FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules,2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A process for the preparation of Eletriptan
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
Present invention relates to a process for the preparation of Eletriptan having compound of structural formula I and pharmaceutically acceptable salt thereof.

Background of the invention:
Eletriptan hydrobromide is chemically known as 3-[[(R)-1-Methyl-2-pyrrolidinyl]methyl]-5-[2-(phenylsulfonyl)ethyl]indole, monohydrobromide and was first disclosed in U.S. patent number 5,545,644 and is represented by the structural formula II.

Eletriptan hydrobromide is well tolerated and effective drug indicated for the acute treatment of migraine with or without aura in adults.

U.S. Patent Number 5,545,644 discloses a process for the preparation of Eletriptan having compound of structural formula I as depicted below in Scheme I, wherein 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-1H-indole having compound of structural formula III is reduced using 5% Pd/C, methanesulfonic acid in acetone under hydrogen atmosphere of 50 psi to give Eletriptan having compound of structural formula I.

The preparation method disclosed in U.S. Patent Number 5,545,644 is very unsafe for commercial scale as said method involves the reduction under hydrogen atmosphere of 50 psi, using 5% Pd/C and methanesulfonic acid in acetone as a solvent.
U.S. Patent Number 8,754,239 discloses a process for the preparation of Eletriptan
hydrobromide having compound of structural formula II as depicted below in
Scheme II, wherein 3-(((R)"1-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-
(phenylsulfonyl)vinyl)-lH-indole having compound of structural formula III is reduced using Raney Nickel in methanol under hydrogen atmosphere of 70-75 psi to give Eletriptan having compound of structural formula I which is further treated with aqueous hydrobromic acid to give Eletriptan hydrobromide having compound of structural formula II.


The preparation method disclosed in U.S. Patent Number 8,754,239 is very unsafe for commercial scale as said method involves the reduction under hydrogen atmosphere of 70-75 psi, using Raney Nickel in methanol.
Indian patent application 2035/MUM/2010 discloses hydrides as reducing agents analogously.
Accordingly there is need to develop a prior art process of preparing Eletriptan having compound of structural formula I and the pharmaceutically acceptable salt thereof, which is simple, economic, safe and industrially viable and avoid use of hydrogen gas and pressure reactor.
Object of the invention:
i) An object of the invention is to provide a simple, economic, safe and
industrially viable process for preparation of Eletriptan having compound of structural formula I and the pharmaceutically acceptable salt thereof.


ii) Another object of present invention is to provide a process for preparation of Eletriptan having compound of structural formula I comprising reduction of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-1H-indole having compound of structural formula III using alkali metal hydride in presence of metal catalyst and acid in an organic solvent.
iii) Yet another object of the present invention is to provide a process for preparation of Eletriptan having compound of structural formula I comprising reduction of 3-(((R)-1-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-lH-indole having compound of structural formula III wherein reduction is carried out at atmospheric pressure, which avoids the use of highly flammable hydrogen gas and pressure reactor which needs special safety precautions.
Summary of the invention:
An aspect of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Eletriptan having compound of structural formula I and pharmaceutically acceptable salt thereof


comprising,
reduction of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-lH-indole having compound of structural formula III using alkali metal hydride in presence of metal catalyst and acid in an organic solvent to get Eletriptan . having compound of structural formula I; and

optionally converting Eletriptan having compound of structural formula I in to pharmaceutically acceptable salt thereof.
A second aspect of the present invention is to provide a process for preparation of Eletriptan hydrobromide having compound of structural formula II


comprising,
reduction of 3-((R)-1-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-lH-indole having compound of structural formula III with alkali metal hydride in presence of metal catalyst and acid in an organic solvent to get Eletriptan having compound of structural formula I, and

converting Eletriptan having compound of structural formula I in to Eletriptan hydrobromide having compound of structural formula II.
Third aspect of present invention is to provide a process for preparation of Eletriptan hydrobromide having compound of structural formula II comprising steps of:
a. adding 10% Palladium carbon, acetic acid and alkali metal hydride
selected from the group consisting of sodium borohydride, potassium
botohydride or sodium cyanoborohydride to a solution of 3-(((R)-l-
Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole
having compound of structural formula III in organic solvent selected
from group consisting of methanol, ethanol, isopropanol, butanol, THF or
mixture(s) thereof at a temperature in the range of 15°C to 35°C;
b. stirring the reaction mixture of step-a at a temperature in the range of
45°C to 75°C for a period of 1 to 5 hours;
c. isolating Eletriptan having compound of structural formula I;
d. converting Eletriptan having compound of structural formula I in to
Eletriptan hydrobromide having compound of structural formula II.

Detail description of the invention:
The present invention relates to a simple, economic, safe and industrially viable process for preparation of Eletriptan having compound of structural formula I and pharmaceutically acceptable salt thereof

comprising,
reduction of 3-(((R)-1-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole having compound of structural formula III using alkali metal hydride in presence of metal catalyst and acid in an organic solvent to get Eletriptan having compound of structural formula I, and

optionally converting Eletriptan having compound of structural formula I in to pharmaceutically acceptable salt thereof.
3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole having compound of structural formula III may be prepared by following the methods disclosed in the prior art.

Reduction of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole having compound of structural formula III can be carried out by using alkali metal hydride in the presence of metal catalyst and acid in an organic solvent to get Eletriptan having compound of structural formula I.
The example of alkali metal hydride can include but not limited to sodium borohydride, potassium borohydride & sodium cyanoborohydride.
The example of metal catalyst can include but not limited to palladium on carbon (Pd/C), platinum on carbon (Pt/C) and raney nickel.
The examples of acid can include but not limited to acetic acid, formic acid, propionic acid and butanoic acid.
The examples of organic solvent can include but not limited to solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, THF or mixture(s) thereof.
Reduction of 3-(((R)-1-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole having compound of structural formula III can be carried out by addition of metal catalyst, acid and alkali metal hydride to a solution of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole having compound of structural formula III in organic solvent at a temperature in the range of 15°C to 35°C followed by stirring the reaction mixture at a temperature in the range of 45°C to 75°C for a period of 1 to 5 hours.
Eletriptan having compound of structural formula I can be isolated by quenching reaction mixture with acid followed by filtration through hyflo bed, concentration of filtrate, addition of water to concentrated filtrate, basification up to pH 8-9 with aqueous ammonia followed by the steps of extracting product in organic solvent and concentration of organic solvent to get Eletriptan having compound of structural formula I.

The example of acid for quenching reaction mixture can include but not limited to inorganic acid such as hydrochloric acid, hydrobromic acid, etc.
The example of organic solvent for extraction of product can include but not limited to alkyl acetate selected from the group of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or mixture(s) thereof and chlorinated hydrocarbons selected from the group of methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform or mixture(s) thereof.
Eletriptan having compound of structural formula I can be converted to acid addition salts thereof selected as but not limited to Eletriptan hydrobromide having compound of structural formula II.
Eletriptan having compound of structural formula I can be treated with hydrobromic acid in organic solvent to provide Eletriptan hydrobromide having compound of structural formula II.
The example of organic solvent can include but not limited to alcohol solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol or mixture(s) thereof.
Example:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of Eletriptan hydrobromide Step I: Preparation of Eletriptan
To a solution of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole (20 g) in isopropyl alcohol (200 ml) was added 10% Palladium

carbon (2 g) carefully. Acetic acid (6.24 g) was charged in to the reaction mass. Sodium borohydride (7.48 g) was added in to the reaction mass at 25°C to 30°C. The reaction mixture was heated to 55°C to 60°C. The reaction mixture was stirred at 55°C to 60°C for 2 to 3 hours. Then reaction mass was cooled to 5°C to 10°C, quenched with aqueous HCl, filtered through hyflo bed and filtrate was concentrated under reduced pressure to obtain residue. To the obtained residue 100 ml water was added. The obtained aqueous solution then washed with ethyl acetate. Aqueous layer was basified to pH 8-9 with aqueous ammonia. Product was extracted with ethyl acetate and ethyl acetate layer was concentrated under reduced pressure to get Eletriptan. Yield- 18 gm HPLC Purity: 99.95%
Step II: Preparation of Eletriptan hydrobromide
To a solution of Eletriptan base (15 g) in isopropyl alcohol (90 ml) was added hydrobromic acid (10 ml). Reaction mass was stirred at 25°C to 30°C for 2 hours. Product was cooled to 15°C, filtered & washed with isopropyl alcohol. Filtered product was dried at 40°C to 45 °C to get Eletriptan hydrobromide. Yield-16.5 gm HPLC Purity: 99.98%

We claim:
1. A process for preparation of Eletriptan having compound of structural formula
I and pharmaceutically acceptable salt thereof

comprising,
reduction of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-
(phenylsulfonyl) vinyl)-1H-indole having compound of structural formula III using alkali metal hydride in presence of metal catalyst and acid in an organic solvent to get Eletriptan having compound of structural formula I; and

optionally converting Eletriptan having compound of structural formula I in to pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1 wherein alkali metal hydride is selected from
the group consisting of sodium borohydride, potassium borohydride & sodium
cyanoborohydride.

3. A process as claimed in claim 1 wherein metal catalyst is selected from the group consisting of palladium on carbon (Pd/C), platinum on carbon (Pt/C) and raney nickel.
4. A process as claimed in claim 1 wherein acid is selected from the group consisting of acetic acid, formic acid, propionic acid and butanoic acid.
5. A process as claimed in claim 1 wherein organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, butanol, THF or mixture(s) thereof.
6. A process as claimed in claim 1 wherein reduction of 3-(((R)-1-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole having compound of structural formula III can be carried out at a temperature in the range of 45 °C to 75 °C for a period of 1 to 5 hours.
7. A process as claimed in claim 1 wherein Eletriptan hydrobromide having compound of structural formula II is prepared by process comprising steps of:
a. adding 10% Palladium carbon, acetic acid and alkali metal hydride
selected from the group consisting of sodium borohydride, potassium
botohydride or sodium cyanoborohydride to a solution of 3-(((R)-l-
Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole
having compound of structural formula III in organic solvent selected
from group consisting of methanol, ethanol, isopropanol, butanol, THF or
mixture(s) thereof at a temperature in the range of 15°C to 35°C;
b. stirring the reaction mixture of step-a at a temperature in the range of
45°C to 75°C for a period of 1 to 5 hours;
c. isolating Eletriptan having compound of structural formula I;
d. converting Eletriptan having compound of structural formula I in to
Eletriptan hydrobromide having compound of structural formula II.
8. A process as claimed in claim land 7 wherein Eletriptan having compound of
structural formula I is treated with hydrobromic acid in organic solvent
selected from the group consisting of methanol, ethanol, isopropanol, butanol

or mixture(s) thereof to provide Eletriptan hydrobromide having compound of structural formula II.