FIELD OF THE INVENTION
The present invention relates an improved process for the preparation of Dabigatran intermediate.
The present invention relates to an improved process for the preparation of Dabigatran intermediate which is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Dabigatran Etexilate mesylate is a direct thrombin inhibitor which is sold under the brand name Pradaxa, the chemical name for Dabigatran Etexilate mesylate is p-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-l-methyl-lH-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The structural formula is:
The empirical formula is C34H41N7O5CH4O3S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base).
Dabigatran Etexilate mesylate is a yellow-white to yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol.
Dabigatran Etexilate and process for its preparation was first disclosed in WO
1998/037075. The disclosed process involves the reaction of ethyl 3-(3-amino-4-
(methylamino)-N-(pyridin-2-yl)benzamido)propanoate with 2-(4-cyanophenylamino) acetic
acid in the presence of N,N-carbonyldiimidazole in tetrahydrofuran to provide ethyl 3-(2-((4-
•E^^'opl^^ ' "r> Z.lmtdazote^5iEEE

carboxamido)propanoate, which is further converted into l-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride by reacting with ammonium carbonate in ethanol, followed by treating with Ethanolic hydrochloric acid. The obtained compound was reacted with n-hexyl chloroformate in presence of potassium carbonate in tetrahydrofiiran/water provides Dabigatran etexilate and further conversion into its mesylate salt was not disclosed. The purity of Dabigatran etexilate prepared as per the disclosed process is not satisfactory, and also the said process involves chromatographic purification which is expensive and difficult to implement in the large scale. Hence the said process is not suitable for commercial scale up.
WO '075 also discloses the synthesis of Dabigatran intermediate which is shown in the scheme given below: Schcme-I
£thyl-3-[[3-amino-4-(methylamino)benzoyl]-pyridin-2-ylamino]propanoate herein referred as compound of Formula I is a key intermediate in the preparation of Dabigatran. The process as enabled in WO '075 involves the use of palladium catalyst for the reduction of nitro intermediate. Catalytic hydrogenation using metal catalyst such as palladium, platinum, Raney nickel etc., requires pressurization equipment, high costs, the reaction time is long and it is necessary to control residual amount of heavy metals in the final Pharma.
Zentiva's WO 2009/111997 Al discloses process for the preparation of Ethyl-3-[[3-amino-4-(methylamino)benzoyl]-pyridin-2-ylamino]proparioate herein referred as compound of Formula I which involves the reduction of HC1 salt of nitro intermediate with Sodium dithionite in ethanol-water mixture as solvent. The process is shown in the scheme given below:

The inventors of the present invention have performed the same invention in the laboratory and the amine intermediate as obtained according to the above process is a dark red coloured viscous liquid. To purify the amine intermediate as obtained according to the above process requires more number of purification steps which is a disadvantage as it losses yield. It is essential that the key intermediate of API must be very pure to obtain pure Dabigatran. The above process is not suitable to prepare Dabigatran with required purity.
Biophore India Pharmaceuticals WO 2014/068587 A2 discloses the preparation of
Dabigatran , intermediate Ethyl-3-[[3-amino-4-(methylamino)benzoyl]-pyridin-2-
ylamino]propanoate which involves the reduction of nitro intermediate to amine intermediate in the presence of a combination of sodium dithionite and potassium carbonate as reducing agent, in presence of a combination of solvents dioxane and water. The product obtained as a brown viscous liquid which is further recrystallization from ethyl acetate.
The process as described in WO '587 is nothing but modification of Zentiva's WO 2009/111997 Al process. The process as enabled in WO '587 involves the use of ethyl acetate for further purification. The problem with the process disclosed in WO '587 is that the amine intermediate as obtained after the reduction is not soluble in'ethyl acetate. Hence, it may not be possible to perform the recrystallization in ethyl acetate due to the low solubility.
The present inventors have developed an improved process for the preparation of
Dabigatran intermediate Ethyl-3-[[3-amino-4-(methylamino)benzoyl]-pyridin-2-
ylaminojpropanoate which results in greater efficiency than the prior art processes with higher product purity by isolating in Water.

OBJECT OF THE INVENTION
The main object of the invention is to provide a simple, cost effective, improved and robust process for the preparation of Dabigatran intermediate Ethyl-3-[[3-amino-4-(methylamino)benzoyl]-pyridin-2-ylamino]propanoate compound of Formula-I yielding at a high yield with high purity without formation of undesired impurities.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparatio of Dabigatran intermediate Ethyl-3-[[3-amino-4-(methylamino)benzoyl]-pyridin-2 ylamino]propanoate compound of Formula-I
Formula-I which comprises reducing compound of Formula-II
rormum-ii in the presence of Iron powder and a Lewis acid.
In a preferred aspect, the present invention provides an improved process for the
^pepgrffli^n^ftem^ ——

which comprises reducing compound of Formula-II
rormula-11 in the presence of Iron powder and Calcium chloride.
In another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula I
which comprises reducing compound of Formula-II
in the presence of Iron powder and FeCh.

In yet another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula I
which comprises,
a. reducing compound of Formula-II
in the presence of Sodium dithionate in water alone as a solvent, b. isolating crystalline compound of Formula-I.
In yet another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula I
which comprises,
a. reducing compound of Formula-II

in the presence of Sodium dithionate in Water alone as a solvent,
b. heating the reaction mass to 60-65°C,
c. cooling the reaction mass of step-b,
d. Isolating pure crystalline compound of Formula-II directly from the step-c reaction mass.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Dabigatran intermediate Ethyl-3-[[3-amino-4-(methy1amino)benzoyl]-pyridin-2-ylaminojpropanoate compound of Formula-I
Formula-I The inventors of the present invention have developed a green chemistry approach for the preparation of Formula-I a key intermediate in the preparation of Dabigatran which involves the reduction of compound of Formula-II
Formula-II in the presence of Iron powder and a Lewis acid.
By adopting the above route the inventors of the present invention have successfully developed the compound of Formula-I with good yield and high purity, the cost of the reducing agents as used in the present invention such as Iron powder as well as Lewis acids are very low and commercially viable comparatively with palladium and Raney nickel as used in the prior art.

The "Lewis acid" used is selected from Calcium chloride (CaCl2), Calcium chloride dihydrate (CaCl2-2H20), Ferric chloride (FeCl3), Aluminium chloride (A1CI3), Aluminium bromide (AlBr3), Boron trifluroide (BF3), Boron trichloride (BC13), Tin(IV) chloride (SnCU), Magnesium chloride (MgCl2).
The reduction of compound of Formula-II preferably carried out in the presence of a solvent selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof.
According to the present invention the solvent used in the reduction of compound of Formula-II may also be used as a hydrogen source.
According to the present invention the reduction of compound of Formula-II may also
carried out in the presence of sodium dithionite in water alone as a solvent. The prior art
process as reported in Zentiva's WO 2009/111997 Al as well as Biophore India
Pharmaceuticals WO 2014/068587 A2 involves the reduction of compound of Formula-II in
the presence of sodium dithionite. The process enabled in WO '997 involves the use of !
ethanol - water mixture as a solvent and the obtained product is a viscous liquid with unwanted impurities.
WO'587 involves the use of dioxane and water as solvent and potassium carbonate as a base. The process as described in WO '587 is nothing but modification of Zentiva's WO 2009/111997 Al process. The process" as enabled in WO '587 involves the use of ethyl acetate for further purification. The problem with the process disclosed in WO '587 is that

Hence, it may not be possible to perform the recrystallization in ethyl acetate due to the high solubility.
To overcome the above issues the inventors of the present inventions have successfully developed the reduction of compound of Formula II using sodium dithionite in Water as a solvent, wherein the current process does not require any further purification of amine intermediate of compound of Formula-I and also the current process does not require the use of any bases as given in WO '587.
The present invention provides an improved process for the preparation of compound of Formula I
which comprises reducing compound of Formula-II
ruxiiiuia-ii
in the presence of Iron powder and Calcium chloride in a solvent selected from water, alcohols or their mixtures.
In a preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula I

which comprises reducing compound of Formula-II
in the presence of Iron powder and Calcium chloride in a mixture of water and methanol as a solvent.
In another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula I
which comprises reducing compound of Formula-II
Formula-II in the presence of Iron powder and FeCfe in a solvent selected from water, alcohols or their mixtures
In yet another preferred embodiment, the present invention provides an improved ■ process for the preparation of compound of Formula I

Formula-1 which comprises reducing compound of Formula-II
in the presence of Iron powder and FeCb in a mixture of water and methanol as a solvent.
In yet another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula I
which comprises,
a. reducing compound of Formula-II
i uiiuuia-u
in the presence of Sodium dithionate in water alone as a solvent,
b. heating the reaction mass to 60-65°C,
c. cooling the reaction mass of step-b,
d. isolating pure crystalline compound of Formula-I directly from the step-c reaction mass.
The compound of Formula-I as prepared according to the present invention is further converted to Dabigatran as per the process enabled in US-6,087,380.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
Examples: Example-1:
In a clean and dry round bottom flask 10 gm of compound of Formula-II, 50 ml of Methanol and Water mixture (1:1) was taken at room temperature and added 20gm of Iron powder followed by lOgm Calcium chloride under efficient stirring. Slowly heated the reaction mixture to 60-65°C for 3-4 hours and after completion reaction mass was cooled to room temperature and filtered over hyflo bed to remove excess of Metal salts. The filtered ML's was distilled under reduced pressure to remove Methanol and the residue obtained was diluted with 20mL Water and extracted with Ethyl acetate (3 X 25mL). The combined organic layer was washed with saturated brine solution and dried over anhydrous sodium sulfate. Removed the solvent and obtained crude was isolated in Water to afford 7.2 gm compound of Formula-I. HPLC: >99%
Example-2:
In a clean and dry round bottom flask 10 gm of compound of Formula-II, 50 ml of Methanol and Water mixture (1:1) was taken at room temperature and added 20gm of Iron powder followed by lOgm Ferric (III) chloride under efficient stirring. Slowly heated the reaction mixture to 60-65°C for 3-5 hours and after completion reaction mass was cooled to room temperature and filtered over hyflo bed to remove excess of iron (III) powder. The filtered ML's was distilled under reduced pressure to remove Methanol and the residue obtained was diluted with 20mL Water and extracted with Ethyl acetate (3 X 25mL). The combined organic layer was washed with saturated brine solution and dried over anhydrous sodium sulfate. Removed the solvent and obtained crude was isolated in Water to afford 7.0gm of compound of Formula-I. HPLC: >99%
Example-3:
propionate)-N-(pyridin-2-yl) benzamide, 50 ml of Methanol and Water mixture (1:1) was

taken at room temperature and added 20gm of Iron powder followed by lOgm Calcium chloride under efficient stirring. Slowly heated the reaction mixture to 60-65°C for 3-4 hours and after completion reaction mass was cooled to room temperature and filtered over hyflo bed to remove excess of Metal salts. The filtered ML's was distilled under reduced pressure to remove Methanol and the residue obtained was diluted with 20mL Water and extracted with Ethyl acetate (3 X 25mL). The combined organic layer was washed with saturated brine solution and dried over anhydrous sodium sulfate. Removed the solvent and obtained crude was isolated in Water to afford 7.2 gm compound of Formula-I. HPLC: >99%