This application claims priority to Indian patent application No. 2881/CHE/2010 Filed on Sep 29, 2010 the contents of which are incorporated by reference in their entirety

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Eletriptan
hydrobromide both α and β polymorphic forms.

The present invention also relates to a process for the preparation of Eletriptan
hydrobromide α and β polymorphic forms free of Eletriptan hydrobromide monohydrate.

The present invention further relates to packing of Eletriptan hydrobromide both α and β polymorphic forms.

BACK GROUND OF THE INVENTION:

Eletriptan is used for the acute treatment of migraine with or without aura in adults. Eletriptan is a selective 5-hydroxytryptamine IB/ID receptor agonist. Eletriptan hydrobromide having structure of formula-I is chemically known as 3-[[(2R)-l-Methyl-2-pyrrolidinyl] methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole hydrobromide and is being sold under the trade name RELPAX®.

European Patent 0592438 describes the preparation of Eletriptan by the catalytic reduction of (R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole of formula-VI, which is prepared by reaction of N-benzyloxycarbonyl-D-proline acid chloride of formula-Ill with 5-bromoindole of formula-II to get the compound of formula-IV, upon reduction of compound of formula-IV to produce (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-lH-indole of formula-V followed by reaction with phenylvinyl sulphone in the presence of a palladium catalyst, a triarylphosphine to produce the compound of formula-VI.

PCT publication WO2009142771 describes p-toluene sulfonic acid, benzene sulphonic acid, trifluoroacetic acid, methane sulphonic acid, formic acid or succinic acid salts of (R)-5-(2-phenylsulphonylethenyl)-3(N-methylpyrrolidine-2-ylmethyl)-1H-indole, process for its preparation of Eletriptan and further conversion to hydrobromide salt.

US patent 6110940 discloses the process for the preparation of Eletriptan hydrobromide α -polymorphic form by reacting 62% w/w hydrobromic acid with Eletriptan base in acetone under reflux condition. The US '940 patent also disclosed process for the preparation of β -polymorphic form by reacting 49% w/w hydrobromic acid with Eletriptan base in 1,2-dimethoxyethane at about 5°C.

The above process involves the high concentration of hydrobromic acid under extreme conditions. Keeping in view of the difficulties in commercialization of the above mentioned processes for the preparation of Eletriptan hydrobromide, still there is a need for the alternate, more convenient process for producing Eletriptan hydrobromide or its α and β polymorphic forms. Hence, the present invention provides a process for the preparation of Eletriptan hydrobromide α and β polymorphic forms free of Eletriptan hydrobromide monohydrate.

SUMMARY AND OBJECT OF THE INVENTION:

The present invention relates to an improved process for the preparation of Eletriptan hydrobromide α and β polymorphic forms free of Eletriptan hydrobromide monohydrate.

One aspect of the present invention provides an improved process for preparation of Eletriptan hydrobromide β-polymorphic form, which comprising the steps of: a) setting free of Eletriptan methane sulphonate salt with base, b) extracting the compound into an organic solvent, c) optionally passing the organic layer through silica gel column, d) removing the solvent, adding alcoholic solvent, e) treating with hydrobromic acid to form Eletriptan hydrobromide f) dissolving the obtained Eletriptan hydrobromide in alcoholic solvent, g) adding step f) solution to an antisolvent containing the seed of Eletriptan hydrobromide β -polymorphic form, and i) isolating Eletriptan hydrobromide β -polymorphic form.

Another aspect of the present invention provides an improved process for preparation of Eletriptan hydrobromide α -polymorphic form which comprising the steps of: a) setting free of Eletriptan methane sulphonate salt with base, b) extracting the compound into an organic solvent, c) optionally passing the organic layer through silica gel column, d) removing the solvent, adding alcoholic solvent, e) treating with hydrobromic acid, and f) isolating Eletriptan hydrobromide α -polymorphic form.

Yet another aspect of the present invention provides a process for preparing Eletriptan hydrobromide α and β polymorphic forms free of Eletriptan hydrobromide monohydrate, which comprises drying Eletriptan hydrobromide α or β form at about 50-150°C till the monohydrate contamination is removed to get pure Eletriptan hydrobromide α or β polymorphic forms free of Eletriptan hydrobromide monohydrate.

Yet another aspect of the present invention provides packing conditions of Eletriptan hydrobromide a and p polymorphic forms, which comprising the steps of: a) placing Eletriptan hydrobromide α or β form in innermost LDPE bag, b) placing the innermost bag in a middle HMLDPE bag, and c) placing the middle bag in an outer triple laminated aluminum bag.

Yet another aspect of the present invention provides packing conditions of Eletriptan hydrobromide a or p polymorphic forms, which comprising the steps of: a) placing Eletriptan hydrobromide α or β form in innermost LDPE bag under nitrogen atmosphere, b) placing the innermost bag in a middle HMLDPE bag with a silica sachet and molecular sieve sachet under vaccumized nitrogen, and c) placing the middle bag in an outer triple laminated aluminum bag with a silica sachet and molecular sieve sachet under vaccumized nitrogen.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of Eletriptan hydrobromide both α and β polymorphic forms.

The present invention also provides a process for the preparation of Eletriptan hydrobromide α and p polymorphic forms free of Eletriptan hydrobromide monohydrate.

The present invention further provides packing of Eletriptan hydrobromide both α and β polymorphic forms.

One embodiment of the present invention provides an improved process for preparation of Eletriptan hydrobromide β -polymorphic form which comprising the steps of:

a) setting free of Eletriptan methane sulphonate salt with base,
b) extracting the compound into an organic solvent,
c) optionally passing the organic layer through silica gel column,
d) removing the solvent, adding alcoholic solvent,
e) treating with hydrobromic acid to form Eletriptan hydrobromide,
f) dissolving the obtained Eletriptan hydrobromide in alcoholic solvent,
g) adding step f) solution to an antisolvent containing the seed of Eletriptan hydrobromide β -polymorphic form, and
h) isolating Eletriptan hydrobromide β -polymorphic form.

According to the present invention Eletriptan methane sulphonate is dissolved in a mixture of water and water immiscible solvent, pH of the solution is adjusted to 7-10 with base and compound is extracted in water immiscible solvent. The organic layer is passed through silica gel column and distilled off the solvent. The residue thus obtained is dissolved in alcoholic solvent and aqueous hydrobromic acid is slowly added for about 20-60 minutes at room temperature and stirred the reaction mass for about 1-2 hours, removed the solvent to get crude Eletriptan hydrobromide. The crude compound is dissolved in an alcoholic solvent and is distilled of completely. The obtained compound is dissolved in an alcoholic solvent. This solution is added to an antisolvent containing the seed of Eletriptan hydrobromide P-form and further diluted with antisolvent or methyltertiarybutylether slowly for about 1-3 hrs, filtered the obtained solid and washed with methyltertiarybutylether or antisolvent, dried the compound at about 40-50°C for about 8-12 hrs to obtain Eletriptan hydrobromide 0-polymorphic form.

According to the present invention base used for pH adjustment is selected from sodium hydroxide, potassium hydroxide preferably aqueous sodium hydroxide. The extraction immiscible solvent is selected from ethylacetate, methylacetate, dichloromethane, chloroform, toluene or diethyl ether and alcoholic solvent is selected from methanol, ethanol, isopropanol or n-butanol. The anti solvent is selected from methyl tertiarybutylether, diisopropyl ether or diethylether.

Another embodiment of the present invention provides an improved process for preparation of Eletriptan hydrobromide a form which comprising the steps of:

a) setting free of Eletriptan methane sulphonate salt with base,
b) extracting the compound into an organic solvent,
c) optionally passing the organic layer through silica gel column,
d) removing the solvent, adding alcoholic solvent,
e) treating with hydrobromic acid, and
f) isolating Eletriptan hydrobromide α -polymorphic form.

According to the present invention Eletriptan methane sulphonate is dissolved in a mixture of water and water immiscible solvent, pH of the solution is adjusted to 7-10 with base and compound is extracted in water immiscible solvent. The organic layer is passed through silica gel column and distilled off the solvent. The residue thus obtained is dissolved in alcohol solvent and aqueous hydrobromic acid is slowly added for about 20-60 min at room temperature and stirred the reaction mass for about 1-2 hours, removed the solvent to get crude Eletriptan hydrobromide. The crude compound is dissolved in ketone solvents, heated to reflux for about 2-3 hrs and slowly cooled the reaction mass to 20-30°C. The obtained solid is filtered and washed with the same solvent. This operation is repeated twice, the compound obtained is dried at about 80-90°C for about 12 hrs to obtain Eletriptan hydrobromide α-polymorphic form.

According to the present invention base used for pH adjustment is selected from sodium hydroxide, potassium hydroxide preferably aqueous sodium hydroxide. The extraction immiscible solvent is selected from ethylacetate, methylacetate, dichloromethane, chloroform, toluene or diethyl ether and alcohol solvent is selected from methanol, ethanol, isopropanol or n-butanol.

Yet another embodiment of the present invention provides a process for preparing Eletriptan hydrobromide α and β polymorphic forms free of Eletriptan hydrobromide monohydrate, which comprises drying Eletriptan hydrobromide α or β form at about 50-150°C till the monohydrate contamination is removed to get pure Eletriptan hydrobromide α or β polymorphic forms free of Eletriptan hydrobromide monohydrate.

According to the present invention Eletriptan hydrobromide α or β polymorphic forms is dried at about 100-130°C for about 10-12 hrs to get pure Eletriptan hydrobromide α and β polymorphic forms respectively free of Eletriptan hydrobromide monohydrate.

Yet another embodiment of the present invention provides packing conditions of Eletriptan hydrobromide a and p polymorphic forms, which comprising the steps of:

a) placing Eletriptan hydrobromide α or β form in innermost LDPE bag,
b) placing the innermost bag in a middle HMLDPE bag, and
c) placing the middle bag in an outer triple laminated aluminum bag.

According to the present invention Eletriptan hydrobromide α or β is packed by placing Eletriptan hydrobromide α or β form first in an innermost LDPE bags which is twisted and tied and then placing the innermost bag in a middle HMLDPE bag which is heat sealed and finally placing the middle bag in an outer triple laminated aluminum bag which is heat sealed.

Yet another embodiment of the present invention provides packing conditions of Eletriptan hydrobromide α and β polymorphic forms which comprising the steps of:

a) placing Eletriptan hydrobromide α or β form in innermost LDPE bag under nitrogen atmosphere,
b) placing the innermost bag in a middle HMLDPE bag with a silica sachet and molecular sieve sachet under vaccumized nitrogen, and
c) placing the middle bag in an outer triple laminated aluminum bag with a silica sachet and molecular sieve sachet under vaccumized nitrogen.

According to the present invention Eletriptan hydrobromide α or β is packed by placing Eletriptan hydrobromide α or β form first in an innermost LDPE bag which is twisted and tied under nitrogen atmosphere and then placing t the innermost bag in a middle HMLDPE bag with a silica sachet and molecular sieve sachet under vaccumized nitrogen and finally placing the middle bag in an outer triple laminated aluminum bag with a silica sachet and molecular sieve sachet under vaccumized nitrogen.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXPERIMENTAL PROCEDURE

Example-1: Preparation of Eletriptan hydrobromide β-polymorphic form:

To a mixture of water (90ml) and ethyl acetate (120ml) was added Eletriptan methane sulphonate (30g) at 25-30°C and stirred for about 10 minutes to get clear solution. The pH of the reaction mass was adjusted to 9-9.5 with 10% sodium hydroxide solution at 25-30°C, stirred for about 20 minutes and separated the layers. The aqueous layer was extracted with ethyl acetate (120ml). Ethyl acetate layers were combined and washed with water (120ml). The ethyl acetate layer was passed though silica column washed the column with ethylacetate (60ml), collected the ethyl acetate elutes and distilled out completely u/v at 40-45 °C to get viscous residue. Methanol (100 ml) was added and stirred for about 20 minutes to get clear solution. 48% aqueous hydrobromic acid solution (10.4g) was slowly added for about 30-45 minutes at 20-25°C. The reaction mixture was stirred at 20-25°C for about an hour and distill out methanol completely u/v at 40-45°C. IPA (100 ml) was added and distill out IPA completely u/v at 45-50°C. Methanol (60 ml) was added and stirred at about 40-45°C to get clear solution.

In a separate flask mixture of MTBE (90 ml) and Eletriptan hydrobromide β-polymorphic form seed was added. The above methanolic solution was added to the mixture and cooled to 10-15°C. Again MTBE (270 ml) was slowly added to the reaction mass over a period of 90-180 minutes at 10-15°C. The reaction mass stirred for about 60-90 minutes at 10-15°C, filtered and washed with MTBE (30 ml). The obtained solid was dried u/v at 40-50°C for about 8-12 hours till moisture content is less than 1.0% to obtain 20.0 g of Eletriptan Hydrobromide β -polymorphic form.

Example-2: Process for preparation of pure Eletriptan hydrobromide β-polymorphic form:

Eletriptan hydrobromide β-polymorphic form (20.0) was dried u/v at 100 to 130°C for about 10-12 hours to get (18.0) of Eletriptan hydrobromide β -polymorphic form free of Eletriptan hydrobromide monohydrate.

Example-3: Preparation of Eletriptan hydrobromide α -polymorphic form:

To a mixture of water (90ml) and ethyl acetate (120ml) was added Eletriptan methane sulphonate (30g) at 25-30°C and stirred for about 10 minutes to get clear solution. The pH of the reaction mass was adjusted to 9-9.5 with 10% sodium hydroxide solution at 25-30°C, stirred for about 20 minutes and separated the layers. The aqueous layer was extracted with ethyl acetate (120ml). Ethyl acetate layers were combined and washed with water (120ml). The ethyl acetate layer was passed through silica column washed the column with ethylacetate (60ml), collected the ethyl acetate elutes and distilled out completely u/v at 40-45 °C to get viscous residue. Methanol (100 ml) was added and stirred for about 20 minutes to get clear solution. 48% aqueous hydrobromic acid solution (10.4g) was slowly added for about 30-45 minutes at 20-25°C. The reaction mixture was stirred at 20-25°C for about an hour and distill out methanol completely u/v at 40-45°C. Methanol was distilled out completely u/v at 40-45°C and IPA (90 ml) was added. IPA was completely distilled off u/v at 80-85°C. Again IPA (90 ml) was added and distilled out completely under vacuum at 80-85°C. Acetone (60ml) was added and distilled out completely under vacuum at 40-45°C. Again acetone (250 ml) was added and heated to reflux for about 2-3 hrs. The reaction mass was slowly cooled to 20-30°C and stirred for about 2 hours at the same temperature. The reaction mass was filtered and washed with acetone (30ml).

Methanol (100 ml) was added and to the above wet material and heated to reflux until clear solution is formed. Methanol was distilled out completely under vacuum at 40-50°C and acetone (60 ml) was added. Again acetone was distilled completely under vacuum at 40-50°C. Finally acetone (250ml) was added, heated to reflux temperature for about 2-3 hours. The reaction mass was slowly cooled to 20-30°C and stirred for about 2-3 hours at the same temperature. The obtained solid was filtered, washed with acetone (30ml) and dried under vacuum at 80-90°C for about 12 hours to get 20.0g of Eletriptan hydrobromide α-polymorphic form.

Example-4: Process for preparation of pure Eletriptan hydrobromide α -polymorphic form:

Eletriptan hydrobromide α-polymorphic form (20.0g) was dried u/v at 100 to 130°C for about 10-12 hours to get (18.0g) of Eletriptan hydrobromide α -polymorphic form free of Eletriptan hydrobromide monohydrate.

Example-5: Packing conditions

Eletriptan hydrobromide α or β-polymorphic form was packed under different packing conditions. Packing system I:

Eletriptan hydrobromide α or β-polymorphic form was placed in innermost LDPE bag twisted, tied and kept in middle HMLDPE bag, which was heat sealed, finally placed it in outer triple laminated aluminum bag, which was heat sealed. Packing system II:
Eletriptan hydrobromide α or β-polymorphic form was placed in innermost LDPE bag twisted, tied under nitrogen atmosphere and kept in middle HMLDPE bag with silica sachet & molecular sieve sachet under vaccumized nitrogen, finally placed it in outermost triple laminated aluminum bag with silica sachet & molecular sieve sachet under vaccumized nitrogen.

We Claim:
1) Process for the preparation of Eletriptan hydrobromide β -polymorphic form comprising the steps of:

a) setting free of Eletriptan methane sulphonate salt with base,

b) extracting the compound into an organic solvent,

c) optionally passing the organic layer through silica gel column,

d) removing the solvent, adding alcoholic solvent,

e) treating with hydrobromic acid to form Eletriptan hydrobromide,

f) dissolving the obtained Eletriptan hydrobromide in alcoholic solvent,

g) adding step

f) solution to an antisolvent containing the seed of Eletriptan hydrobromide β -polymorphic form, and

h) isolating Eletriptan hydrobromide β -polymorphic form.

2) Process for preparation of Eletriptan hydrobromide a form which comprising the Steps of:

a) setting free of Eletriptan methane sulphonate salt with base,

b) extracting the compound into an organic solvent,

c) optionally passing the organic layer through silica gel column,

d) removing the solvent, adding alcoholic solvent,

e) treating with hydrobromic acid, and

f) isolating Eletriptan hydrobromide α -polymorphic form.

3) The process according to claim 1& 2, wherein said organic solvent is selected from ethylacetate, methyalacetate, dichloromethane, chloroform, diethyl ether, toluene or mixture thereof.

4) The process according to claim 1& 2, wherein said alcoholic solvent is selected from methanol, ethanol, isopropanol, n-butanol or mixture thereof.

5) The process according to claim 1, wherein anti solvent is selected from methyl tertiarybutylether, diisopropyl ether, diethyl ether or mixture thereof.

6) The process according to claim 1 & 2, wherein said base used for setting free of acid is selected from sodium hydroxide or potassium hydroxide.

7) Process for the preparation of anhydrous Eletriptan hydrobromide α or β polymorphic forms which comprises keeping Eletriptan hydrobromide at about 80-150°C.

8) The process according to claim 7, wherein keeping of the temperature is carried out under reduced pressure.

9) Packing conditions of Eletriptan hydrobromide α and β polymorphic forms, which comprising the steps of:

a) placing Eletriptan hydrobromide α or β form in innermost LDPE bag,

b) placing the innermost bag in a middle HMLDPE bag, and

c) placing the middle bag in an outer triple laminated aluminum bag.

10) Packing conditions of Eletriptan hydrobromide α and β polymorphic forms which comprising the steps of:

a) placing Eletriptan hydrobromide α or β form in innermost LDPE bag under nitrogen atmosphere,

b) placing the innermost bag in a middle HMLDPE bag with a silica sachet and molecular sieve sachet under vaccumized nitrogen, and

c) placing the middle bag in an outer triple laminated aluminum bag with a silica sachet and molecular sieve sachet under vaccumized nitrogen.