DESC:FIELD OF INVENTION:
The present invention relates to a short and efficient process for the preparation of Etripamil or its salt thereof.

BACKGROUND OF THE INVENTION:
Etripamil which is chemically methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-methylamino]ethyl]benzoate of structural formula (I)

(I)

belongs to the class of organic compounds known as phenylbutylamines. Like other non-dihydropyridine calcium-channel blockers, Etripamil slows atrioventricular nodal conduction and prolongs atrioventricular nodal refractory periods by inhibiting calcium ion influx through the calcium slow channels in the atrioventricular node cells.

Arrhythmia, or abnormal heart rhythms, is caused by abnormal excitation and conduction to the heart. Atrial fibrillation is arrhythmia arising from abnormalities in the intrinsic pacemaker conductive potential of the heart. In atrial fibrillation, the electrical discharges are rapid and irregular, resulting in an irregular rhythm of heart contraction. In a normal heart, electrical discharges are generated in the sino-atrial node. In atrial fibrillation, electrical discharges are not generated exclusively in the sino-atrial node and come from other parts of the atria. These rapid and irregular discharges result in rapid and ineffectual atrial contractions that reduce the ability of the atria to supply blood to the ventricles.

The recurrent arrhythmia is designated as paroxysmal. Paroxysmal supraventricular tachycardia (PSVT) presents as episodes of regular and paroxysmal palpitations with sudden onset and termination. There are presently several therapeutic modalities to treat PSVT patients. The previously reported calcium channel blockers, such as verapamil and diltiazem, do not provide immediate relief from cardiac arrhythmia, stable angina, or migraine. Etripamil or its acid addition salt is known to exhibit very high solubility in aqueous solution.

US10010523 discloses the molecule and describes synthesis of Etripamil oxalate salt.

EP3283067B1 discloses an aqueous composition formulated for nasal administration comprising a pharmaceutically acceptable acetate or methanesulfonate salt of Etripamil.

EP2170050B1 discloses pharmaceutical composition of Etripamil to treat cardiovascular disorders.

US10117848B2 discloses an aqueous composition formulated for nasal administration comprising a pharmaceutically acceptable salt or free base of Etripamil. US’848 disclose the process for synthesis of methyl 3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate(compound I) comprising the step of preparing 5-Bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile comprising reacting (3,4-Dimethoxyphenyl)acetonitrile in THF with sodium bis(trimethylsilyl)amide (NaHMDS) and stirring at -30ºC followed by addition of 2-bromopropane or 1,3-dibromopropane. The crude product obtained was purified by flash chromatography to obtain 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile as an oil. The process further includes the step of preparation of methyl 3-(2-(methylamino)ethyl)benzoate (compound III) comprising refluxing methyl 3-bromomethylbenzoate in methanol with potassium cyanide followed by purification of the residue obtained by flash chromatography to obtain methyl 3-(cyanomethyl)benzoate. To the solution of the residue obtained was added sodium borohydride followed by addition of trifluoroacetic acid. The mixture was warmed and water was carefully added to the mixture (with gas evolution), extracted, washed to obtain methyl 3-(2-aminoethyl)benzoate which was used in the next step without purification. Alternately, methyl 3-(2-aminoethyl)benzoate was prepared by reacting methyl 3-(2-aminoethyl)benzoate in THF with BOC2O to give methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate which was then reacted with NaHMDS to give methyl 3-(2-(tert-butoxycarbonyl(methyl)amino) ethyl)benzoate. In an alternate process, to the solution of methyl 3-(2-(tert-butoxycarbonyl(methyl)amino) ethyl)benzoate in DCM was added trifluoroacetic acid (TFA), reaction was warmed, solvents were evaporated and the residue was partitioned and the aqueous layer was back-extracted with the solvent several times. The combined organics were dried and evaporated to a colorless oil. The compound (II) and the compound (III) were reacted to obtain compound (I) which was then converted to its acetate salt.

The process disclosed in US10117848B2 is cumbersome, lengthy and industrially not feasible.

Thus, there remains a need in the art to provide an efficient process for synthesis of Etripamil. This remains the object of the invention.

SUMMARY OF THE INVENTION
In accordance with the above, the present invention provides an efficient process for synthesis of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-methylamino]ethyl]benzoate, Etripamil or a salt thereof, of Formula (I)

(I)
comprising;
(i) Hydrolyzing (R)-1-phenylethan-1-amine (S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoate in acidic medium to obtain (S)-4-cyano-4 (3,4–dimethoxy phenyl)-5-methyl hexanoic acid;
(ii) Reacting (S)-4-cyano-4 (3,4–dimethoxy phenyl)-5-methyl hexanoic acid with methyl 3-(2-(methylamino)ethyl)benzoate in presence of base, coupling agent and an activating agent to obtain methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido)ethyl) benzoate;
(iii) Reducing methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido)ethyl)benzoate at a suitable temperature with a reducing agent in presence of Lewis acid catalyst to obtain methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl) amino)ethylbenzoate; and
(iv) Optionally converting to its pharmaceutically acceptable salt.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in its preferred and optional embodiments so that various aspects of the invention will be fully understood without limiting the scope of the invention.

In an embodiment, the present invention relates to a short and efficient process for synthesis of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-methylamino]ethyl]benzoate, Etripamil or a salt thereof, of Formula (I)

(I)
comprising;
(i) Hydrolyzing (R)-1-phenylethan-1-amine(S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoate in acidic medium to obtain (S)-4-cyano-4 (3,4 –dimethoxy phenyl)-5-methyl hexanoic acid;
(ii) Reacting (S)-4-cyano-4 (3,4–dimethoxy phenyl)-5-methyl hexanoic acid with methyl 3-(2-(methylamino)ethyl)benzoate in presence of base, coupling agent and an activating agent to obtain methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethyl hexanamido) ethyl) benzoate;
(iii) Reducing methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido)ethyl)benzoate at a suitable temperature with a reducing agent in presence of Lewis acid catalyst to obtain methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl) (methyl) amino) ethylbenzoate; and
(iv) Optionally converting to its pharmaceutically acceptable salt.

The process is depicted in Scheme 1 below:




In an embodiment, (R)-1-phenylethan-1-amine(S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoate is dissolved in a suitable solvent and the reaction mixture is acidified using suitable acid to obtain a base product.

In an embodiment, this product may be isolated or used for further reaction without isolation.

The suitable solvent used may be selected from but not limited to methyl acetate, ethyl acetate, tetrahydrofuran, t-butyl methyl ether, methanol, ethanol, isopropanol, t-butanol, isobutanol, acetone, water or mixture thereof.

The reaction may be carried out at room temperature.

The suitable acid is hydrochloric acid.

In another embodiment, the base product obtained is reacted with methyl 3-(2-(methylamino) ethyl) benzoate in presence of a suitable base, suitable coupling agent and suitable activating agent in a suitable solvent to get methyl(S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethyl hexanamido) ethyl)benzoate.

The suitable solvent used may be selected from but not limited to methyl acetate, ethyl acetate, dimethyl carbonate, methanol, ethanol, isopropanol, t-butanol, isobutanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, toluene, xylene, methylene dichloride (MDC), dimethyl sulfoxide, N-methyl pyrrolidone, water or mixture thereof.

Suitable base may be inorganic base or organic base.

Inorganic bases may be selected from but not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert. butoxide, potassium acetate, sodium acetate, cesium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, sodium methoxide, potassium methoxide, aq ammonia, alone or combination thereof.

Organic bases may be selected from but not limited to pyridine, dimethyl amine, triethyl amine, N,N-diisopropylethyl amine, N-methyl piperidine, 4-Dimethylaminopyridine (4-DMAP) alone or combination thereof.

Suitable coupling agent may be selected from but not limited to (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexa fluorophosphate also known as HATU, O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), dicyclohexylcarbodiimide (DCC), O-benzotriazole-N,N’,N’-tetramethyl uronium hexafluoro phosphate (HBTU), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCl), Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), Benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), Bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP), Diisopropylcarbodiimide (DIC), 4-(N,N-Dimethylamino)pyridine (DAMP) alone or combination thereof

Preferably, the activating agent may be selected from but not limited to 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 2-hydroxypyridine-N-oxide (HOPO), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1,1'-Carbonyldiimidazole, Disuccinimidyl carbonate, Oxyma and such like.

The reaction may be carried out at room temperature.

In another embodiment, methyl(S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethyl hexanamido) ethyl)benzoate is treated with suitable reducing agent in presence of Lewis acid catalyst in a suitable solvent and at suitable temperature to get Etripamil.

The suitable solvent used is selected from but not limited to methyl acetate, ethyl acetate, tetrahydrofuran (THF), t-butyl methyl ether, methanol, ethanol, isopropanol, t-butanol, isobutanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, toluene, xylene, dichloromethane, dimethyl sulfoxide, N-methyl pyrrolidone or mixture thereof.

Suitable reducing agent may be selected from but not limited to sodium borohydride, lithium aluminium hydride, sodium cyano borohydride, sodium triacetoxy borohydride, alone or combination thereof.

The Lewis acid catalyst is boron trifluoride diethyl etherate.

Suitable temperature at which the reduction reaction is carried out ranges from -20 to 20°C, preferably -10 to 10°C, more preferable -5 to 0°C.

In yet another embodiment, the reduced reaction mixture is then heated to 40 to 90°C, preferably 50 to 80°C, more preferably 65 to 70°C.

In another embodiment, the temperature of the reaction mass is then further lowered to 15 to 35°C, preferably 25 to 30°C.

The intermediates may be isolated or used directly for further reaction without isolation.

The intermediates as well as the final product may be isolated by the processes known in the art.

In an alternate embodiment, the Etripamil obtained may be further converted into its pharmaceutically acceptable salt as per the known processes in the art.

The solvent for the salt formation process comprises polar or non-polar, protic or aprotic solvent selected from the group consisting of C1-C5 alcohols; ethers such as THF, diethyl ether and such like; esters such as ethyl acetate; ketones such as acetone, methyl ethyl ketone and such like; aliphatic or aromatic hydrocarbons, halogenated hydrocarbons alone or mixtures thereof.

The pharmaceutically acceptable salts are prepared using the acids such as oxalic acid, hydrochloric acid and such like in suitable amounts.

In another embodiment, Etripamil or its pharmaceutically acceptable salt can then be further formulated as a single or in combination with other active agents, in a suitable dosage form together with pharmaceutically acceptable carrier, diluent, or excipients.

According to yet another aspect of the present invention there is provided use of Etripamil or its pharmaceutically acceptable salt, in the preparation of a medicament useful in treating paroxysmal supraventricular tachycardia (PSVT).

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Examples
Example 1: Synthesis of methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido)ethyl)benzoate
(R)-1-phenylethan-1-amine(S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoate (300g) and water were charged at 25-30ºC. The pH of the solution was adjusted adding 1:1 HCl and the reaction mixture was stirred for 1 hour. To the reaction mixture 900ml of methylene dichloride (MDC) was added and the mixture was stirred for 20 minutes. The layers were separated and the aqueous layer was extracted with 600ml of MDC. The combined layers were then washed with 500ml of water. The organic layer was distilled out under vacuum to obtain (S)-4-cyano-4 (3,4–dimethoxy phenyl)-5-methyl hexanoic acid as oil (weight: 210g).

To the oil obtained above 1 lit of MDC was charged and stirred for 10 minutes followed by addition of triethylamine (130 ml). The reaction mixture was stirred. EDC.HCl (165.7g) and HOBT (10.9 g) were added at room temperature followed by addition of methyl 3-(2-(methylamino) ethyl)benzoate (139.3g) at same temperature and stirred for 2.0 hours and TLC was checked. To the reaction mixture water was added and stirred, the aqueous layer extracted with MDC and separated. This was followed by addition of HCl solution to the organic layer, the mixture was stirred and the layers were separated. The organic layer was washed with water, stirred and again the layers were separated. This was followed by addition of 5% potassium carbonate solution. The reaction mixture was stirred and the layers were separated. The organic layer was distilled out to get methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethyl hexanamido) ethyl) benzoate.
Yield: 307 g.

Example 2: Synthesis of methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethylbenzoate oxalate.
Methyl(S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido) ethyl) benzoate obtained in example 1 (300 g) was charged followed by THF. The reaction mass was cooled to 0 to -5°C and NaBH4 (61 g) was added to it followed by stirring. This was followed by slow addition of boron trifluoride diethyl etherate (200 ml) and the reaction mass was further stirred at -5 to 0°C. To the reaction mass HCl solution was added slowly at 0°C followed by stirring. The reaction mass was then heated to a temperature of 65-70ºC. After completion of the reaction, the reaction mass was cooled to room temperature. THF solvent was distilled out under vacuum and the reaction mass was further cooled to room temperature. Ethyl acetate and water was added to reaction mass, then separated the layers. Aq. Layer extracted with Ethyl acetate. Combined Ethyl acetate layer washed with water, further Ethyl acetate layer washed with brine solution, then distilled out the organic layer under vacuum to obtain Etripamil base oil, (methyl(S)-3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5methylhexyl)(methyl) amino) ethyl)benzoate).

Yield of the oil: 260 g
Oxalate Formation

Ethyl acetate was charged (1.0L) into the above oil followed by Oxalic acid (65g) in acetone to the reaction mass at 25-30°C and heated to 50°C. The reaction mass was stirred for 30 minutes, the solid was filtered, washed with ethyl acetate and dried. The solid was dried under vacuum to obtain Etripamil oxalate salt (methyl 3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl) benzoate oxalate.

Yield (dry weight): 200 g.

Example 3: Synthesis of methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido) ethyl) benzoate
(R)-1-phenylethan-1-amine(S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoate (300g) and water were charged at 25-30ºC. The pH of the solution was adjusted by adding 1:1 HCl and the reaction mixture was stirred for 1 hour. To the reaction mixture, 900ml of methylene dichloride (MDC) was added and the mixture was stirred for 20 minutes. The layers were separated, and the aqueous layer was extracted with 600 ml of MDC. The combined layers were then washed with 500 ml of water. The organic layer was distilled out under vacuum to obtain (S)-4-cyano-4-(3,4–dimethoxy phenyl)-5-methyl hexanoic acid as oil (weight: 210g).

To the oil obtained above 2 lit of acetone was charged and stirred for 10 minutes followed by addition of triethylamine (130 ml). The reaction mixture was stirred. EDC.HCl (165.7g) and HOBT (10.9 g) were added at room temperature followed by addition of methyl 3-(2-(methylamino) ethyl) benzoate (139.3g) at the same temperature and stirred for 3 hours. Upon completion of reaction, water and ethyl acetate were added and stirred, the layers were separated. To the aqueous layer ethyl acetate was added followed by addition of HCl solution to the organic layer, the mixture was stirred, and the layers were separated. The organic layer was washed with water, stirred and again the layers were separated. This was followed by addition of 5% potassium carbonate solution. The reaction mixture was stirred, and the layers were separated. The organic layer was distilled out to get methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido) ethyl) benzoate.
Yield: 268 g.

Example 4: Synthesis of methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido) ethyl) benzoate
(R)-1-phenylethan-1-amine(S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoate (300g) and water were charged at 25-30ºC. The pH of the solution was adjusted by adding 1:1 HCl and the reaction mixture was stirred for 1 hour. To the reaction mixture 900 ml of methylene dichloride (MDC) was added and the mixture was stirred for 20 minutes. The layers were separated, and the aqueous layer was extracted with 600 ml of MDC. The combined layers were then washed with 500 ml of water. The organic layer was distilled out under vacuum to obtain (S)-4-cyano-4 (3,4–dimethoxy phenyl)-5-methyl hexanoic acid as oil (weight: 210g).
To the oil obtained above 2 lit of toluene was charged and stirred for 10 minutes followed by addition of triethylamine (130 ml). The reaction mixture was stirred. EDC.HCl (165.7g) and HOBT (10.9 g) were added at room temperature followed by addition of methyl 3-(2-(methylamino) ethyl) benzoate (139.3g) at same temperature and stirred for 3 hr. Upon completion of reaction, water was added to it and stirred and the layers were separated. Toluene layer was washed with 5% HCl solution, with 5% potassium carbonate solution followed by washing with 10 ml water. Separated toluene layer was distilled out completely at 50-55°C and dried under vacuum to get methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido) ethyl) benzoate.
Yield: 315 g

Example 5: Synthesis of methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido) ethyl) benzoate
(R)-1-phenylethan-1-amine(S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoate (300g) and water were charged at 25-30ºC. The pH of the solution was adjusted by adding 1:1 HCl and the reaction mixture was stirred for 1 hour. To the reaction mixture 900ml of methylene dichloride (MDC) was added and the mixture was stirred for 20 minutes. The layers were separated, and the aqueous layer was extracted with 600ml of MDC. The combined layers were then washed with 500 ml of water. The organic layer was distilled out under vacuum to obtain (S)-4-cyano-4 (3,4–dimethoxy phenyl)-5-methyl hexanoic acid as oil (weight: 210g).
To the oil obtained above 2 lit of Dimethyl Carbonate was charged and stirred for 10 minutes followed by addition of triethylamine (130 ml). The reaction mixture was stirred. EDC.HCl (165.7g) and HOBT (10.9 g) were added at room temperature followed by addition of methyl 3-(2-(methylamino) ethyl) benzoate (139.3g) at same temperature and stirred for 3 hours. Upon completion of reaction, water was added to it and the dimethyl carbonate layer was separated. The layer was washed with 5% HCl solution followed by water and the layers were separated. Further, organic layer was basified with 5% potassium carbonate and finally washed with water. Organic layer was distilled out completely at 50-55°C under vacuum to get methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido) ethyl) benzoate.
Yield: 312 g.

Example 6: Synthesis of methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethylbenzoate
300g Methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethyl hexanamido) ethyl) benzoate obtained in example 1 and 1500ml THF were charged into the RBF. The reaction mass was cooled and 162 ml BH3.DMS was charged in the reaction mass (RM) slowly with stirring for 30 minutes. Reaction was stirred at room temperature. Upon completion of reaction (RM monitor by TLC), the Reaction mass was cooled to room temperature and 1N HCl (aq.) was added to the reaction mass slowly. Then the reaction mass was heated to reflux for 4 hours, then cooled and distilled completely. The reaction mass was basified with liq. ammonia followed by addition of ethyl acetate and reaction mass was filtered through buchner funnel. The organic layer was separated and aqueous layer was washed with ethyl acetate. The combined the organic layers were distilled to yield Etripamil base (methyl (S)-3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5methyl hexyl) (methyl) amino) ethyl)benzoate).
Yield: 258 g

Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
,CLAIMS:1. A short and efficient process for synthesis of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-methylamino]ethyl]benzoate, Etripamil or a salt thereof, of Formula (I)
(I)
comprising;
(i) Hydrolyzing (R)-1-phenylethan-1-amine(S)-4-cyano-4-(3,4-dimethoxy phenyl)-5-methylhexanoate in acidic medium to obtain (S)-4-cyano-4 (3,4 –dimethoxy phenyl)-5-methyl hexanoic acid;

(ii) Reacting (S)-4-cyano-4 (3,4–dimethoxy phenyl)-5-methyl hexanoic acid with methyl 3-(2-(methylamino)ethyl)benzoate in presence of a base, a coupling agent and an activating agent to obtain methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethyl hexanamido) ethyl) benzoate;

(iii) Reducing methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-N,5-dimethylhexanamido)ethyl)benzoate at a suitable temperature with a reducing agent in presence of Lewis acid catalyst to obtain methyl (S)-3-(2-(4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexyl) (methyl) amino)ethylbenzoate; and

(iv) Optionally converting to its pharmaceutically acceptable salt.

2. The process as claimed in claim 1, wherein the base for step (ii) may be organic or inorganic base.

3. The process as claimed in claim 2, wherein the organic base is selected from but not limited to pyridine, dimethyl amine, triethyl amine, N,N-diisopropylethyl amine, N-methyl piperidine, 4-Dimethylaminopyridine (4-DMAP) alone or combination thereof

4. The process as claimed in claim 2, wherein the inorganic base is selected from but not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert. butoxide, potassium acetate, sodium acetate, cesium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, sodium methoxide, potassium methoxide, aq ammonia, alone or combination thereof.

5. The process as claimed in claim 1, wherein the coupling agent for step (ii) is selected from but not limited to (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), dicyclohexylcarbodiimide (DCC), O-benzotriazole-N,N’,N’-tetramethyl uronium hexafluoro phosphate (HBTU), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCl), Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), Benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), Bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP), Diisopropylcarbodiimide (DIC), 4-(N,N-Dimethylamino)pyridine (DAMP) alone or combination thereof.

6. The process as claimed in claim 5, wherein the coupling agent may be used with an activating agent such as 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 2-hydroxypyridine-N-oxide (HOPO), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1,1'-Carbonyldiimidazole, Disuccinimidyl carbonate, Oxyma and such like.

7. The process as claimed in claim 1, wherein the solvent for the process steps (i) to (iii) is selected from but not limited to methyl acetate, ethyl acetate, tetrahydrofuran, t-butyl methyl ether, methanol, ethanol, isopropanol, t-butanol, isobutanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, formic acid, acetic acid, acetonitrile, toluene, xylene, methylene dichloride, dimethyl sulfoxide, N-methyl pyrrolidone, water or mixture thereof.

8. The process as claimed in claim 1, wherein the process step (i) and (ii) may be carried out at room temperature.

9. The process as claimed in claim 1, wherein the reducing agent for step (iii) is selected from but not limited to sodium borohydride, lithium aluminium hydride, sodium cyano borohydride, sodium triacetoxy borohydride alone or combination thereof.

10. The process as claimed in claim 1, wherein the Lewis acid catalyst is boron trifluoride diethyl etherate.

11. The process as claimed in claim 1, wherein the process step (iii) is carried out at a temperature ranging from -20 to 20°C, preferably -10 to 10°C, more preferable -5 to 0°C, which is then heated to 40 to 90°C, preferably 50 to 80°C, more preferably 65 to 70°C and further lowered to 15 to 35°C, preferably 25 to 30°C.

12. The process as claimed in claim 1, wherein the acid to obtain pharmaceutically acceptable salt in step (iv) is selected from oxalic acid or hydrochloric acid in suitable amounts.

13. The process as claimed in claim 1, wherein the solvent for process step (iv) is selected from the group consisting of C1-C5 alcohols; ethers such as THF, DMF, diethyl ether and such like; esters such as ethyl acetate; ketones such as acetone, methyl ethyl ketone and such like; aliphatic or aromatic hydrocarbons, halogenated hydrocarbons alone or mixtures thereof.

14. A pharmaceutical composition comprising Etripamil or its pharmaceutically acceptable salt prepared by the process claimed in claim 1 together with pharmaceutically acceptable excipients.

15. The pharmaceutical composition as claimed in claim 14, wherein said composition may comprise other pharmaceutically active agents.

16. Use of Etripamil or its pharmaceutically acceptable salt prepared by the process claimed in claim 1 in paroxysmal supraventricular tachycardia (PSVT).