FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"PROCESS FOR THE PREPARATION OF FLECAINIDE
ACETATE"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Flecainide acetate which involves intermediate (2,5-diethoxyphenyl)-imidazol-l-yl-methanone by treating 2,5-bis(2,2,2-trifluoroethoxy) benzoic acid with l,1'-Carbonyldiimidazole, isolating N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)ben2amide as its hydrochloride salt.
BACKGROUND OF THE INVENTION
Flecainide acetate, chemically known as N-(2-piperidinylmethyl)-2,5-bis(2,2,2-rrifluoroethoxy)benzamide acetate and represented by Formula I is an antiarrhythmic agent used for the prevention of paroxysmal supraventricular tachycardias (PSVT), including atrioventricular nodal re-entrant tachycardia, atrioventricular re-entrant tachycardia and other supraventricular tachycardias of unspecified mechanism associated with disabling symptoms; paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms and documented ventricular arrhythmias, such as sustained ventricular tachycardia (sustained VT), that are presumed to be life-threatening by the physician.


US 3,900,481 discloses a process for preparation of Flecainide acetate comprising reaction of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid derivatives with 2-aminomethylpyridine to obtain N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy) benzamide followed by reduction of the resulting N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide. The product was found to have several impurities due to degradation of the product during the prolonged reaction. Additional purification steps rendered the overall process lengthy and less cost-effective.
GB 2045760 discloses preparation of Flecainide which involves reaction of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid derivatives having trichloromethyl as the leaving group with 2-aminomethylpyridine to obtain N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide which on further reduction of N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide gave the product. This process leads to formation of chloroform as by product which is dangerous for the environment on an industrial scale as it is known to depresses the central nervous system.
Organic Process Research & Development 2007, 11, 1065-106S discloses preparation of a Flecainide intermediate, N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy) benzamide by treating 2,5-bis(2,2,2-rrifluoroethoxy)benzoic acid with 2-aminomethylpyridine in presence of boric acid in toluene.
Similarly, various other processes for the preparation of Flecainide and its pharmaceutically acceptable salts have also been disclosed in US 4,675,448, US 6,458,957, US 6,288,271, US 6,599,922, US 6,849,762, US 20040220409 Al and US 20050059825 Al. But these processes are either silent about purity or yield and also have drawbacks like poor selectivity of reaction conditions, reagent etc, which decrease the yield and purity.
Therefore, there is a need to develop an efficient process for the preparation of Flecainide acetate (I) which is highly selective and cost effective on commercial scale. The present inventors while trying to develop an efficient commercially viable process found that by utilizing l,l'-Carbonyldiimidazole (CDI) and by proceeding through the

hydrochloride salt of N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide, it was possible to improve the yield of Flecainide acetate considerably and was able to provide the final product with desired purity. Thus reaction of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid with l,1'-Carbonyldiimidazole (CDI) to obtain (2,5-diethoxyphenyl)-imidazol-l-yl-methanone followed by coupling with 2-aminomethylpyridine in presence of base to obtain N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide, further treatment with hydrochloric acid to give N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide hydrochloride salt followed by reduction with catalyst gave Flecainide which on treatment with acetic acid gave Flecainide acetate (I) in good yield and with desired purity. It was found that Flecainide acetate (I) was found to have an improved impurity profile and purity without loss in yield even if N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide was isolated as its hydrochloride salt. The preparation of N-(2-pyridinyhnethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide hydrochloride salt and its use for subsequent hydrogenation step helped in removing unwanted impurities which invariably used to hamper the hydrogenation reaction. Thus the reaction rate of the hydrogenation reaction was enhanced and provided highly pure Flecainide acetate.
Therefore, the inventor's utilization of l,1'-CarbonyIdiimidazole (CDI) as coupling
reagent and preparation of N-(2-pyridinylmethyl)-2,5-bis(2,2,2-
trifluoroethoxy)benzamide hydrochloride salt renders the process cost effective and provides the final product of desired purity on an industrial scale.
OBJECT OF THE INVENTION
It is therefore an object of the present invention to provide a process for the preparation of Flecainide acetate (I) by utilizing l,l'-Carbonyldiimidazole for preparation of (2,5-diethoxyphenyl)-imidazol-1 -yl-methanone.

Another object of the present invention is to prepare N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide hydrochloride salt and utilizing it to provide Flecainide acetate (I) of desired purity.
SUMMARY OF THE INVENTION
An aspect of the invention relates to a process for the preparation of Flecainide acetate (I) comprising reaction of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid with 1,1'-carbonyldiimidazole (CDI) in an organic solvent to give (2,5-diethoxy-phenyl)-imidazol-1-yl-methanone, which on coupling with 2-aminomethylpyridine in presence of a base and an organic solvent gave N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide, further treatment with hydrochloric acid gave N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide HC1 salt, which on hydrogenation in presence of a catalyst in an organic solvent gave Flecainide, further treatment with acetic acid to give Flecainide acetate (I) of desired purity.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides a process for the preparation of Flecainide acetate (I) comprising;
i) reaction of 2,5-bis-(2,2,2-trifluoroethoxy)benzoic acid with lJ'-Carbonyl
diimidazole (CDI) in an organic solvent to give (2,5-diethoxy-phenyl)-
imidazol-1-yl-methanone, ii) coupling (2,5-Diethoxy-phenyl)-imidazol-l-yl-methanone with 2-
aminomethylpyridine in presence of base and in same organic solvent to give
N-(2"pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide, iii) preparing hydrochloride salt of N-(2-pyridinylmethyl)-2,5-bis(2,2,2-
trifluoroethoxy) benzamide in an organic solvent, iv) reduction of hydrochloride salt of N-(2-pyridinylmethyl)-2,5-bis-(2,2,2-
trifluoroethoxy) benzamide in presence of a catalyst and an organic solvent
gave Flecainide,

v) further treatment with acetic acid in an organic solvent gave Flecainide acetate (I) of desired purity.
In another embodiment, the present invention provides a process for the preparation of Flecainide acetate (I) comprising treatment of N-(2-pyridinylmethyl)-2s5-bis(2,2,2-trifluoroethoxy)benzamide with hydrochloric acid in an organic solvent to give N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide HC1 salt and further hydrogenation in presence of a catalyst and in an organic solvent to give Flecainide which on treatment with acetic acid gave Flecainide acetate (I) of desired purity.
The process of present invention for the preparation of Flecainide acetate (I) is represented schematically as follows,


2,5-Bis(2,2,2-trimoroethoxy)benzoic acid is activated by heating it with 1,1'-Carbonyldiimidazole (CDI) at a temperature between 45 to 60°C in an organic solvent to obtain (2,5-diethoxy-phenyl)-imidazol-l-yl-methanone. The organic solvent utilized includes but is not limited to the group comprising of halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, nitrile, ester and the like. The preferred organic solvent is ethyl acetate.
(2,5-Diethoxy-phenyl)-imidazol-l-yl-methanone was then coupled with 2-aminomethylpyridine in presence of a base at temperature between 50 and 65° C in an organic solvent to obtain N-(2-pyridinylmethyl)-2,5-bis-(2,2,2-trifluoroethoxy) benzamide. The organic solvent used includes but is not limited to the group comprising of halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, nitrile, ester and the like. The preferred organic solvent is ethyl acetate.
The term "base" used herein includes but is not limited to inorganic bases selected from the group comprising of alkali or alkaline metal hydroxide, carbonates, bicarbonates, alkoxide and the like and organic bases is selected from the group comprising of amines such as alkyl amine and the like. The preferred base is a carbonate like potassium carbonate.
N-(2-pyridinylmethyl)-2,5-bis-(2,2,2-triiluoroethoxy)benzamide thus obtained was converted to its hydrochloride by treating with hydrochloric acid in an organic solvent at reflux temperature to give N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy) benzamide hydrochloride. The organic solvent used includes but is not limited to the group comprising of alcohol, halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, ester, ketone and the like. The preferred organic solvents are ethyl acetate and isopropanol.
Reduction of N-(2-pyridinylmethyl)-2,5-bis-(2,2,2-trifluoroethoxy)benzamide hydrochloride salt with catalyst in an organic solvent under hydrogen pressure at a temperature in between 45 to 60 C gave Flecainide. The reduction was done at around

10 Kg/cm of hydrogenation of pressure. The organic solvent used includes but is not limited to the group comprising of alcohol, ester and the like. The preferred organic solvents are ethyl acetate and methanol.
The term "catalyst" used herein includes but is not limited to heterogeneous catalyst particularly palladium on carbon, platinum on carbon, platinum oxide, Raney Nickel and homogenous catalyst particularly Wilkinson's catalyst and the like. The preferred one is platinum on carbon particularly 6% platinum on carbon (50% wet). The reduction took place in 30 to 90 minutes with minimal formation of impurities during the reaction.
Flecainide was treated with acetic acid in an organic solvent at refluxing temperature to give Flecainide acetate. The organic solvent used for this step which includes but not limited to the group comprising of alcohol, halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, ester, ketone and the like. The preferred organic solvent is methanol.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
Following are the advantages of the present invention,
i) The present invention involves use of selective reagent 1,1'-
Carbonyldiimidazole (CDI) for coupling reaction which requires mild
reaction condition and leads to faster reaction rate and easy isolation of
product, ii) It has also been found that the prior art reduction process utilizing N-(2-
pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide as such or acetic

acid as solvent was associated with drawback of prolonged time duration for completion of reaction upto 24 hours. However, the present invention proceeds with reduction of N-(2-pyridmylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide hydrochloride which results in lower duration for reduction up to 30 to 90 minutes, which considerably minimizes degradation and provides highly pure Flecainide which is further converted to Flecanide acetate.
The invention is further explained with the help of following illustrative example, however, in no way this example should be construed as limiting the scope of the invention.
EXAMPLES:
EXAMPLE 1:- PREPRATION OF HYDROCHLORIDE SALT OF N-(2-PYRIDINYLMETHYL)-2,5-BIS(2,2,2-TRIFLUOROETHOXY)BENZAMIDE
Ethyl acetate (450ml) was added into a flask followed by N, N-Carbonyl diimidazole (45.86gms) with stirring under nitrogen. 2,5-Bis-(2,2,2-Trifluoroethoxy)benzoic acid (75gms) was added gradually to the mixture and stirred further at 50-55°C. The reaction mixture was maintained for 2.0 hours between 50-55°C under nitrogen atmosphere till completion of reaction to obtain (2,5-diethoxy-phenyl)-imidazol-I-yI-methanone. In another round bottom flask 2-aminomethyl pyridine was dissolved in 450 ml of ethyl acetate followed by addition of potassium carbonate (32.47gms). The reaction mixture was stirred at 5-15°C. (2,5-Diethoxy-phenyl)imidazol-l-yl-methanone in ethyl acetate obtained in the earlier step was added gradually at 5-15°C under nitrogen atmosphere. The temperature of reaction mixture was raised to 25- 30°C and stirred for 2hours at same temperature. After completion of reaction, 750 ml of DM water was added to the reaction mixture at 25-30°C and stirred at 55-60°C for 30 minutes. The organic layer was separated at 55-60°C and washed with water (750ml) at 55-60°C. The organic layer containing N-(2-pyridinylmethyl)-2,5-bis (2,2,2-

trifluoroethoxy)benzamide was added to concentrated Hydrochloric acid (27.3 gin) slowly at temperature 25-35°C. The temperature of the reaction mixture was raised and refluxed to 75-85°C for 2-3 hours. The reaction mixture was cooled slowly to 25-35 °C and stirred for 1 hour. The product separating out was filtered and washed with Ethyl acetate (50 ml). The solid was suck dried and dried below 60°C under vacuum to give hydrochloride salt of N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy) benzamide. Yield= 80 g Purity= 99.8%
EXAMPLE 2:- PREPRATION OF FLECAINIDE
Hydrochloride salt of N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide (50 gm) was charged in methanol (750 ml) into the autoclave reactor. To this solution, 3 gm of 10% platinum on carbon in 50% moisture was added and the autoclave reactor was flushed with nitrogen followed by hydrogen gas. A pressure of 10 Kg/cm2of hydrogen gas was applied in autoclave reactor and the reaction mixture was heated up to 50-65°C. After completion of reaction, the hydrogen gas was released and the reaction mixture was filtered and washed with methanol. The filtrate was heated at 45-60°C and treated with sodium carbonate solution at 25-30°C. The mixture was filtered and the filtrate was distilled to remove methanol below 45°C. DM water (250 ml) was added to residue and the mixture was stirred and filtered to obtain solid. The solid was combined with solid obtained in preceding filtration. Aqueous sodium carbonate solution (2%) was added to the solid and stirred at 40-45°C. The mixture was filtered and washed with water. The solid was dried under reduced pressure to obtain Flecainide. Yield = 40g Purity = 99.5%

EXAMPLE 3: PREPRATION OF FLECAINIDE ACETATE
Flecainide (25 gm) was dissolved in methanol (250 ml) at 55-65°C. To this solution, acetic acid (5.4 gm) was added drop wise at same temperature. The reaction mixture was refluxed for half an hour and charcoal (2.5 gm) was added. The reaction mixture was stirred at 65°C for 2 -3 hrs, filtered, washed with hot methanol and concentrated to obtain residue. Toluene (25 ml) was added and concentrated to give residue. Isopropyl alcohol (100 ml) was added and stirred for 1 hrs at 55-70°C. The reaction mixture was cooled to 25-3.0°C with stirring and filtered. Flecainide acetate was washed with cyclohexane (50 ml) and dried. Yield = 20 gm Purity = 99.8%

WE CLAIM:
1. A process for the preparation of Flecainide acetate (I) comprising reaction of 2,5-bis (2,2,2-trifluoroethoxy)benzoic acid with l,1'-carbonyldiimidazole (CDI) to give (2,5-diethoxy-phenyl)-imidazol-l-yl-methanone, which on coupling with 2-aminomethylpyridine in presence of a base and an organic solvent gave N-(2-pyriduiylmethy])-2,5-bis(2,2,2-rrifluoroethoxy)ben2amide, further treatment with hydrochloric acid in a second organic solvent gave N-(2-pyridinylmethyl)-2,5-bis(2,2,2-triftuoroethoxy)benzamide HC1 salt, which on hydrogenation in presence of a catalyst gave Flecainide, further treatment with acetic acid gave Flecainide acetate (I).
2. A process as claimed in claim 1, wherein the base used is selected from alkali or alkaline metal hydroxide, carbonates, bicarbonates, alkoxide, alkyl amine.
3. A process as claimed in claim 2, wherein the base is potassium carbonate.
4. The process as claimed in claim 1, wherein the organic solvent employed in the coupling reaction is selected from the group comprising of halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, nitrile and ester.
5. The process as claimed in claim 1, wherein the second organic solvent employed is selected from the group comprising of alcohol, halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, ketone and ester.
6: A process for the preparation of Flecainide acetate (I) comprising treatment of
N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide with
hydrochloric acid to give N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide HC1 salt, which on hydrogenation in the presence of a catalyst gave Flecainide, further treatment with acetic acid gave Flecainide acetate (I).

7. The process as claimed in claim 1 and 6, wherein the catalyst used is selected from palladium on carbon, platinum on carbon, platinum oxide, Raney Nickel and Wilkinson's catalyst.
8. The process as claimed in claim 7, wherein the catalyst is platinum on carbon.