BACKGROUND OF THE INVENTION
This invention relates to an economical process for preparation of eletriptan hydrobromide a-form of formula-I and its monohydrate of formula-III by the hydrgenation of the precursor of formula-II.
The invention also describes a method for achieving to get a-polymorphic crystalline from of eletriptan hydrobromide a-form of formula-I
Eletriptan, 3-(((R)-1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-1H-indole, is described in U.S. Pat. No. 5607951 (WO1992/06973). Process for this product is reported in EP1088817, as well as, WO/2002/50063.
Conversion of the product of formula-II to the product of formula-III is carried out by catalytic hydrogenation in the presence of an acid using Pd/C as catalyst.
US Patent 5545644 describes indole derivatives including Eletriptan.The patent gives a method for their preparation, where the hydrogenation is carried out using Pd/C in the presence of methane sulfonic acid.
A similar method is described in US Patent 5639779.
PCT WO/2002/50063A1 has also reported Pd/C catalyzed hydrogenation of a double bond. The substrate used is N-acetyl derivative of the product formula-II. The N-acetyl derivative of the product of formula-II is used in order to control the formation of the of bisindole derivative.
US Patent 2003/016074A1 undertakes the hydrogenation of the product of formula-II as acetyl derivative using Pd/C, PtO2, Ru, Rh or Raney-Ni.
Several patents describe the preparation of a-polymorphic form of eletriptan hydrobromide
WO1996/06842 A and WO2000/32589A claim the preparation of a-polymorph. In WO2000/32589A describe two methods, a) treating eletriptan base with acetone and aqueous hydrobromic acid and slurrying the oil formed in isopropyl alcohol, b)treating eletriptan base with acetone containing aqueous hydrobromic acid, refluxing and slurrying a second time in acetone.
US6927296 B2 describes a-polymorphic form using 2-butanone and aqueous hydrobromic acid. The mixture is subjected to azeotropic distillation along with toluene.
The conversion of the product of formula-II to the product of formula-I has been described in several aforementioned patents.
Analysis of these patents expose a few shortcomings. These are as given below
a) The process is successful most preferably with Pd/C and the catalyst is used in more quantities making the process uneconomical
b) The process is effective in the presence of an acid, preferably methane sulfonic acid and this makes it an environmental load.
c) Hydrogenation of N-acetyl derivative of the product of formula-II to the product of formula-I has been claimed using Raney Nickel in US Patent 2003/016674A1. It is observed that this reaction gives the indole derivative of formula-IV as an impurity. Additionally it requires another step of deacetylation

Formula-IV
d) Scale up by the methods mentioned herein gives an overall yield of 73%
Summary of invention:
The objective of the invention is to develop an economical method for the conversion of the product of formula-II to the product of formula-III and its conversion to hydrobromide salt a-form of the product of formula-I
Considering that conversion of the product of formula-II to the product of formula-III has been achieved by using Raney Nickel as catalyst.
The product of formula-III has been converted to the product of formula-I

Detailed description of the Invention:
The main objective of the invention is to develop an economical method for the synthesis for Eletriptan hydrobromide a-form of formula-I.
It is an objective of the invention to use an economically viable catalyst for the hydrogenation of the product of formula-II to the product of formula-III
It is another objective to carry out an environmentally friendly conditions.
It is yet another objective to convert the product of formula-III to formula-I in an economical fashion.
The objective has been achieved by the hydrogenation of the product of formula-II

Formula-II
to the product of formula-III

Formula-III
by conducting the hydrogenation using catalysts like Pd/C, PtO2 or Raney Nickel in the absence of an acid in a solvent selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, methylethylketone, ethyl acetate, acetonitrile or N,N-dimethylformamide either alone or as a mixture of any of two solvent and converting the product formula-III to the product of formula-I

Formula-I
by treating of the product of formula-III in a solvent selected from the group acetone, methyethylketone, isopropyl alcohol, toluene or n-butanol, preferably a ketonic solvent in 95% yield and >99.7% HPLC purity.
The invention has achieved the preparation of a-polymorph of the product of formula-I
The conversion of the product of formula-II to the product of formula-III was attempted using the catalysts selected from the group consisting of Pd/C, PtO2, Rh, Ru and Raney Ni in solvent selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, methylethylketone, ethyl acetate, acetonitrile or N,N-dimethylformamide either alone or as a mixture of any of the two solvents. Hydrogenation was tried in the presence of an acid selected from hydrochloric acid, sulphuric acid, phosphoric acid or methanesulfonic acid. Reaction was taking place smoothly in the presence of an acid, preferably methane sulfonic acid. In the absence of an acid, the reaction was sluggish and incomplete. Studies revealed that the preferred catalyst is Pd/C and the catalyst is Pd/C and the catalyst has to be used in higher performance in order to achieve a smooth process, catalyst was used in 30-50% w/w. This process hence, becomes, economically unfavorable.
Hence further studies for hydrogenation were carried out using Raney Nickel as catalyst without using an acid.
Hydrogenation was carried out in a solvent selected from an alkanol consisting methanol, ethanol, isopropanol, n-butanol, acetone, methylethylketone, ethyl acetate, acetonitrile or N,N-dimethylformamide.
Preferably hydrogenation is conducted in a solvent selected from the group consisting of methyl alcohol, isopropyl alcohol, acetone or methylethylketone.
Raney Nickel was used a catalyst in 5% to 30% and preferably in 10% to 20%. Hydrogenation was conducted preferably at 10 to 90oC for 2 to 10 hours and more preferably at 25 to 75oC for 4 to 6 hours.
Isolation of the product of formula-III in a solvent selected from the group consisting of isopropyl alcohol, acetone, ethyl acetate or methylethylketone containing 48% aqueous hydrobromic acid. This isolation method eliminated small quantities of bis impurity.
The product of formula-III was isolated in 90-95% yield with a melting range of 115-119oC and HPLC purity of > 99%.
The product of formula-III was treated in a solvent selected from the group consisting of isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, acetone, toluene along or a mixture of any of the two solvents.
The treatment was carried out at 50-120oC, preferably 60-100oC and isolated as anhydrous eletriptan hydrobromide in a-polymorphic form. The a-polymorph was isolation in 85-90% yield having a melting range of 160-170oC.
This polymorph has XRD values as 9.49, 10.48, 15.64, 16.31, 16.84, 18.03, 19.01, 19.63, 19.89, 20.46, 21.00, 22.49, 24.21, 25.53, 26.34, 27.32 and 29.29. The DSC exotherm is 169oC. The HPLC purity of the a-polymorph is 99.7%.

Thus this invention has achieved the following achievement
a) By preferably conduction hydrogenation using Raney Nickel as catalyst, a tremendous amount of economy has been achieved.
b) Since hydrogenation is proceeding in the absence of an acid, the process is environmentally friendly
c) Process has achieved formation of a-polymorph of eletriptan hydrobromide with high yield and purity
The following examples exemplify the invention. That should not construed in limiting the range of application of the invention
Example-1
3-(((R)-1-Methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-1H-indole(which was prepared according to the procedure described in WO1992/06973) 2 kg and methanol (20 L) charged into hydrogenator. Raney Nickel (0.5kg) was added carefully under vacuum and evacuated. The reactor was applied with a hydrogen pressure of 10-15psi. The reaction was maintained till the hydrogen consumption ceases (usually 4-5 hours). The reaction mixture was filtered and filtrate concentrated under reduced pressure. The remaining residue dissolved in ethyl acetate (10 L) and 48% aqueous hydrobromic acid (1.1 kg) added. The mixture was stirred for 30 minutes and filtered. The obtained product was dried at 45-50oC under reduced pressure for 4-5 hours to give 2.41 kg of eletriptan hydrobromide monohydrate with a melting point of 118-119oC and purity by HPLC 99.5%
Example-2
Eletriptan hydrobromide monohydrate (1.0 kg) which was prepared in example-1 was charged into toluene (10 L) and refluxed for 2 hours. The reaction mass was distilled till the volumes reduced to 3 L and cooled to 25-30oC. Stir for 30 minutes and filtered off. The wet material was dried at 50-55oC to give 0.9 kg of eletriptan hydrobromide with a melting point of 169-171oC and purity by HPLC 99.8%. PXRD data in Fig-I shows a-polymorph
Example-3
Eletriptan hydrobromide monohydrate (1.0 kg) which was prepared in example-1 was charged into isospropylalcohol (8 L) and refluxed for 2 hours. The reaction mass was distilled till the volumes reduced to 2 L and cooled to 25-30oC. Stirred for 30 minutes and filtered off. The wet material was dried at 45-50oC to give 0.93 kg of eletriptan hydrobromide with a melting point of 168-170oC and purity by HPLC 99.7%. PXRD data in Fig-II shows a-polymorph
Example-4
Eletriptan hydrobromide monohydrate (0.4 kg) which was prepared in example-1 was charged into acetone (4 L) and refluxed for 2 hours. The reaction mass was distilled till the volumes reduced to 1.2 L and cooled to 25-30oC. Stirred for 30 minutes and filtered off. The wet material was dried at 45-50oC to give 0.36 kg of eletriptan hydrobromide with a melting point of 169-171oC and purity by HPLC 99.8%.

CLAIMS

01. A process for preparation of eletriptan hydrobromide having a-form polymorphic nature of formula-I by
a) reducing (((R)-1-methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)-vinyl)-1H-indole of formula II in presence of a metal catalyst and hydrogen in an organic solvent
b) isolating the eletriptan hydrobromide monohydrate (formula-III)
c) converting the eletriptan hydrobromide monohydrate to eletriptan hydrobromide a-form
d)
02. A process, as claimed in claim-1a, wherein the reduction is carried out using hydrogen and a metal catalyst

03. A process, as claimed in claim-1a, wherein the metal catalyst used is Raney-nickel

04. A process, as claimed in claim-1a, wherein the reduction is carried out in an alcoholic solvents methanol, ethanol, butanol, isopropanol or ketonic solvents like acetone, methylethyl ketone or ethyl acetate or acetonitrile or dimethylformamide, either alone or a mixture of any of the two solvents

05. A process, as claimed in claim-1a, wherein the reduction is carried out at 10-90oC, preferably 25-75 oC

06. A process, as claimed in claim-1b, where in eletriptan hydrobromide monohydrate is isolated in an organic solvent by adding aqueous hydrobromic acid

07. A process, as claimed in claim 1b, wherein the eletriptan hydrobromide monohydrate is having a melting range of 115-119oC

08. A process as claimed in claim-1c, wherein eletriptan hydrobromide monohydrate is converted to eletriptan hydrobromide by refluxing in an organic solvent

09. A process as claimed in claim-8, wherein the organic solvent used is selected from group consisting of acetone, 2-propanol, n-butanol, t-butanol, toluene either alone or a mixture of any of these solvents

10. A process as claimed in claim-1c, wherein the eletriptan hydrobromide monohydrate was refluxed, distilled, cooled and filtered to get eletriptan hydrobromide a-form.

11. A process as claimed in claim-12, wherein cooling the reaction mixture to 0-35oC

12. A process as claimed in claim-1c, wherein eletriptan hydrobromide a-form having a melting point 160-170oC

13. A process as claimed in claim-1c, wherein a crystalline XRD pattern having peaks at 9.49, 10.48, 15.64, 16.31, 16.84, 18.03, 19.01, 19.63, 19.89, 20.46, 21.00, 22.49, 24.21, 25.53, 26.34, 27.32, 29.29 is represented in figures-I and II.