FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
1. Title of the invention
Process for preparation of crystalline forms of Eletriptan hydrobromide
2. Applicant(s)
Name Nationality Address
USV Limited Indian company incorporated Arvind vitthal Gandhi chowk,B.S.D.Marg Govandi, Station
under Companies Act, 1956 Road, Mumbai-400 088, Maharashtra, India.
3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of invention:
The present invention relates to an improved process for the preparation of 3-(N-methyl-2(R)-pyrrolidinylmethyl) -5-[2-(phenylsulfonyl)ethyl]- 1H-indole hydrobromide (Eletriptan hydrobromide), in particular Eletriptan hydrobromide monohydrate. The present invention further relates to an improved process for preparation of Eletriptan hydrobromide beta form or alpha form.

Background of invention:
Eletriptan hydrobromide is chemically designated as 3-[[(2R)-l-Methyl-2-pyrrolidinyl]methyl]-5-[2-(phenylsulfonyl)ethyl]-l H-indole monohydrobromide or 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl) ethyl]-1H-indole hydrobromide. Eletriptan is marketed by Pfizer under the brand name RELPAX®. Each RELPAX® Tablet for oral administration contains 24.2 or 48.5 mg of Eletriptan hydrobromide equivalent to 20 mg or 40 mg of Eletriptan respectively. It is administered as single doses.of 20 mg or 40 mg. RELPAX® is a prescription medicine used to treat migraine headaches with or without aura in adults. Eletriptan is a selective 5-hydroxytryptamine IB/ID (5-HT1B/1D) receptor agonist. It binds with high affinity to 5-HT[lB, ID, IF] receptors. It has modest affinity to 5-HT[lA, IE, 2B, 7] receptors and little or no affinity for 5-HT[2A, 2C, 3, 4, 5A, 6] receptors. It has no significant affinity or pharmacological activity at adrenergic alphai, alpha2, or beta; dopaminergic D1 or D2; muscarinic; or opioid receptors.
US5545644 discloses the process for preparation of alpha form and beta form of Eletriptan hydrobromide.
US6110940 discloses the process for preparation of beta form of Eletriptan hydrobromide by reacting a solution of Eletriptan base in 1,2-dimethoxyethane with aqueous 49% w/w hydrobromic acid at about 5°C. The resulting slurry is stirred at room temperature for a further 18 hours. The product obtained is filtered and dried.

US'940 also discloses the process for the preparation of alpha form of Eletriptan hydrobromide by reacting a solution of Eletriptan base in acetone with an aqueous solution of HBr at room temperature. The reaction mixture is evaporated to give yellow oil. This yellowish oil is then triturated with ether and dissolved in 2-propanol. This solution is then cooled to yield the alpha form.
WO2008137134 discloses the process for preparation of Eletriptan hydrobromide beta form by reacting Eletriptan base and hydrobromic acid in isopropanol. Optionally, seeding of crystals of Eletriptan hydrobromide beta form is done before the reaction with HBr to facilitate the crystallization of beta form so as to obtain a suspension. The obtained suspension is maintained for about 30 minutes to about 24 hours so as to increase the yield of the desired product. This document also describes the process for preparation of Eletriptan hydrobromide alpha form by providing a solution of Eletriptan hydrobromide in ethanol at room temperature and precipitating crystals of Eletriptan hydrobromide alpha form to obtain a suspension. Precipitation is done by cooling the solution at a temperature of about -5 to -20°C. The yield of the precipitated alpha form may be increased by cooling for about 24 hrs to about 3 days.
US7238723 discloses the process for preparation of Eletriptan hydrobromide monohydrate by treating a solution of Eletriptan base in acetone-water or in tetrahydrofuran-water with aqueous 48% w/w hydrogen bromide. Additionally, it discloses the process for preparation of Eletriptan hydrobromide monohydrate by reprocessing Eletriptan hydrobromide.
WO2010121673 describes a synthetic process for Eletriptan or its salt. This document discloses that the disclosed process gives monotropic beta polymorphic form which is stable, non hygroscopic and comprises of needle shaped crystals. It further provides the stability studies of Eletriptan hydrobromide beta form.
WO2011004391 discloses an improved process for the preparation of alpha and beta polymorphic forms of Eletriptan hydrobromide which comprises dissolving Eletriptan base in a solvent; treating with 48% aqueous hydrobromic acid to obtain a solution; and adding the solution to an antisolvent containing seed of respective polymorphic

form; adding an antisolvent; and isolating Eletriptan hydrobromide alpha or beta polymorphic form.
Prior art discloses processes for preparation of Eletriptan hydrobromide beta form, alpha form and monohydrate. There still exists a problem with many of these processes, in terms of consistency and reproducibility. The present invention provides a simple, cost effective, consistent, industrially feasible and reproducible process for the preparation of Eletriptan hydrobromide monohydrate, beta form and alpha form.
Object of the Invention:
An object of the present invention is to provide a simple, cost effective, consistent, industrially feasible and reproducible process for the preparation of Eletriptan hydrobromide monohydrate, beta form and alpha form.
Another object of the present invention is to provide a process for preparation of Eletriptan hydrobromide monohydrate from 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethenyl]-lH-indole hydrobromide without isolation of Eletriptan base.
Summary of the invention:
According to one aspect of the present invention, there is provided a process for preparation of Eletriptan hydrobromide monohydrate comprising the steps of,
a) subjecting 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethenyl]-lH-indole hydrobromide to reduction in a mixture of organic solvent and water to obtain 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide monohydrate;
b) optionally purifying said 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide monohydrate (Eletriptan hydrobromide monohydrate).
Another aspect of the present invention provides a process wherein said 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide obtained in step a) is treated with HBr in an organic solvent or a mixture of organic solvent and water to obtain 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl

sulfonyl) ethyl]-1H-indole hydrobromide monohydrate with the required HBr content.
Preferably, reduction in step a) is carried out using hydrogen at a temperature of about 30°C to 60°C, pressure of about 1 to 10 Kg/cm2 for about 6 to 12 hours in presence of catalyst selected from palladium, platinum, platinum oxide, rhodium, ruthenium or Raney nickel. Preferably, organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetic acid or mixture thereof.
Another aspect of the present invention provides purification of Eletriptan hydrobromide monohydrate comprising the steps of,
a) treating 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenylsulfonyl) ethyl]-lH-indole hydrobromide monohydrate (Eletriptan hydrobromide monohydrate) with water or a mixture of organic solvent and water at a temperature of about 50°C to 100°C to obtain a solution;
b) optionally treating the solution obtained in step a) with neutral alumina and/or activated charcoal; and
c) isolating pure 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl)ethyl]-lH-indole hydrobromide monohydrate (Eletriptan hydrobromide monohydrate).
Preferably, organic solvent is selected from acetone, methylethyl ketone, methylisobutyl ketone, methanol, ethanol, n-propanol, isopropanol or mixture thereof.
Another aspect of the present invention provides a process for preparation of Eletriptan hydrobromide crystalline form comprising the steps of,
a) dissolving Eletriptan base in a suitable solvent to obtain a solution;
b) optionally, adding seed crystal of the desired Eletriptan hydrobromide crystalline form to the solution obtained in step a) to obtain a mixture;
c) adding HBr to the mixture obtained in step a) or step b) followed by stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating Eletriptan hydrobromide crystalline form from the mixture obtained in step c).

Preferably, when the crystalline form is beta form, said solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether, methanol, ethanol, isopropanol, n-propanol or mixture thereof; when said crystalline form is alpha form, said solvent is selected from methanol, ethanol, n-propanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether or mixture thereof; when said crystalline form is monohydrate, said solvent is selected from water, methanol, ethanol, isopropanol, n-propanol, ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether or mixture thereof.
Preferably, Eletriptan base used for the preparation of Eletriptan hydrobromide crystalline form can be obtained from Eletriptan hydrobromide monohydrate.
Brief Description of the Drawings:
Fig. 1: X-ray diffraction pattern of Eletriptan hydrobromide monohydrate obtained
according to the present invention.
Fig. 2: X-ray diffraction pattern of Eletriptan hydrobromide beta form obtained
according to the present invention.
Fig. 3: X-ray diffraction pattern of Eletriptan hydrobromide alpha form obtained
according to the present invention.
Detailed description of the invention:
The present invention provides a simple, cost effective, consistent, industrially feasible and reproducible process for the preparation of Eletriptan hydrobromide monohydrate, beta form and alpha form.
One embodiment of the present invention provides a process for preparation of Eletriptan hydrobromide monohydrate comprising the steps of,
a) subjecting 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenylsulfonyl) ethenyl]-lH-indole hydrobromide to reduction in a mixture of organic solvent and water to obtain 3-(N-methyl-2(R)- pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide monohydrate;
b) optionally purifying the 3-(N-methyl-2(R)- pyrrolidinyl methyl)- 5-[2-(phenyl

sulfonyl ethyl]-lH-indole hydrobromide monohydrate (Eletriptan hydrobromide monohydrate).
Preferably, reduction is carried out in the presence of reducing agent selected from hydrogen gas, hydride, ammonium formate or formic acid; catalyst selected from palladium, platinum, Raney nickel, platinum oxide, rhodium or ruthenium; and organic solvent selected from methanol, ethanol, n-propanol, isopropanol, acetic acid or mixture thereof, preferably methanol. Reduction in presence of water facilitates the formation of Eletriptan hydrobromide monohydrate.
In a preferred embodiment, 3-(N-me%l-2(R)-pyrrolidinylmefhyl)-5-[2-(phenylsulfonyl) ethenyl]-lH-indole hydrobromide is subjected to hydrogenation in presence of 10% Pd/C, methanol and Water at a pressure of about 1 to 10 Kg/cm2, preferably 5 Kg/cm2 at temperature of 30-60°C, preferably at 40-50°C for 6 to 12 hours, preferably for 8 to 10 hours to obtain 3-(N-methyl-2(R)- pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide monohydrate. Preferably, water is used in an amount of about 5 equivalents with respect to 3-(N-mefhyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenylsulfonyl) ethenyl] -1 H-indole hydrobromide.
Another embodiment of the present invention provides a process wherein 3-(N-methyl-2(R)- pyrrolidinyl methyl)- 5-[2-(phenyl sulfonyl ethyl]-1 H-indole hydrobromide monohydrate is treated with HBr in an organic solvent or a mixture of organic solvent and water to obtain 3-(N-methyl-2(R)-pyrrolidinyl methyl)- 5-[2-(phenyl sulfonyl ethyl]-1 H-indole hydrobromide monohydrate with the required HBr content.
In a preferred embodiment, the reaction mixture obtained after hydrogenation of 3-(N-methyl-2(R)-pyrrolidinylmethyl) -5-[2-(phenylsulfonyl)ethenyl]- 1 H-indole hydrobromide monohydrate is filtered and the filtrate is concentrated to obtain an oily residue. The obtained oily residue is stripped with isopropanol followed by addition of HBr/isopropanol (IPA) to obtain a reaction mixture The reaction mixture is further refluxed to obtain a clear solution. The clear solution is treated with water and this mixture is refluxed for 30 to 90 min, preferably for 60 min followed by cooling to

room temperature in about 2 to 5 hours and stirred at the same temperature for 10 to 15 hours. The solid precipitated out is filtered and dried to obtain 3-(N-methyl-2(R)-pyrrolidinylmethyl)- 5-[2-(phenylsulfonyl)ethyl]- lH-indole hydrobromide monohydrate with required HBr content. The compound thus obtained is further purified.
Prior art discloses the preparation of Eletriptan hydrobromide monohydrate from Eletriptan base or by reprocessing of Eletriptan hydrobromide. The present invention provides a consistent process for preparation of Eletriptan hydrobromide monohydrate from 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenylsulfonyl) ethenyl]-1 H-indole hydrobromide without isolating Eletriptan base.
Solvent treatment involves stripping oily residue with organic solvent to remove the traces of methanol, which provides the final product in high yield and purity. This treatment converts the oily residue into solid which enables easy handling. Treatment of 3-(N-methyl-2(R)-pyrrolidinylmethyl)- 5-[2-(phenylsulfonyl)ethyl]- 1 H-indole hydrobromide with HBr enables enrichment of the bromide content of 3-(N-methyl-2(R)-pyrrolidinylmethyl)- 5-[2-(phenylsulfonyl)ethyl] -1 H-indole hydrobromide monohydrate.
During the coupling reaction, there is possibility that 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenylsulfonyl)ethenyl]-lH-indole hydrobromide is formed with less HBr content. Therefore, HBr is added to enrich the bromide content of 3-(N-methyl- 2(R)-pyrrolidinylmethyl)- 5-[2-(phenylsulfonyl)ethyl]- lH-indole hydrobromide.
Another embodiment of the present invention provides a process for purification of Eletriptan hydrobromide monohydrate comprising the steps of,
a) treating 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl) ethyl]-1 H-indole . hydrobromide monohydrate (Eletriptan hydrobromide monohydrate) with water or a mixture of organic solvent and water at a temperature of about 50 to 100°C to obtain a solution;
b) optionally treating the solution obtained in step a) with neutral alumina and/or

activated charcoal; and c) isolating pure 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethy]]-lH-indole hydrobromide monohydrate (Eletriptan hydrobromide monohydrate).
Organic solvent is selected from acetone, methylethyl ketone, methylisobutyl ketone, methanol, ethanol, n-propanol, isopropanol or mixture thereof, preferably acetone or isopropanol.
Preferably, Eletriptan hydrobromide monohydrate is treated with water or mixture of water with acetone or isopropanol to obtain a mixture. The obtained mixture is heated to get a clear solution. The obtained clear solution is treated with neutral alumina and/or activated charcoal at the same temperature to obtain a hot mixture. The hot mixture is filtered and the filtrate is gradually cooled to room temperature. The mixture is stirred at the same temperature for 10-15 hours, preferably for 12 hours to precipitate a solid. The obtained solid is filtered and dried to obtain Eletriptan hydrobromide monohydrate.
Water used for dissolving Eletriptan hydrobromide monohydrate is in an amount of about 10 volumes with respect to Eletriptan hydrobromide monohydrate. When a mixture of water and organic solvent is used, it has to be ensured that sufficient amount of water is present in the mixture so as to facilitate the formation of monohydrate.
Preferably, neutral alumina and/or charcoal used for purification of Eletriptan hydrobromide monohydrate are in the range of 10 to 100% w/w with respect to Eletriptan hydrobromide monohydrate. The use of alumina in the purification of the Eletripan hydrobromide monohydrate helps in the removal of traces of metal impurities such as palladium, platinum metal as well as polar and non polar impurities. The use of alumina also improves the colour of the obtained Eletriptan hydrobromide monohydrate. Pure Eletriptan hydrobromide monohydrate obtained has KF value of about 3.8% and metal content well below 10 ppm.

Eletriptan hydrobromide monohydrate obtained by the process of present invention is characterized by X-ray diffraction pattern as shown in Figure 1. It is further characterized by X-ray powder diffraction pattern (XRPD) having characteristic peaks expressed as 2-theta values of about 9.81, 11.45, 12.48, 13.19, 13.58, 14.08, 15.11, 16.15, 16.94, 17.50, 18.70, 18.98, 19.68, 19.96, 20.56, 21.84, 21.98, 22.54, 22.85, 23.05,23.58, 23.77,24.13,24.90 and 30.49 degrees.
According to one embodiment of the present invention, there is provided a process for preparation of Eletriptan hydrobromide crystalline form comprising the steps of,
a) dissolving Eletriptan base in a suitable solvent to obtain a solution;
b) optionally, adding seed crystal of the desired Eletriptan hydrobromide crystalline form to the solution obtained in step a) to obtain a mixture;
c) adding HBr to the mixture obtained in step a) or step b) followed by stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating Eletriptan hydrobromide crystalline form from the mixture obtained in step c).
Preferably, when said crystalline form is beta form, said solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether, methanol, ethanol, isopropanol, n-propanol or mixture thereof; when said crystalline form is alpha form, said solvent is selected from methanol, ethanol, n-propanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether or mixture thereof; when said crystalline form is monohydrate, said solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether or mixture thereof.
Preferably, Eletriptan hydrobromide monohydrate obtained by the process of the present invention can be converted to Eletriptan base.
According to another embodiment of the present invention, there is provided a
process for preparation of Eletriptan hydrobromide beta form comprising the steps of,
a) dissolving Eletriptan base in a suitable solvent other than Ci to C4 alcohol,

tetrahydrofuran (THF) or 1,2-dimethoxyethane to obtain a solution;
b) optionally adding seed of Eletriptan hydrobromide beta form to the solution obtained in step a) to obtain a mixture;
c) adding HBr to the mixture obtained in step b) followed by stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating Eletriptan hydrobromide beta form from the mixture obtained in step c).
In a preferred embodiment, Eletriptan base is treated with a suitable solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether (MTBE) or mixture thereof to obtain a solution. Preferably, seeds of Eletriptan hydrobromide beta form are added to the solution to obtain a mixture followed by addition of HBr in a drop-wise manner under stirring at a temperature in the range of 0 to 40°C, preferably at 15 to 35°C, more preferably at 25 to 30°C. The mixture is further maintained at the same temperature for 1 to 5 hours. The product obtained is filtered and dried to obtain Eletriptan hydrobromide beta form.
In another preferred embodiment, Eletriptan base is treated with a suitable solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether (MTBE) or mixture thereof to obtain a solution. HBr is added in a dropwise manner to the obtained solution under stirring at a temperature in the range of 0 to 40°C, preferably at 15 to 35°C, more preferably at 25 to 30°C to obtain a mixture. The mixture is further maintained at the same temperature for 1 to 5 hours. The product obtained is filtered and dried to obtain Eletriptan hydrobromide beta form.
Prior art reports the use of 1,2-dimethoxyethane as solvent for preparation of Eletriptan hydrobromide beta form. As per ICH guidelines, 1,2-dimethoxy ethane is class 2 solvent with concentration limit of 1 OOppm. The use of class 2 solvents should be limited in pharmaceutical products in order to protect patients from potential adverse effects. It is more likely that solvents used in the reaction may get trapped in the final product and such final product may contain residual solvent as impurities

with concentration of more than lOOppm. The final product with class 2 solvents in a concentration of more than lOOppm is not acceptable as per the ICH guidelines.
It has been found by the inventors of the present invention that use of ester, MTBE or diisopropyl ether as a solvent in the synthesis of Eletriptan hydrobromide beta form provides Eletriptan hydrobromide beta form with improved stability. It appears that solvents such as ester, MTBE or diisopropyl ether (DIPE) plays an important role in controlling the conversion of beta form to any other polymorphic form.
It has been observed that Eletriptan hydrobromide beta form obtained by using solvents such as 1,2-dimethoxyethane or THF is very sensitive and easily gets converted to monohydrate form. The product obtained using these solvents requires immediate drying.
Prior art reports the use of high quantity of hydrobromic acid for the preparation of Eletriptan hydrobromide. For 1 mole of Eletriptan base, 37 moles of HBr is reported to be used. The process of the present invention employs the use of equimolar amount of HBr with respect to Eletriptan base for the preparation of Eletriptan hydrobromide crystalline forms. The use of equimolar amount of HBr satisfies the required bromide content in the final product.
An alternate embodiment of the present invention provides a process for preparation of Eletriptan hydrobromide beta form comprising the steps of,
a) dissolving Eletriptan base in a suitable solvent selected from C\ to C4 alcohol, ester, ether or mixture thereof to obtain a solution;
b) optionally adding seed crystal of Eletriptan hydrobromide beta form to the solution obtained in step a) to obtain a mixture;
c) adding HBr to the mixture obtained in step a) or step b) followed by stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating Eletriptan hydrobromide beta form from the mixture obtained in step c).
Alcohol is selected from methanol, ethanol, n-propanol, isopropanol, butanol or mixture thereof. Ester is selected from methyl acetate, ethyl acetate, isopropyl acetate,

butyl acetate, amyl acetate or mixture thereof. Ether is selected from diethyl ether, diisopropyl ether (DIPE), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), 1,4-dioxane or mixture thereof.
In a preferred embodiment, Eletriptan base is dissolved in a suitable solvent selected from methanol, ethanol, n-propanol, isopropanol, butanol or mixture thereof to obtain a solution. The solution is cooled to 5°C followed by addition of seed crystal of Eletriptan hydrobromide beta form to obtain a mixture. HBr is added to the cold mixture followed by stirring the mixture at the same temperature. The mixture is maintained at low temperature, preferably at 0 to 5°C for 1-5 hours. Eletriptan hydrobromide beta form thus obtained is isolated from the mixture.
In a preferred embodiment, Eletriptan base is dissolved in methanol-ethyl acetate mixture at 25 to 30°C to obtain a solution. The ratio of methanol and ethyl acetate in the mixture is 1:10 to 3:10 (v/v). The seed crystals of Eletriptan hydrobromide beta form are added to the obtained solution followed by addition of HBr under stirring at a temperature in the range of 25 to 30°C to obtain a mixture. The mixture is further maintained at the same temperature for 1 to 5 hours, preferably for 1-3 hours. The product obtained is filtered and dried to obtain Eletriptan hydrobromide beta form.
Eletriptan hydrobromide beta form prepared according to the present invention is found to be stable. Stability studies of Eletriptan hydrobromide beta form obtained by the process of the present invention, at different temperatures and humidity, are under progress. Stability studies performed at 20°C/45%RH showed that Eletriptan hydrobromide beta form is stable for a period of three months.
Eletriptan hydrobromide beta form obtained by the process of the present invention is characterized by X-ray diffraction pattern as shown in Figure 2. It is further characterized by X-ray powder diffraction pattern (XRPD) having characteristic peaks expressed as 2-theta values of about 5.49, 10.90, 12.68, 13.12, 15.57, 16.34, 16.82, 17.08, 17.37, 18.00, 19.05, 19.37, 19.98, 21.32, 21.55, 21.93, 22.47, 23.16, 23.46, . 24.27,24.63, 25.47,26.84,27.67,28.38,28.96, 31.11 and 32.13 degrees.
According to another embodiment of the present invention, there is provided a

process for preparation of Eletriptan hydrobromide alpha form or monohydrate form comprising the steps of,
a) dissolving Eletriptan base in a suitable solvent other than C1- C4 alcohol, THF or acetone to obtain a solution;
b) optionally, adding seed crystal of Eletriptan hydrobromide alpha form or monohydrate form to the solution obtained in step a) to obtain a mixture;
c) adding HBr to the mixture obtained in step a) or step b) followed by stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating Eletriptan hydrobromide alpha form or monohydrate form from the mixture obtained in step c).
In a preferred embodiment, Eletriptan base is dissolved in a suitable solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, MTBE or mixture thereof to obtain a solution. The seed crystals of Eletriptan hydrobromide alpha form are added to the solution at a temperature in the range of 0 to 40°C, preferably at 15 to 35°C, more preferably at 25 to 30°C to obtain a mixture followed by addition of HBr in a dropwise manner under stirring. The mixture is further maintained for 1 to 5 hrs, preferably for 1-3 hrs at the same temperature. The product thus obtained is filtered and dried to obtain Eletriptan hydrobromide alpha form.
In a preferred embodiment, Eletriptan base is dissolved in a suitable solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, MTBE or mixture thereof to obtain a solution. The seed crystals of Eletriptan hydrobromide monohydrate are added to the solution at a temperature in the range of 0 to 40°C, preferably at 15 to 35°C, more preferably at 25 to 30°C to obtain a mixture followed by addition of HBr in a drop wise manner under stirring. The resulting mixture is further maintained at the same temperature for 1 to 5 hours, preferably for 1-3 hours. The product obtained is filtered and dried to obtain Eletriptan hydrobromide monohydrate.
An alternate embodiment of the present invention provides a process for preparation of Eletriptan hydrobromide alpha form comprising the steps of,

a) dissolving Eletriptan base in a suitable solvent selected from C1 to C4 alcohol to obtain a solution;
b) optionally adding seed crystals of Eletriptan hydrobromide alpha form to the solution obtained in step a) to obtain a mixture;
c) adding HBr to the mixture obtained in step b) followed by stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating Eletriptan hydrobromide alpha form from the mixture obtained in step c).
In a preferred embodiment, Eletriptan base is dissolved in a suitable solvent selected from methanol, ethanol, n-propanol, isopropanol, butanol or mixture thereof to obtain a solution. The seed crystals of Eletriptan hydrobromide alpha form are added to the solution at a temperature in the range of 0 to 40°C, preferably at 15 to 35°C, more preferably at 25 to 30°C to obtain a mixture followed by addition of HBr in a dropwise manner under stirring. The resulting mixture is further maintained at the same temperature for 1 to 5 hours, preferably for 1-3 hours. Eletriptan hydrobromide alpha form thus obtained is isolated from the mixture.
Eletriptan hydrobromide alpha form obtained by the process of the present invention is characterized by X-ray diffraction pattern as shown in Figure 3. It is further characterized by X-ray powder diffraction pattern (XRPD) having characteristic peaks expressed as 2-theta values of about 9.46, 10.43, 15.60, 16.25, 16.73, 17.50, 17.95, 18.98, 19.23, 19.56, 19.82, 20.42, 20.94, 21.78, 22.28, 22.58, 22.90, 24.14, 25.13, 25.46, 25.82, 26.17, 26.42, 26.83, 27.28, 27.95, 29.11, 30.13, 30.59, 31.25, 34.32, 35.07, 36.77, 37.79,41.02 and 45.48 degrees.
Another embodiment of the present invention provides a process for preparation of seed crystal of Eletriptan hydrobromide beta form comprising the steps of,
a) dissolving Eletriptan base in a suitable solvent selected from 1,2-dimethoxy ethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone or mixture thereof to obtain a solution;

b) adding HBr to the solution obtained in step a) to obtain a mixture;
c) stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating seed crystal of EJetriptan hydrobromide beta form.
In a preferred embodiment, Eletriptan base is dissolved in 1,2-dimethoxyethane to obtain a solution. The solution is optionally cooled to 0-5°C. A solution of HBr in IPA is added to the obtained solution to obtain a mixture. The mixture is maintained for 1 to 15 hours. The resulting mixture is filtered to isolate Eletriptan hydrobromide beta form.
Similarly, seed crystal of Eletriptan hydrobromide alpha form and monohydrate can be prepared.
Eletriptan base used can be prepared by any method known in the art or by conversion of Eletriptan hydrobromide to Eletriptan base. Eletriptan hydrobromide can be prepared by any method known in the art or as disclosed in our pending patent application 2035/MUM/2010.
3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl) ethenyl]-lH-indole hydrobromide, prepared as disclosed in our pending Indian Patent Application 2035/MUM/2010, is catalytically reduced using hydrogen in the presence of a suitable catalyst such as 10% Pd/C (50% wet) at a pressure of about 1 to 10 Kg/cm2, preferably 5 Kg/cm2 at temperature of 30-50°C, preferably at 40°C for 6 to 12 hours, preferably for 8 to 10 hours to obtain a reaction mixture. The obtained reaction mixture is filtered and the filtrate is concentrated to reduce the volume to l/5th of the original volume. The obtained mixture is further treated with 10% aqueous NaHC03 followed by extraction with ester. The obtained organic layer is washed with water; dried over sodium sulfate and concentrated to obtain Eletriptan base.
Another embodiment of the present invention is to provide a process for the preparation of Eletriptan hydrobromide beta form, alpha form or monohydrate which comprises the steps of,
a) catalytically reducing 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl)ethenyl]-lH-indole hydrobromide to obtain a solution containing 3-

(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenylsulfonyl)ethyl]-lH-indole hydrobromide;
b) treating the obtained solution with a suitable solvent and seed crystals of desired form to obtain a mixture;
c) maintaining the mixture at a temperature in the range of 0 to 40°C; and
d) isolating the desired form of Eletriptan hydrobromide.
Suitable solvent is selected from ester or ether. Ester is selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, amyl acetate or mixture thereof, preferably ethyl acetate. Ether is selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane preferably diisopropyl ether or MTBE.
In a preferred embodiment, 3-(N-methyl-2(R)-pyrrolidinylmethyI)-5-[2-(phenyl sulfonyl)ethenyl]-lH-indole hydrobromide is catalytically reduced using hydrogen in the presence of a suitable catalyst such as 10% Pd/C (50% wet) to obtain a reaction mixture. After completion of reaction, the reaction mixture is filtered and the filtrate is concentrated to obtain an oily residue. The oily residue is treated with ethyl acetate containing the seed of the desired form at a temperature in the range of 0 to 40°C to obtain a mixture. The mixture is maintained at the same temperature for about 1- 5 hours. The product obtained is separated by filtration.
Eletriptan hydrobromide monohydrate or beta form or alpha form obtained according to the present invention is more than 99.8% pure and have all known impurities below 0.15% and all unknown impurities below 0.1% thus complying the ICH guidelines.
Eletriptan hydrobromide monohydrate or beta form or alpha form obtained according to the present invention has particle size distribution such that about 90% of the particles have particle size less than about 150 microns, preferably less man about 100 microns, more preferably less than about 90 microns.
The important features of the present invention are,
a) The process of the present invention is simple, cost effective, industrially feasible, commercially viable, consistent and reproducible.

b) Consistent process for preparation of Eletriptan hydrobromide monohydrate from 3-(N-methyl-2(R)-pyrroiidinylmethyl)-5-[2-(phenylsulfonyl) ethenyl]-lH-ifldoJe hydrobromide without isolation of Eletriptan base using water and/or organic solvent.
c) Solvent such as ester or ether used for the preparation of Eletriptan hydrobromide beta form plays an important role in the stability of the polymorphic form.
d) Equimolar quantity of HBr with respect to Eletriptan base is used in the preparation of Eletriptan crystalline forms.
HBr as used herein means solution of HBr in any organic solvent selected from alcohol, ester, ether, ketone or the like. Preferably HBr is used as HBr/isopropanol (IPA) in the concentration of 10 to 30% HBr in IPA, preferably 15 to 25% HBr in IPA.
Room temperature as used herein refers to a temperature in the range of 20 to 40°C, preferably 25 to 30°C.
Identification of solid obtained by the present invention can be made by methods known in the art such as X-Ray powder diffraction pattern (XRPD), Fourier Transform Infrared (FT-IR) spectra, and differential scanning calorimetry (DSC).
X-ray powder diffraction pattern was obtained on Xpert'PRO, PANalytical, diffractometer equipped with accelerator detector using Copper Ka (n = 1.5406 A) radiation with scanning range between 2-theta 4-50° at a scanning speed of 2°/min.
The following examples are for illustrative purposes only and are not intended, nor should they be interpreted, to limit the scope of the invention in any manner.
Examples
Example 1: Preparation of Eletriptan hydrobromide monohydrate
150 gm 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethenyl]-lH-indole hydrobromide dissolved in 3.0 L of Methanol was charged in a hydrogenator. 10% Pd/C (60 gm) & 30 ml water were carefully added to the hydrogenator. Hydrogenation was carried out at a pressure of 5 Kg/cm2 at 40-50°C for 8 tolO hrs.

After completion of the reaction, the reaction mixture was filtered and the filtrate was evaporated to get an oily residue. The obtained oily residue was stripped with isopropanol (600 ml). 750 ml isopropanol (IPA) was added to the obtained residue followed by addition of 135 ml of HBr/IPA. The reaction mixture was heated to obtain a clear solution. 45 ml water was added to the clear solution followed by further refluxing the mixture at 78 to 81 °C for about one hour. The mixture was cooled to 25 to 30°C and stirred at the same temperature for 12 hours. The solid which precipitated out was filtered & dried in an oven at 60 to 65°C to obtain Eletriptan hydrobromide monohydrate. KF was found to be about 3.8%. Yield: 132gm, 88%; Purity: Approx. 99%
Example 2: Purification of Eletriptan hydrobromide monohydrate Example 2A
Eletriptan hydrobromide monohydrate obtained in example 1 (120 gm) in 1.2 lit water was heated to 70 to 80°C till a clear solution was obtained. The clear solution was refluxed for one hour. The hot solution was cooled to 25 to 30°C and stirred at the same temperature for 12 hours. The solid which precipitated out was filtered and dried in an oven at 60 to 65°C for 12 hours. KF was found to be about 3.8% Yield: 105gm, 88%; Purity: 99.60%
Example 2B
Eletriptan hydrobromide monohydrate obtained in example 1 (22 gm) in 220 ml acetone was refluxed to 56°C followed by addition of water (16 ml) at the same temperature till a clear solution was obtained. To this clear solution, 22 gm of neutral alumina and 2.2 gm of activated charcoal were added and the mixture was refluxed for one hour. The hot solution was filtered through hyflow bed and cooled to 25 to SOT . The mixture was stirred at the same temperature for 12 hrs. The solid which precipitated out was filtered and dried in an oven at 60 to 65°C. KF was found to be about 3.8%.Yield: 14.5gm, 66%; Purity: 99.80%
Example 2C:
Eletriptan hydrobromide monohydrate obtained in example 1 (40 gm) in 400 ml

isopropanol was refluxed to 78 to 8i°C followed by addition of water (14 ml) at the same temperature till a clear solution was obtained. To this clear solution, 20 gm of neutral alumina and 4 gm of activated charcoal were added and the mixture was refluxed for one hour. The hot solution was filtered through hyflow bed and cooled to 25 to 30°C . The mixture was stirred at the same temperature for 12 hrs. The solid which precipitated out was filtered and dried in an oven at 60 to 65°C. KF was found to be about 3.8%. Yield: 34 gm, 85%; Purity: 99.70%
Example 2D:
Eletriptan hydrobromide monohydrate obtained in example 1 (10 gm) in a mixture of 80 ml water and 20 ml acetone was heated at 70 to 80°C to obtain a clear solution. This solution was further refluxed for one hour. The hot solution was cooled to 25 to 30°C followed by stirring at the same temperature for 12 hrs. The solid which precipitated out was filtered and dried in an oven at 60 to 65°C for 12 hours. KF was found to be about 3.8%.Yield: 8.5 gm, 85%; Purity: 99.60%
Example 2E:
Eletriptan hydrobromide monohydrate obtained in example 1(10 gm) in a mixture of 80 ml water and 20 ml isopropanol was heated at 70 to 80°C to obtain a clear solution. This solution was further refluxed for one hour. The hot solution was cooled to 25 to 30°C followed by stirring at the same temperature for 12 hrs. The solid which precipitated out was filtered and dried in an oven at 60 to 65°C for 12 hours. KF was found to be about 3.8%.Yield: 8.8 gm, 88%; Purity: 99.60%
Example 3: Preparation of seed crystals of Eletriptan hydrobromide monohydrate
5g of Eletriptan base was dissolved in 50ml of acetone to obtain a solution. 2.3ml of aqueous HBr (47 % w/w) was added to the obtained solution in a drop wise manner under stirring at 25 to 30°C to obtain a mixture. The obtained mixture was maintained at the same temperature for 1 to 5 hours. The solid thus obtained was filtered and dried at 50-60°C to obtain the titled product.

Example 4: Preparation of Eletriptan hydrobromide monohydrate Example 4A
5g of Eletriptan base is dissolved in 50 ml of ethyl acetate to obtain a solution. The seeds of Eletriptan hydrobromide monohydrate (prepared as in Example 3) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner to the obtained mixture under stirring. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 4B
5g of Eletriptan base is dissolved in 50 ml of methyl acetate to obtain a solution. The seeds of Eletriptan hydrobromide monohydrate (prepared as in Example 3) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner to the obtained mixture under stirring. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 4C
5g of Eletriptan base is dissolved in 50 ml of isopropyl acetate to obtain a solution. The seeds of Eletriptan hydrobromide monohydrate (prepared as in Example 3) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner to the mixture under stirring. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 4D:
5g of Eletriptan base is dissolved in 15 ml of methanol to obtain a solution. Seeds of Eletriptan hydrobromide monohydrate (prepared as in Example 3) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.

Example 4E:
5g of Eletriptan base is dissolved in 15 mi of ethanol to obtain a solution. Seeds of Eletriptan hydrobromide monohydrate (prepared as in Example 3) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 4F:
5g of Eletriptan base is dissolved in 30 ml of isopropanol to obtain a solution. Seeds of Eletriptan hydrobromide monohydrate (prepared as in Example 3) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 4G:
5g of Eletriptan base is dissolved in 30 ml of diisopropyl ether to obtain a solution. Seeds of Eletriptan hydrobromide monohydrate (prepared as in Example 3) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr/isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 5: Preparation of seed crystals of Eletriptan hydrobromide beta form Example 5A
5g of Eletriptan base was dissolved in 75ml of 1,2-dimethoxy ethane to obtain a solution. The solution was cooled to 5°C followed by addition of 7.1 ml of 15% HBr in isopropanol in a dropwise manner under stirring. The solution was maintained at the same temperature for 3 - 5 hours. The solid thus obtained was filtered and dried at 50-80°C to obtain the titled product.

Example 5B
5g of Eletriptan base was dissolved in 75ml of 1,2-dimethoxy ethane to obtain a solution. 7.1 ml of 15% HBr in isopropanol was added to the obtained solution in a dropwise manner under stirring at 25 to 30°C. The solution was maintained at the same temperature for 1 to 5 hours. The solid thus obtained was filtered and dried at 50-80°C to obtain the titled product.
Example 6:Preparation of Eletriptan hydrobromide beta form Example 6A
5g of Eletriptan base was dissolved in 50 ml of ethyl acetate to obtain a solution. The seeds of beta form (prepared as in Example 5A or 5B) were added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol was added in a dropwise manner to the obtained mixture under stirring at 25 to 30°C. The mixture was maintained at the same temperature for 3-5 hours. The solid thus obtained was filtered and dried at 50-80°C to obtain the titled product.
Example 6B
5g of Eletriptan base is dissolved in 50 ml of methyl acetate to obtain a solution. The seeds of beta form (prepared as in Example 5A or 5B) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner to the obtained mixture under stirring at 25 to 30°C. The mixture is maintained at the same temperature for 3-5 hours. The solid thus obtained is filtered and dried at 50-80°C to obtain the titled product.
Example 6C
5g of Eletriptan base is dissolved in 50 ml of isopropyl acetate to obtain a solution. The seeds of beta form (prepared as in Example 5 A or 5B) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner to the obtained mixture under stirring at 25 to 30°C. The mixture is maintained at the same temperature for 3-5 hours. The solid thus obtained is filtered and dried at 50-80°C to obtain the titled product.

Example 6D
5g of Eletriptan base is dissolved in 10 ml of methanol to obtain a solution. The solution is cooled to 5°C followed by addition of seeds of beta form (prepared as in Example 5 A or 5B) to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the cold mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-80°C to obtain the titled product.
Example 6 E
5g of Eletriptan base is dissolved in 10 ml of ethanol to obtain a solution. The solution is cooled to 5°C followed by addition of seeds of beta form (prepared as in Example 5A or 5B) to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the cold mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-80°C to obtain the titled product.
Example 6F
5g of Eletriptan base is dissolved in 20 ml of isopropanol to obtain a solution. The solution is cooled to 5°C followed by addition of seeds of beta form (prepared as in Example 5A or 5B) to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the cold mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-80°C to obtain the titled product.
Example 6G
5g of Eletriptan base is dissolved in 30 ml of diisopropyl ether to obtain a solution. The seeds of beta form (prepared as in Example 5 A or 5B) are added to the obtained solution to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the resulting mixture at 25 to 30°C. The mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-80°C to obtain the titled product.

Example 6H
5g of Eletriptan base was dissolved in 50 ml of ethyl acetate to obtain a solution. 7.1 ml of 15% HBr in isopropanol was added in a dropwise manner under stirring to the obtained solution at 25 to 30°C to obtain a mixture. The obtained mixture was maintained at the same temperature for 3-5 hours. The solid thus obtained was filtered and dried at 50-80°C to obtain the titled product.
Example 61
5g of Eletriptan base is dissolved in 50 ml of methanol-ethyl acetate (1:10 v/v) mixture at 25 to 30°C to obtain a solution. Seeds of beta form of Eletriptan hydrobromide (prepared as in Example 5A or 5B) are added to the solution followed by dropwise addition of 7.1 ml of 15% HBr in isopropanol under stirring to obtain a mixture. The obtained mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-80°C to obtain the titled product.
Example 7: Preparation of seed crystals of Eletriptan hydrobromide alpha form
5g of Eletriptan base was dissolved in 75ml of acetone to obtain a solution. To the solution was further added 7.1 ml of 15% HBr in isopropanol in a dropwise manner under stirring at 25 to 30°C to obtain a mixture. The obtained mixture was maintained at the same temperature for 1 to 5 hours. The solid thus obtained was filtered and dried at 50-60°C to obtain the titled product.
Example 8: Preparation of Eletriptan hydrobromide alpha form Example 8A
5g of Eletriptan base is dissolved in 50 ml of ethyl acetate to obtain a solution. The seeds of Eletriptan hydrobromide alpha form (prepared as in Example 7) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.

Example 8B
5g of Eletriptan base is dissolved in 50 ml of methyl acetate to obtain a solution. The seeds of Eletriptan hydrobromide alpha form (prepared as in Example 7) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a drop wise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 8C
5g of Eletriptan base is dissolved in 50 ml of isopropyl acetate to obtain a solution. The seeds of Eletriptan hydrobromide alpha form (prepared as in Example 7) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 8D
5g of Eletriptan base is dissolved in 10 ml of methanol to obtain a solution. The seeds of Eletriptan hydrobromide alpha form (prepared as in Example 7) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 8E
5g of Eletriptan base is dissolved in 10 ml of ethanol to obtain a solution. The seeds of Eletriptan hydrobromide alpha form (prepared as in Example 7) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.

Example 8F
5g of Eletriptan base was dissolved in 30 ml of isopropanol to obtain a solution. The seeds of Eletriptan hydrobromide alpha form (prepared as in Example 7) were added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol was added in a dropwise manner under stirring to the obtained mixture. The resulting mixture was maintained at the same temperature for 1-3 hours. The solid thus obtained was filtered and dried at 50-60°C to obtain the titled product. Alternatively, the above process can be followed without seeding.
Example 8G
5g of Eletriptan base is dissolved in 30 ml of diisopropyl ether to obtain a solution. The seeds of Eletriptan hydrobromide alpha form (prepared as in Example 7) are added to the obtained solution at 25 to 30°C to obtain a mixture. 7.1 ml of 15% HBr in isopropanol is added in a dropwise manner under stirring to the obtained mixture. The resulting mixture is maintained at the same temperature for 1-3 hours. The solid thus obtained is filtered and dried at 50-60°C to obtain the titled product.
Example 9: Preparation of Eletriptan base
108g3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenylsulfonyl) ethenyl]-lH-indole hydrobromide in 1620 ml methanol was subjected to hydrogenation in the presence of 43.2gm of 10% Pd/C (50% wet), as disclosed in our pending Indian Patent Application 2035/MUM/2010. After the completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to reduce the volume from 15 volumes to 3 volumes. To this 324 ml methanolic solution, 1250ml of 10% aqueous NaHC03 was added to obtain a mixture. The obtained mixture was extracted with ethyl acetate (3x180ml). The combined ethyl acetate layers were washed with water and dried over sodium sulfate. The dried ethyl acetate layers were concentrated under vacuum to obtain Eletriptan Base.

We claim,
1. A process for preparation of Eletriptan hydrobromide monohydrate comprising
the steps of,
a) subjecting 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethenyl]-lH-indole hydrobromide to reduction in a mixture of organic solvent and water to obtain 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide monohydrate;
b) optionally purifying said 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide monohydrate (Eletriptan hydrobromide monohydrate).

2. The process as claimed in claim 1, wherein said 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide monohydrate obtained in step a) is treated with HBr in an organic solvent or a mixture of organic solvent and water to obtain 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-(phenyl sulfonyl) ethyl]-lH-indole hydrobromide monohydrate with the required HBr content.
3. The process as claimed in claim 1, wherein said reduction in step a) is carried out using hydrogen at a temperature of about 30°C to 60°C, pressure of about 1 to 10 Kg/cm2 for about 6 to 12 hours in presence of catalyst selected from palladium, platinum, platinum oxide, rhodium, ruthenium or Raney nickel.
4. The process as claimed in claim 2, wherein said organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetic acid or mixture thereof.
5. The process as claimed in claim 1, wherein said purification of Eletriptan hydrobromide monohydrate comprises the steps of,
a) treating 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-[2-{phenylsulfonyl)
ethyl]-lH-indole hydrobromide monohydrate (Eletriptan hydrobromide monohydrate) with water or a mixture of organic solvent and water at a temperature of about 50°C to 100°C to obtain a solution;

b) optionally treating the solution obtained in step a) with neutral alumina and/or activated charcoal; and
c) isolating pure 3-(N-methyl-2(R)-pyrrolidinylmethy])-5-[2-(phenyl sulfonyl)ethyl]-lH-indole hydrobromide monohydrate (Eletriptan hydrobromide monohydrate).

6. The process as claimed in claim 5, wherein said organic solvent is selected from acetone, methylethyl ketone, methylisobutyl ketone, methanol, ethanol, n-propanol, isopropanol or mixture thereof.
7. The process as claimed in claim 1, wherein said Eletriptan hydrobromide monohydrate is converted to Eletriptan base.
8. The process as claimed in claim 7, wherein said Eletriptan base is converted to Eletriptan hydrobromide crystalline form comprising the steps of,

a) dissolving Eletriptan base in a suitable solvent to obtain a solution;
b) optionally, adding seed crystal of the desired Eletriptan hydrobromide crystalline form to the solution obtained in step a) to obtain a mixture;
c) adding HBr to the mixture obtained in step a) or step b) followed by stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating Eletriptan hydrobromide crystalline form from the mixture obtained in step c).
9. A process for preparation of Eletriptan hydrobromide crystalline form
comprising the steps of,
a) dissolving Eletriptan base in a suitable solvent to obtain a solution;
b) optionally, adding seed crystal of the desired Eletriptan hydrobromide crystalline form to the solution obtained in step a) to obtain a mixture;
c) adding HBr to the mixture obtained in step a) or step b) followed by stirring the mixture at a temperature in the range of 0 to 40°C; and
d) isolating Eletriptan hydrobromide crystalline form from the mixture obtained in step c).

10. The process as claimed in claim 8 or claim 9, wherein when said crystalline form is beta form, said solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether, methanol, ethanol, isopropanol, n-propanol or mixture thereof; when said crystalline form is alpha form, said solvent is selected from methanol, ethanol, n-propanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether or mixture thereof; when said crystalline form is monohydrate, said solvent is selected from water, methanol, ethanol, isopropanol, n-propanol, ethyl acetate, methyl acetate, isopropyl acetate, diisopropyl ether, methyl tert butyl ether or mixture thereof.