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 hydrobromide
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 hydrobromide the compound represented by the structural formula I.

Background of the invention:
Eletriptan hydrobromide is chemically known as 3-[[(R)-1-Methyl-2-pyrrolidinyl]methyi]-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 I.

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 5,545,644A discloses a process for the preparation of Eletriptan the compound represented by structural formula II as depicted below in Scheme I, wherein 3-(((R)-1-Methylpyn"olidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-1H-indole compound represented by structural formula III is hydrogenated using 5% Pd/C, methanesulfonic acid as a catalyst in acetone as a solvent under hydrogen atmosphere of 50 psi to give Eletriptan; the compound represented by structural formula II.

PCT patent publication no. 2009142771A2 discloses a process for the preparation of Eletriptan hydrobromide the compound represented by strctural formula I as depicted below in Scheme II, wherein methane sulfonate salt of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-1H-indole compound represented by structural formula IV is hydrogenated by using Pd/C, methanesulfonic acid as a catalyst in acetone as a solvent under hydrogen atmosphere and further basified using aq. NH3 to provide Eletriptan the compound represented by structural formula II which is further treated with p-toluene sulfonic acid to give p-toluene sulfonic acid salt of the Eletriptan the compound represented by structural formula V which is further treated with aqueous NH3 and further with hydrobromic acid to give Eletriptan hydrobromide the compound represented by structural formula I.


US patent publication no. 20120071669A1 discloses a process for the preparation of Eletriptan hydrobromide; the compound represented by structural formula I as depicted below in Scheme III, wherein 5-Bromo-3-(1-Methyl pyrroli din-2(R)-yl methyl)-1H-indole the compound represented by structural formula VI is reacted with phenyl vinyl sulfone the compound represented by structural formula VII using Tri-O-Tolylphosphine, Pd(OAc)2 and TEA to obtain 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-lH-indole hydrobromide the compound represented by structural formula VIII which is further purified two times using toluene as solvent and further hydrogenated using 10% Pd/C in methanol under hydrogen atmosphere of 5 Kg/cm to provide Eletriptan hydrobromide the compound represented by structural formula I.


Accordingly there is need to develop a prior art process of preparing Eletriptan hydrobromide the compound of formula I which is simple, economic, safe and industrially viable and providing the better yield and purity of the final API.
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 hydrobromide the compound represented by structural formula I.


ii) Another object of present invention is to provide a process for preparation of Eletriptan hydrobromide the compound represented by structural formula I comprising converting PTSA salt of the 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-lH-indole the compound represented by structural formula IX into HBr salt of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-lH-indole the compound represented by structural formula VIII which is further hydrogenated using metal catalyst in an organic solvent to provide Eletriptan hydrobromide the compound represented by structural formula I.
iii) Further object of the present invention is to provide a process for preparation of Eletriptan hydrobromide the compound represented by structural formula I which avoids the yield loss due to purification of intermediate providing Eletriptan hydrobromide the compound represented by structural formula I with better yield and purity.
Summary of the invention:
In accordance with the aspect of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Eletriptan hydrobromide the compound represented by structural formula I.

According to another aspect of the present invention, there is provided a process for preparation of Eletripan hydrobromide (Formula I):

comprising,
a) converting p-toluene sulfonic acid salt of 3-(((R)-1 -Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)- 1H-indole the compound represented by structural formula IX into hydrobromide salt of the 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented by structural formula VIII, and

b) hydrogenating hydrobromide salt of the 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented by structural formula VIII using metal catalyst to obtain Eletriptan hydrobromide the compound represented by structural formula I,


Detail description of the invention:
The present invention relates to a simple, economic, safe and industrially viable process for preparation of Eletriptan hydrobromide the compound represented by structural formula I.
According to one aspect of the present invention, there is provided a process for preparation of Eletripan hydrobromide:

comprising,
a) converting p-toluene sulfonic acid salt of 3-(((R)-l-Methylpyrrolidin-2-
yl)methyl)-5^((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound
represented by structural formula IX into hydrobromide salt of the 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented by structural formula VIII, and

b) hydrogenating hydrobromide salt of the 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-lH-indole the compound represented by structural formula VIII using metal catalyst to obtain Eletriptan hydrobromide the compound represented by structural formula I,


The p-toluene sulfonic acid salt of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented by structural formula IX may be prepared by process known in the art such as those described in PCT publication no. 2009142771A2 which is incorporated herein by reference only.
In an embodiment of the present invention, the p-toluene sulfonic acid salt of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-lH-indole the compound represented by structural formula IX -is converted to HBr salt of 3-(N-methyl-2(R)-pyiTolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-1H-indole the compound represented by structural formula VIII in the step (a).
In a preferred embodiment, the conversion of p-toluene sulfonic acid salt of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-lH-indole the compound represented by structural formula IX to HBr salt of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-lH-indole the compound represented by structural formula VIII can be carried out by basification followed by HBr salt formation.
In a preferred embodiment, the examples of the base(s) used in the step (a) are inorganic or organic base(s). The organic base preferably a tertiary amine and/or an aromatic amine. As tertiary amine preferably triethyl amine (TEA), N,N-diisopropyl

ethyl amine (DIPEA), tributyl amine (TBA), or N,N-dimethyl amine. Aromatic amine pyridine or a pyridine derivative can be used.
The base is an inorganic base selected from ammonia, alkali metal hydroxides, carbonates and bicarbonates. Preferable alkali metal is sodium or potassium. Preferred base is aq. ammonia or triethyl amine or disopropyl ethyl amine.
The examples of the base used in the step (a) can include but not limited to aq. Ammonia (NH3), triethyl amine (TEA) or disopropyl ethyl amine (DIPEA).
The examples of the base used in the step (a) is aq. NH3, TEA or DIPEA.
In a preferred embodiment, the formation of HBr salt of 3-(N-methyl-2(R)-pyiTolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-lH-indole the compound represented by structural formula VIII in the step (a) can be carried out by addition of solution of HBr. HBr is used as an aqueous, alcoholic or acidic solution. Preferably, HBr in isopropanol or acetic acid is used.
The formation of HBr salt of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-lH-indole the compound represented by structural formula VIII in the step (a) carried out by addition of solution of HBr. The examples of solution of HBr is HBr in isopropanol or HBr in acetic acid.
In another embodiment of the present invention, hydrogenation of HBr salt of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented by structural formula VIII can be carried out by using metal catalyst and in an organic solvent to get Eletriptan hydrobromide the compound represented by structural formula I.
In a preferred embodiment, hydrogenation of HBr salt of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented

by structural formula VIII is carried out by using metal catalyst and in an organic solvent to get Eletriptan hydrobromide (formula I).
In a preferred embodiment, step (b) is carried out in the presence of hydrogen gas (H2) and metal catalyst selected from palladium, Raney nickel, platinum on carbon (Pt/C), platinum oxide, rhodium or ruthenium.
The example of metal catalyst can include but not limited to palladium like palladium on carbon (Pd/C), platinum on carbon (Pt/C), platinum oxide, raney nickel, rhodium or ruthenium.
In a preferred embodiment, the examples of organic solvent can include but not limited to alcohol solvent selected from C1 to C4 alcohol such as methanol, ethanol, isopropanol, butanol or mixture thereof and chlorinated solvent selected from dichloromethane, chloroform or the mixture thereof.
Solvent in step (b) is methanol and dichloromethane.
In a preferred embodiment, the product obtained in step(b) further optionally purified using acetonitrile and water or any combination thereof.
In a preferred embodiment, the product obtained in step(b) further optionally purified using acetonitrile, charcoal and water or any combination 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 (R,E)-3-((l-methylpyrrolidine-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1H-indole hydrobromide the compound represented by structural formula VIII
In the round bottom flask water (900 ml), p-tuluene sulfonic acid salt of (R,E)-3-((l-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-lH-indole (180 g, 0.3257 mol) and dichloromethane (900 ml) was charged. The pH of the reaction mass was adjusted to 10.0 by using aq. ammonia solution and reaction mass was stirred for 60 minute. The layers were separated and aq. phase was extracted with dichloromethane (360 ml). The combined organic layer was washed with water (360 ml) and dried over sodium sulphate. The organic phase was concentrated under vacuum to obtain a residue which was stripped with acetone (180 ml). The residue was diluted with acetone (360 ml) and heated to 40 to 50°C for 1 hour, further reaction mixture cooled to 25 to 35°C and charged IPA-HBr (158.2 g, 0.2931 mol) at 25 to 35°C and maintained for 20 to 22 hours. The precipitated material was cooled to 0 to 5°C and stirred for 2 hours. The precipitated material was filtered, washed with IPA and dried under vacuum to get (R,E)-3-((1-methylpyrrolidine-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-lH-indole hydrobromide. Yield: 100 g, 66%; Purity 98%.
Step II: Preparation of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethyI]-lH-indole hydrobromide (Eletriptan hydrobromide) crude
In the hydrogenator (R,E)-3-((1-methylpyrrolidine-2-yl)methyl)-5-(2-
(phenylsulfonyl)vinyl)-lH-indole hydrobromide (90 g; 0.195 mol) was dissolved in dichloromethane (1620 ml) and methanol (180 ml) to obtain reaction mass. To the

reaction mass 10% Palladium on carbon (36 g) was added and hydrogenation was
carried out at a pressure of 15 Kg/cm at 30°C for 25 to 30 hours. After completion of reaction, the reaction mixture was filtered through hyflo bed and the filtrate was concentrated to get the semisolid residue. To the residue; water (450 ml) was added and the reaction mixture was stirred for 2 hours to get a free solid. The obtained solid was filtered and wet solid was purified by dissolving in water (270 ml) at 85 to 90°C. The solid precipitated at 25-35°C was filtered dried to get Eletriptan hydrobromide crude. Yield: 80 g, 85%; Purity 98 to 99%
Stage-Final: Purification of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl]-lH-indole hydrobromide
3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl]-1H-indole
hydrobromide (70 g) was dissolved in acetonitrile (1705 ml) and treated with
activated charcoal (3.5g) for 2 hours at 60°C. The reaction mass was filtered through
hyflo bed and the filtrate was cooled gradually to 25 to 30°C and further maintain at 0
to 5°C for 2 hrs to obtain a solid. The solid was filtered and washed with acetonitrile.
The wet solid was dissolved in water (210 ml) at 85 to 90°C and cooled to 25 to
35°C. The reaction mass stirred for 2 hours, filtered and dried to obtain pure 3-(N-
methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl]-lH-indole
hydrobromide. Yield: 55 g, 78%; Purity 99.8%

We Claim:
1. A process for preparation of Eletripan hydrobromide (Formula I):

comprising,
a) converting p-tolucnc sulfonic acid salt of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented by structural formula IX into hydrobroraide salt of the 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1 H-indole the compound represented by structural formula VIII, and

b) hydrogenating hydrobromide salt of the 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented by structural formula VIII using metal catalyst to obtain Eletriptan hydrobromide the compound represented by structural formula I,


2. The process as claimed in claim 1, wherein the conversion of p-toluene sulfonic acid salt of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-1H-indole the compound represented by structural formula IX to HBr salt of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl)-1H-indole the compound represented by structural formula VIII can be carried out by basification followed by HBr salt formation.
3. The process as claimed in claim 1 or 2, wherein the base is aq. NH3, TEA or DIPEA.
4. The process as claimed in any of claims 1 or 3, wherein HBr is HBr in isopropanol or HBr in acetic acid.

5. The process as claimed in any of claims 1 to 4, wherein step (b) is carried out in the presence of hydrogen gas and metal catalyst selected from palladium, Raney nickel, platinum on carbon (Pt/C), platinum oxide, rhodium or ruthenium.
6. The process as claimed in any of claims 1 to 5, wherein step (b) is carried out in organic solvent selected from dichloromethane, methanol, ethanol, isopropanol, butanol or mixture thereof.

7. The process as claimed in any of claims 1 to 6, wherein step (b) is carried out using 10% Palladium on carbon in solvent methanol and dichloromethane.
8. The process as claimed in any of claims 1 to 6, wherein step (b) product further optionally purified using acetonitrile or water any combination thereof.
9. A process for preparation of Eletripan hydrobromide (Formula I):


comprising,
a) converting p-toluene sulfonic acid salt of 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1H-indole the compound represented by structural formula IX into hydrobromide salt of the 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1 H-indole the compound represented by structural formula VIII, and

b) hydrogenating hydrobromide salt of the 3-(((R)-l-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl) vinyl)-1 H-indole the compound represented by structural formula VIII using metal catalyst to obtain Eletriptan hydrobromide the compound represented by structural formula I,

wherein,
step a) base is aq. NH3, TEA or DIPEA;

HBr is HBr in isopropanol or HBr in acetic acid;
step b) metal catalyst is 10% Palladium on carbon and hydrogen gas in solvent methanol and dichloromethane
10. The process as claimed in claim 9, wherein step (b) product further optionally purified using acetonitrile, charcoal and water.