-amino-4-(meyhylamino)-N-(pyridine-2-yi)benzamido)propionate