Improved Process for the Preparation of Almotriptan and its Pharmaceutical Acceptable Salts

Field of the Invention:

The present invention relates to an improved process for the preparation of almotriptan and its pharmaceutically acceptable salts as well as their novel polymorphic forms thereof. Almotriptan is chemically known as l-[[[3-[2-(dimethylamino) ethyl]-lH-indol-5-yl] methyl] su1fonyl] pyrrolidine

Formu1a-1

and its pharmaceutically acceptable salts.

Almotriptan binds with high affinity to 5-HTID, 5-HTIB and 5-HTIF receptors. The malate salt of almotriptan is indicated for the acute treatment of migraine with or without aura in adu1ts. Almotriptan malate is commercially available under the brand name of AXERT® and ALMOGRAN®.

Background of the Invention:

Almotriptan and its pharmaceutically acceptable salts as well as the process for their preparation are disclosed in US 5565447. The disclosed process comprises of the decarboxylation of 1 -[2-carboxy-3-dimethylaminoethyl)-5-indolyl]methanesu1fonyl] pyrrolidine using copper oxide and quinoline. The decarboxylation reaction requires very high temperature and hence is difficu1t to carry out in a commercial scale.

ES 2084560 describes a process for the preparation of almotriptan based on Fisher indole synthesis using a phenyl hydrazine and 4-chloro-butyraldehyde diethyl acetal to provide l-[[3-(2-aminoethyl)-5-indolyl]methanesu1fonyl]pyrrolidine, which is further treated with aqueous formaldehyde and then sodium borohydride to provide almotriptan. Thus obtained almotriptan is converted into DL-malate salt. This process provides almotriptan in poor yields. Moreover it was observed that the purity of the intermediates and final products are not of adequate quality and are having approximately 75-80% of purity by HPLC.

WO 2006/129190 describes a process for the preparation almotriptan malate. The disclosed process comprises of treating 5-(l-pyrrolidinyl-su1fonylmethyl)-lH-indole-3-ethanol with methane su1fonyl chloride and then dimethylamine followed by column purification of almotriptan. The said application schematically represents the conversion of almotriptan into almotriptan succinate and subsequent conversion in to almotriptan malate. Other than the schematic representation, the applicant has not disclosed/exemplified the process for the preparation of almotriptan succinate and neither has disclosed any physical properties. Moreover the preparation of 5-(l-pyrrolidinyl-su1fonylmethyl)-lH-indole-3-ethanol involves the usage of n-butyl lithium. As this process involves the usage of reagents like n-butyl lithium and purification techniques like column chromatography, which are commercially not recommendable.

WO 2008/151584 describes a process for the preparation of almotriptan malate, which involves the conversion of 4-(pyrrolidinylsu1fonylmethyl) phenyl hydrazine 4-chloro-l-hydroxybutane-l-su1fonate or 4-(pyrrodinylsu1fonylmethyl) phenyl hydrazine toluene su1fonate into crude almotriptan and then converting the crude almotriptan into its fumarate salt. Thus formed almotriptan fumarate is converted into crystalline almotriptan free base. The crystalline free base was treated with malic acid to provide almotriptan malate. Even though this process avoids some of problems of above reported process, it involves the additional steps like isolation of intermediate complex and almotriptan free base, which is time consuming and decrease the yields of the products. Moreover the fumarate salt of almotriptan is obtained in very poor purity of about 92%.

US 2007/112055 describes the process for the preparation of crystalline almotriptan free base, which involves treating the organic layer containing almotriptan with aqueous succinic acid then basifying the aqueous layer containing almotriptan succinate, followed by extraction of almotriptan into isopropyl acetate and then its conversion into crystalline almotriptan. Even though this process involves the formation of almotriptan succinate, which has been carried out in solution phase only and does not involve its isolation, further it does not disclosed its physical properties.

Polymorphism is the formation of a variety of crystalline forms of the same compound having distinct crystal structures and physical properties like melting points, X-ray diffraction pattern, infrared absorption pattern in fingerprint region, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. The difference in the physical properties of different crystalline forms resu1ts in some forms having distinct advantageous physical properties compared to other crystalline forms of the same compound. The discovery of new polymorphic forms of pharmaceutically usefu1 compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Those skilled in the art can understand that crystallization of an active pharmaceutical ingredient offers the best method for controlling important qualities like chemical quality, particle size, and polymorphic content. There is a need in the art for the preparation of new polymorphic form of pharmaceutically acceptable salts of almotriptan.

Hence there is a need in the art for an improved process for the preparation of almotriptan malate through a high pure intermediate salt compounds, which avoids the addition crystallization steps to make it economically affordable.

Brief Description of the Invention:

The present invention relates to an improved process for the preparation of almotriptan and its pharmaceutically acceptable salts as well as their novel polymorphic forms.

The first aspect of the present invention is to provide an improved process for the preparation of almotriptan malate compound of formu1a-la, which comprises of the following steps,

a) treating the l-(4-hydrazinylbenyzlsu1fonyl)pyrrolidine or its salt compound of formu1a-2 with protected derivative of 4-chlorobutraldehyde compound of formu1a-3 in presence of disodium hydrogen phosphate in a suitable solvent, to provide 2-(5-((pyrrolidin-l -ylsu1fonyl)methyl)-l H-indol-3-yl)ethanamine compound of formu1a-4,

b) reacting the 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine compound of formu1a-4 with formalin in presence of sodiumborohydride in aqueous sodium hydroxide, in a suitable solvent to provide almotriptan, which on in-situ treatment with suitable acid in a suitable solvent provides corresponding almotriptan acid addition salt compound of formu1a-1,

c) optionally purifying the obtained almotriptan acid addition salt compound of formu1a-1,

d) treating the above pure almotriptan acid addition salt compound of formu1a-1 with a suitable base in a suitable solvent to provide almotriptan, which on in-situ treatment with malic acid in a suitable solvent provides almotriptan malate compound of formu1a-la.

The second aspect of the present invention is to provide an improved process for the preparation of almotriptan malate compound of formu1a-la, which comprises of the following steps;

a) treating the alkali metal salt of 4-chloro-l-hydroxybutane-l-su1fonate compound of formu1a-5 with a suitable aqueous base, and then extracting the obtained 4-chlorobutraldehyde into a suitable solvent, which on in-situ reaction with l-(4-hydrazinylbenzyl su1fonyl)pyrrolidine compound of formu1a-2 or its salts thereof in presence of disodium phosphate in a suitable solvent provides 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine compound formu1a-4,

b) reacting the 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine compound formu1a-4 with formalin in presence of sodiumborohydride in aqueous sodium hydroxide, in a suitable solvent to provide almotriptan, which on in-situ treatment with suitable acid in a suitable solvent provides corresponding almotriptan acid addition salt compound of formu1a-1,

c) optionally purifying the obtained almotriptan acid addition salt compound of formu1a-1,

d) treating the above pure almotriptan acid addition salt compound of formu1a-1 with suitable base in a suitable solvent to provide almotriptan, which on in-situ treatment

with malic acid in a suitable solvent provides almotriptan malate compound of formu1a-la.

The third and fourth aspect of the present invention is to provide novel crystalline forms of almotriptan succinate. The crystalline forms of the present invention are characterized by its PXRD, IR spectrum and DSC thermograms.

The fifth aspect of the present invention is to provide a novel crystalline form of almotriptan oxalate. The crystalline form of the present invention is characterized by its PXRD, IR spectrum and DSC thermogram.

Brief Description of the Drawings:

Figure-1: Illustrates the PXRD of crystalline form-1 of almotriptan succinate Figure-2: Illustrates the PXRD of crystalline form-2 of almotriptan succinate Figure-3: Illustrates the PXRD of crystalline form-M of almotriptan oxalate Figure-4: Illustrates the PXRD of crystalline almotriptan malate prepared as per the present invention.

Detailed Description of the Invention:

As used herein the term "a1coholic solvents" refers to methanol, ethanol, n-propanol, isopropnol, n-butanol and isobutanol; "chloro solvents" refers to methylene chloride, chloroform and ethylene dichloride; "ketone solvents" refers to acetone, methyl ethyl ketone, methyl isobutyl ketone; "hydrocarbon solvents" refers to toluene, hexane, heptane and cyclohexane; "nitrile solvents" refers to acetonitrile; "ester solvents" refers to ethyl acetate, methyl acetate and isopropyl acetate; "ether solvents" refers to tetrahydrofuran, diethyl ether and methyl tert-butyl ether.

The term "protected 4-chlrobutyraldehyde" refers to a derivative of 4-chlorobutyraldehyde in which the aldehyde group is protected by converting it into an acetal or an adduct.

The present invention relates to an improved process for the preparation of almotriptan and its pharmaceutically acceptable salts as well as their novel polymorphic forms thereof. Almotriptan is chemically known as l-[[[3-[2-(Dimethylamino) ethyl]-lH-indol-5-yl] methyl] su1fonyl] pyrrolidine represented by the following structural formu1a-1.

Formu1a-1 and its pharmaceutically acceptable salts thereof.

Accordingly the first aspect of the present invention provides an improved process for the preparation of almotriptan malate compound of formu1a-la,

Formu1a-la which comprises of treating the l-(4-hydrazinylbenyzlsu1fonyl)pyrrolidine compound of formu1a-2 or its salts thereof

Formu1a-2 preferably hydrochloride salt of the compound of formu1a-2, with protected 4-chlrobutralehyde derivative, 4-chloro-l,l-diethoxybutane compound of formu1a-3,

Formu1a-3 in presence of a disodium hydrogen phosphate in a suitable solvents selected from a1coholic solvents, ether solvents, chloro solvents, water or mixtures thereof, preferably aqueous a1cohols, to provide 2-(5-((pyrrolidin-l-yl-su1fonyl)methyl)-lH-indol-3-yl)ethanamine compound formu1a-4,

Formu1a-4

Reacting the 2-(5-((pyrrolidin-1 -yl-su1fonyl)methyl)-1 H-indol-3 -yl)ethanamine compound formu1a-4 with formalin in presence of sodiumborohydride in aqueous sodium hydroxide, in a suitable a1coholic solvent to provide almotriptan, which on in-situ treatment with suitable acid like succinic acid or oxalic acid in a suitable solvent selected from a1cohol solvents, ester solvents, hydrocarbon solvent, ketone solvents, nitrile solvents, chloro solvents or mixtures thereof, provides corresponding almotriptan acid addition salt compound of formu1a-1,

Optionally purifying the obtained almotriptan acid addition salt compound of formu1a-1 using a suitable solvent selected from a1coholic solvents, ester solvents, hydrocarbon solvent, ketone solvents, nitrile solvents, chloro solvents, water or mixtures thereof to provide high pure almotriptan acid addition salt compound of formu1a-1.

The pure almotriptan acid addition salt compound of formu1a-1 is treated with a suitable base selected from alkali metal hydroxide like sodium hydroxide, potassium hydroxide; alkali metal carbonate like sodium carbonates, potassium carbonate and bicarbonates like sodium bicarbonate, potassium bicarbonate; ammonia or their aqueous solution, in a suitable solvent selected from a1cohol solvents, ester solvents, hydrocarbon solvent, ketone solvents, nitrile solvents or mixtures thereof, to provide almotriptan which on in-situ treatment with malic acid in a suitable solvent described above to provide almotriptan malate compound of formu1a-la.

The second aspect of the present invention provides an improved process for the preparation of almotriptan malate compound of formu1a-la, which comprises of treating the alkali metal salt compound of 4-chloro-l-hydroxybutane-l-su1fonate compound of formu1a-5, preferably sodium or potassium salt of 4-chloro-l-hydroxybutane su1fonate,

Formu1a-5

Wherein Z is Na or K ion, with a suitable aqueous base selected from sodium carbonate or potassium carbonate, followed by extraction of the obtained 4-chlorobutaraladhyde compound of formu1a-6 into a suitable chloro solvent,

Formu1a-6 which on in-situ treatment with l-(4-hydrazinyl benyzlsu1fonyl)pyrrolidine compound of formu1a-2 or its salts thereof,

Formu1a-2 preferably hydrochloride salt of compound of formu1a-2, in presence of disodium hydrogen phosphate in a suitable solvents selected from a1coholic solvents, ether solvents, chloro solvents, water or mixtures thereof, preferably aqueous a1cohol provides 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine compound formu1a-4,

Formu1a-4

Reacting the 2-(5-((pyrrolidin-1 -ylsu1fonyl)methyl)-1 H-indol-3 -yi)ethanamine compound formu1a-4 with formalin in presence of sodiumborohydride in aqueous sodium hydroxide in a suitable a1coholic solvent to provide almotriptan, which on in-situ treatment with suitable acid like succinic acid or oxalic acid in a suitable solvent selected from a1cohol solvents, ester solvents, hydrocarbon solvent, ketone solvents, nitrile solvents, chloro solvents or mixtures thereof, provides corresponding almotriptan acid addition salt compound of formu1a-1,

Optionally purifying the obtained almotriptan acid addition salt compound of formu1a-1 using a suitable solvent selected from a1coholic solvents, ester solvents, hydrocarbon solvent, ketone solvents, nitrile solvents, chloro solvents, water or mixtures thereof to provide high pure almotriptan acid addition salt compound of formu1a-1.

The pure almotriptan acid addition salt compound of formu1a-1 is treating with a suitable base selected from alkali metal hydroxide like sodium hydroxide, potassium hydroxide, alkali metal carbonate like sodium carbonates, potassium carbonate and bicarbonates like sodium bicarbonate, potassium bicarbonate; ammonia or their aqueous solution, in a suitable solvent suitable solvent selected from a1cohol solvents, ester solvents, hydrocarbon solvent, ketone solvents, nitrile solvents or mixtures thereof to provide almotriptan, which on in-situ treatment with malic acid in a suitable solvent described above provides almotriptan malate compound of formu1a-la.

The almotriptan malate can be further purified by recrystallisation from a suitable solvents selected from a1coholic solvents, ketone solvents, ester solvents or mixtures thereof to get high pure almotriptan malate.

The third aspect of the present invention provides a novel crystalline form of almotriptan succinate compound of formu1a-lb having the following structure.

Formu1a-lb The crystalline almotriptan succinate compound of formu1a-lb of the present invention is characterized by its powder X-ray diffractogram having 20 peaks at about 9.2, 14.7, 16.1, 16.9, 18.0, 18.7, 20.3, 21.8, 22.9, 23.4, 24.7, 26.0, 29.8, 35.0 and 41.3 ± degrees 20. This novel crystalline form of the presence invention is herein designated as "form-1". The crystalline form-1 is also characterized by its IR spectrum having peaks at 3373.62, 2981.26, 2887.95, 2397.10, 1708.66, 1563.89, 1463.94, 1411.65, 1373.46, 1358.76, 1322.83, 1322.83, 1202.40, 1122.84, 1015.63, 829.03, 804.79 and 656.64 cm"1 and also characterized by its DSC thermogram showing endothermic peak at 178.14°C.

The present invention also provides a process for the preparation of crystalline form-1 of almotriptan succinate compound of formu1a-lb, which comprises of the following steps,

a) heating a mixture of almotriptan and succinic acid in a suitable solvent selected from a1coholic solvents, nitrile solvents, water or mixtures thereof to reflux,

b) stirring the reaction mixture for 45 minutes at reflux,

c) cooling the reaction mixture to 25-30°C and stirring the reaction further for 2 hours,

d) filtering the solid, washing with suitable solvent,

e) drying the solid to get the crystalline form-1 of almotriptan succinate.

The fourth aspect of the present invention provides another novel crystalline almotriptan succinate compound of formu1a-lb characterized by its Powder X-ray diffractogram having 29 peaks at about 6.7, 10.2, 12.2, 13.7, 14.5, 15.2, 15.8, 16.9, 17.4, 19.0,19.9,20.3,21.2, 23.4,24.4,25.0,26.5,27.0, 28.5 and 32.9 ± degrees 29. This novel crystalline form of the present invention is herein designated as "form-2". The crystalline form-2 of the present invention is also characterized by its IR spectrum having peaks at 3424.20, 3218.62, 3198.16, 2976.28, 2918*4, 2478.49, 1711.46, 1559.15, 1486.01, 1398.27, 1342.21, 1320.92, 1236.06, 1218.29, 1175.83, 1133.61, 986.79, 959.54, 818.70, 754.90, 667.41 and 610.17 cm"1 and also characterized by its DSC thermo gram showing endothermic peak at 169.96°C.

The present invention also provides a process for the preparation of crystalline form-2 of almotriptan succinate compound of formu1a-lb, which comprises of the following steps,

a) heating a mixture of almotriptan and succinic acid in a suitable solvent selected from ester solvents; ketone solvents, hydrocarbon solvents, a1coholic solvent, water or mixtures thereof to reflux,

b) stirring the reaction mixture for 45 minutes at reflux,

c) cooling the reaction mixture to 25-30°C and stirring the reaction further for 2 hours,

d) filtering the solid, washing with suitable solvent,

e) drying the solid to get the crystalline form-2 of almotriptan succinate.
The fifth aspect of the present invention is to provide crystalline form of almotriptan oxalate compound of formu1a-1c having the following structure.

Formu1a-1c The novel crystalline form almotriptan oxalate of the present invention is characterized by its powder X-ray diffractogram having 20 peaks at about 6.5,11.7, 12.9, 14.6, 15.9, 17.8, 18.4, 19.9, 20.3, 20.7, 21.9, 25.5,26.6, 36.0 and 39.7 ± degrees 20. This crystalline form of the presence invention is herein designated as crystalline "form-M'

The crystalline form-M of the present invention is also characterized by its IR spectrum 3418.28, 3298.26, 2927.01, 2683.12, 2512.94, 1731.28, 1631.54, 1483.10, 1434.19, 1310.03, 1196.21, 1011.26, 963.96, 805.23, 710.27 and 643.84 cm"1 and by its DSC thermo gram showing endothermic peaks at 208.30°C and 227.33°C.

The novel crystalline form-M of almotriptan oxalate is prepared by heating a mixture of almotriptan and oxalic acid in a suitable a1coholic solvents to reflux temperature and then cooling the reaction mixture to 25-30°C followed by stirring the reaction mixture for 2 hours, then the obtained solid was filtered, washed with a1coholic solvent and dried to get crystalline form-M of almotriptan oxalate.

The novel crystalline form-1, form-2 of almotriptan succinate compound of formu1a-lb and novel crystalline form-M of almotriptan oxalate compound of formu1a-1c were used to prepare high pure almotriptan and its pharmaceutically acceptable salts especially malate.

XRD analysis of pharmaceutically acceptable salts of almotriptan were carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.0457min. FT-IR spectrum of pharmaceutically acceptable salts of almotriptan was recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of pharmaceutically acceptable salts of almotriptan was carried out on
Waters DSC Q-10 model differential scanning calorimeter.

The related substance of pharmaceutically acceptable salts of almotriptan was analyzed by HPLC using the following conditions: Column: X-terra, 259 x 4.6 mm, 5.0 um; Flow rate: 1.0 ml/min; wavelength: 227 nm; Temperature: 40°C; Load: 10 u1; Run time: 50 min; and using monobasic sodium phosphate in water and methanol as diluents.
The following impurities are the possible impurities which are formed during the process for the preparation of almotriptan and its pharmaceutically acceptable salts.
The present invention is represented by the following schematic representation

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore shou1d not be construed as limitation of the scope of the invention. Examples:

Example-l: Preparation of 2(5-((pyrrolidin-l-ylsu1fonyI)methyl)-lH-indol-3-yl) ethanamine compound of formu1a-4:

A mixture of l-(4-hydrazinylbenzylsu1fonyl)pyrrolidine hydrochloride (35.0 grams), hydrochloric acid (6.6 ml) and water (330 ml) was stirred for an hour at 25-30°C. In another vessel a mixture of 4-chloro-l,l-diethoxybutane (27.2 grams), hydrochloric acid (12.5 ml), water (82 ml) and methanol (375 ml) was stirred for an hour at 25-30°C and then added this mixture to the mixture containing l-(4-hydrazinylbenzylsu1fonyl) pyrrolidine. The reaction mixture was cooled to 0-5°C and stirred for an hour. The solid obtained was filtered and washed with aqueous methanol. Water (90 ml), disodium hydrogen phosphate (15 grams), methanol (560 ml) and hydrochloric acid (30 grams) was added to the obtained wet solid, heated the reaction mixture to reflux and stirred at reflux for 12 hours. The methanol was distilled off from the reaction mixture and water (375ml) was added to it. The reaction mixture was neutralized with sodium carbonate, washed with methylene chloride, saturated with sodium carbonate and then extracted into methylene chloride. The methylene chloride from the reaction mixture was distilled off under reduced pressure. Thus obtained residue isolated using diisopropyl ether. Yield: 30 grams

Example-2: Preparation of 2(5-((pyrroIidin-l-ylsu1fonyl)methyl)-lH-indoI-3-yl) ethanamine compound of formu1a-4:

A mixture of 4-chloro-l,l-diethoxybutane (4.6 grams), hydrochloric acid (0.95 ml) and water (47.5 ml) was stirred for an hour at 20-25°C. Methanol (52.5 ml) was added to l-(4-hydrazinylbenzylsu1fonyl) pyrrolidine hydrochloride (5 grams) in water (15 ml) and the reaction mixture was acidified with hydrochloric acid at 10-15°C and to this 4-chlorobutraldehyde layer was added to it and stirred for 3 hours at 10-15°C. The reaction mixture was cooled to 10-15°C and stirred for 2 hours. The obtained solid was filtered and washed with water. The solid was dissolved in methanol and aqueous disodium hydrogen phosphate (2.67 grams in 18 ml of water) at 10-15°C and reaction mixture was acidified with hydrochloric acid. The reaction mixture was heated to reflux and stirred at reflux for 10 hours. The methanol was distilled off completely under reduced pressure then water (15 ml) was added to it. The reaction mixture was washed with methylene chloride. The reaction mixture was basified with sodium carbonate and the reaction mixture was extracted into methylene chloride. The methylene chloride was distilled off under reduced pressure to give the title compound. Yield: 2.5 grams

Example-3: Preparation of almotriptan succinate compound of formu1a-lb:

A solution of 2(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl) ethanamine compound of formu1a-4 (15 grams) in methanol (300 ml) was cooled to 0-10°C. Sodium borohydride (9.28 grams) in aqueous sodium hydroxide (0.3 gram in 130 ml water) and formalin solution (63 ml in 64 ml of methanol) was added to the above reaction mixture slowly at 5-15°C and then stirred for an hour. The reaction mixture was quenched with aqueous hydrochloric acid and stirred for 20 minutes at 25-30°C. The pH of the reaction mixture was adjusted to 6.5 with aqueous acetic acid. The methanol from the reaction mixture was distilled off under reduced pressure and then reaction mixture washed with ethyl acetate. Potassium carbonate (75 grams) was added to the reaction mixture, stirred for 35 minutes at 25-35°C and then the reaction mixture extracted into ethyl acetate. Succinic acid (5.7 grams) was added to the ethyl acetate layer and stirred for 15 hours 25-35°C. The solid was filtered, washed with ethanol. Isopropyl a1cohol (12 ml) was added to the wet solid and heated to reflux then stirred for an hour at reflux. The reaction mixture was cooled slowly to 25-30°C in 90 minutes. The solid obtained was filtered, washed with isopropyl a1cohol and then dried to get the title compound. Yield: 18 grams Purity by HPLC: 97.81%

ExampIe-4: Preparation of almotriptan malate compound of formu1a-la:

Ethyl acetate (15 ml) was added to a solution of almotriptan succinate (2.3 grams in 23 ml of water) and stirred for 15 minutes. The reaction mixture was basified with ammonia and stirred for 30 minutes at 25-30°C. The layers were separated, aqueous layer extracted with ethyl acetate and organic layer washed with water. The solvent from the organic layer was distilled off under reduced pressure. Methanol was added to the residue and then distilled off the methanol. The residue was dissolved in methanol and subjected to carbon treatment and then filtered through hyflow and the bed was washed with methanol. Malic acid solution (0.8 gram in 2 ml methanol) was added to the filtrate and then the reaction mixture was heated to reflux, stirred for an hour. The reaction mixture was cooled to 25-30°C and stirred for 2 hours. The solid obtained was filtered, washed with methanol and the dried to get the title compound. Yield: 1.8 grams Yield: 99.51 %

Example-5: Purification of almotriptan malate compound of formu1a-la:

A mixture of almotriptan (1.7 grams) and methanol (10 ml) was heated to reflux and stirred for 1.5 hours. The reaction mixture was cooled to 25-30°C and stirred for 2 hours.

The solid obtained was filtered, washed with methanol and dried to get the pure title compound. Yield: 1.5 grams Purity by HPLC: 99.95%

Example-6: Preparation of 2(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yI) ethanamine compound of formu1a-4:

Sodium carbonate (18 grams) was added to a solution of 4-chlorobutraldehyde sodium bisu1phate (54 grams in 750 ml of water), stirred for 30 minutes at 25-35°C and extracted the 4-chlorobutraldehyde into methylene chloride (350 ml). l-(4-hydrazinyl benzylsu1fonyl) pyrrolidine hydrochloride (75 grams) was added to aqueous sodium bicarbonate (52 grams in 750 ml) and then the above extracted 4-chlorobutraldehyde in methylene chloride was added to it. The reaction mixture was stirred for 1.5 hours at 25-30°C and then methylene chloride distilled off at 40-45°C. Hyflow was added to the residue and stirred for 45 minutes at 25-30°C. The reaction mixture was filtered and extracted the filtrate with methylene chloride. The hyflow solid is slurried with methylene chloride. The extracted methylene chloride layer was dried with sodium su1phate and then distilled off methylene chloride under reduced pressure at below 40°C. The residue was dissolved in methanol then water (450 ml), disodium hydrogen phosphate (43 grams) and hydrochloric acid (20.3 ml) was added to it and heated to reflux temperature. The reaction mixture was stirred at reflux (65-70°C) for 12 hours and then distilled off the solvent under reduced pressure at below 60°C. Water (1200 ml) was added to the reaction mixture, washed with methylene chloride and sodium carbonate (450 grams) was added to it. The reaction mixture extracted into methylene chloride and distilled off the solvent from reaction mixture to get the title compound. Yield: 23 grams.

Example-7: Preparation of 2(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indoI-3-yl) ethanamine compound of formu1a-4:

Hydrochloric acid (300 ml) was added to 4-((pyrrolidin-l-ylsu1fonyl)methyl aniline (35 grams) was added and cooled to -10°C. Sodium nitrite solution (13.6 grams in 80 ml) was added to it and stirred for 1.5 hours at -10 to 0°C. The reaction mixture was added slowly to the cooled mixture of stannous chloride dihydrate (164.6 grams) and hydrochloric acid (120 ml) at -10 to 0°C and stirred for 1.5 hours. The obtained l-(4-hydrazinylbenzylsu1fonyl)pyrrolidine hydrochloride was filtered off and washed with hydrochloric acid. 4-chloro-l,l-diethoxybutane (27.2 grams), hydrochloric acid (12.5 ml) and water (82 ml) was stirred for an hour at 25-30°C. In another vessel a previously obtained l-(4-hydrazinylbenzylsu1fonyl)pyrrolidine hydrochloride (35 grams), hydrochloric acid (12.5 ml) and water (82 ml) was stirred for an hour at 25-30°C and to this mixture to the above 4-chlorobutraldehyde layer was added and stirred for 2 hours.

The reaction mixture was cooled to 0-5 °C and stirred for an hour. The solid obtained was filtered, washed with aqueous methanol. Water (90 ml), disodium hydrogen phosphate (15 grams), methanol (560 ml) and hydrochloric acid (30 grams) was added to the obtained wet solid, heated the reaction mixture reflux and stirred at reflux for 12 hours.

The methanol was distilled off from the reaction mixture and water was added to it. The reaction mixture was basified with sodium carbonate. The reaction mixture was washed with methylene chloride, saturated with sodium carbonate and then extracted int methylene chloride. The methylene chloride from the reaction mixture was distilled off under reduced pressure to get the title compound. Yield: 29 grams.

Example-8: Purification of almotriptan succinate compound of formu1a-lb:

Almotriptan succinate (3.2 grams) was dissolved in water (32 ml), added ethyl acetate (25 ml) and basified the reaction mixture with aqueous ammonia. The reaction mixture was stirred for 30 minute at 25-30°C and the ethyl acetate layer was separated. Aqueous layer was extracted with ethyl acetate and then total ethyl acetate layer was distilled off under reduced pressure at below 60°C. The residue was dissolved in ethanol (10 ml) and succinic acid (1.09 ml) was added and heated to reflux temperature then stirred for 60 minutes at reflux. The reaction mixture was cooled to 25-30°C and stirred for 2 hours.

Filtered the solid, washed with ethanol and dried to get the pure title compound. Yield: 2.1 grams Purity by HPLC: 99.72%

Example-9: Preparation of crystalline form-1 almotriptan succinate compound of formu1a-lb:

A mixture of almotriptan (3 grams) in ethanol (15 ml) and succinic acid (1.17 grams) was heated reflux and stirred for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 2 hours at 25-35°C. Filter the solid, washed with ethanol and then dried to get the crystalline form-1 of almotriptan succinate: Yield: 2.4 grams

Example-10: Preparation of crystalline form-1 almotriptan succinate compound of formu1a-lb:

A mixture of almotriptan (3 grams) and succinic acid (1.17 grams) in acetonitrile (15 ml) was heated to reflux and stirred for 45 minutes at reflux. The reaction mixture was cooled to 25-35°C and stirred for 2 hours at 25-35°C. Filter the solid, washed with acetonitrile and then dried to get the crystalline form-1 of almotriptan succinate: Yield: 2.2 grams

Example-11: Preparation of crystalline form-2 almotriptan succinate compound of formu1a-lb:

A mixture of almotriptan (3 grams) and succinic acid (1.17 grams) in acetone (15 ml) was heated to reflux and stirred for 45 minutes at reflux. The reaction mixture was cooled to 25-35°C and stirred for 2 hours at 25-35°C. Filter the solid, washed with acetonitrile and then dried to get the crystalline form-2 of almotriptan succinate: Yield: 2.6 grams

Example-12 & 13: Preparation of crystalline form-2 almotriptan succinate compound of formu1a-lb:

The crystalline form-2 of almotriptan succinate has been prepared analogues manner to example-11 using the appropriate solvent as shown in the following table in place of acetone.

Example-14: Preparation of crystalline form-M of almotriptan oxalate compound of formu1a-1c:

A mixture of almotriptan (5 grams) and oxalic acid (2 grams) in ethanol (25 ml) was heated to reflux and stirred for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 2 hours at 25-35°C. Filter the solid, washed with ethanol and then dried to get the crystalline form-M of almotriptan oxalate. Yield: 2.8 grams

We Claim:
1. An improved process for the preparation of almotriptan malate compound of formu1a-la, Formu1a-la

which comprises of the following steps,

a) treating the l-(4-hydrazinylbenyzlsu1fonyl)pyrrolidine compound of formu1a-2 or
its salt thereof,

Formu1a-2

with 4-chloro-l,l-diethoxybutane compound of formu1a-3,

Formu1a-3

in presence of disodium hydrogen phosphate in a suitable solvent, to provide 2-(5-((pyrrolidin-1 -ylsu1fonyl)methyl)-1 H-indol-3-yl)ethanamine compound of formu1a-4,

Formu1a-4

b) reacting the 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine
compound of formu1a-4 with formalin in presence of sodiumborohydride in
aqueous sodium hydroxide, in a suitable solvent to provide almotriptan, which on
in-situ treatment with suitable acid like succinic acid or oxalic acid in a suitable
solvent provides corresponding almotriptan acid addition salt compound of
formu1a-1,

c) optionally purifying the obtained almotriptan acid addition salt compound of formu1a-1,

d) treating the above pure almotriptan acid addition salt compound of formu1a-1 with a suitable base in suitable solvent to provide almotriptan, which on in-situ treatment with malic acid in a suitable solvent provides almotriptan malate compound of formu1a-la.

2. An improved process for the preparation of almotriptan malate compound of formu1a-la, which comprises of the following steps,

a) treating the alkali metal salt compound of 4-chloro-l-hydroxybutane-l-su1fonic acid compound of formu1a-5

Formu1a-5

Wherein in Z is Na or K ion,

with a suitable aqueous base, and then extracting the obtained 4-chloro butraldehyde compound of formu1a-6 into a suitable solvent,

Formu1a-6

which on in-situ treatment with l-(4-hydrazinylbenzylsu1fonyl)pyrrolidine compound of formu1a-2 or its salts thereof

Formu1a-2

in presence of disodium hydrogen phosphate in a suitable solvent to
provide 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine
compound formu1a-4,
Formu1a-4

b) reacting the 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine compound formu1a-4 with formalin in presence of sodiumborohydride in aqueous sodium hydroxide, in a suitable solvent to provide almotriptan, which on in-situ treatment with suitable acid like oxalic acid or succinic acid in a suitable solvent provides corresponding almotriptan acid addition salt compound of formu1a-1,

c) optionally purifying the obtained almotriptan acid addition salt compound of formu1a-1,

d) treating the above pure almotriptan acid addition salt compound of formu1a-1 with suitable base in a suitable solvent to provide almotriptan, which on in-situ treatment with malic acid in a suitable solvent provides almotriptan malate compound of formu1a-la.

3. The process of claim 1 or 2, comprising at least one of the following;

i) in step a) wherein the suitable solvent is selected from a1coholic solvents, ether solvents, chloro solvents, water or mixtures thereof; and base is selected from aqueous sodium carbonate and potassium carbonate;

ii) in step b) & c), wherein the suitable solvent is selected from a1cohol solvents, ester solvents, hydrocarbon solvent, ketone solvents, nitrile solvents, chloro solvents and water or mixtures thereof;

iii) in step d) suitable solvent is selected from a1cohol solvents, ester solvents, hydrocarbon solvent, ketone solvents, nitrile solvents, chloro solvents and water or mixtures thereof; and base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia or mixtures thereof.

4. A process for the preparation of almotriptan malate compound of formu1a-la,
which comprises of the following steps,

a) treating the hydrochloride salt of l-(4-hydrazinylbenyzlsu1fonyl)pyrrolidine hydrochloride compound of formu1a-2 with 4-chloro-l,l-diethoxybutane compound of formu1a-3 in presence of disodium hydrogen phosphate in aqueous methanol to provide 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine compound of formu1a-4,

b) reacting the 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine compound of formu1a-4 with formalin in presence of sodiumborohydride in aqueous sodium hydroxide, in methanol to provide almotriptan, which on in-situ treatment with succinic acid in ethanol or acetonitrile provides almotriptan succinate compound of formu1a-lb,

c) purifying the almotriptan succinate compound of formu1a-lb using ethanol, ethyl acetate, water or mixtures thereof,

d) treating the almotriptan succinate compound of formu1a-lb with aqueous ammonia and then extracting the almotriptan with ethyl acetate, and then treating it with malic acid in methanol to provide almotriptan malate compound of formu1a-1 a.

5. An improved process for the preparation of almotriptan malate compound of
formu1a-la, which comprises of the following steps,

a) treating the sodium 4-chloro-l-hydroxybutane-l-su1fonate compound of formu1a-5a with aqueous sodium carbonate, and then extracting the obtained 4-chloro butraldehyde compound of formu1a-6 into methylene chloride, which on in-situ reaction with l-(4-hydrazinylbenzyl su1fonyl)pyrrolidine hydrochloride compound of formu1a-2a in the presence of disodium hydrogen phosphate in aqueous methanol, provides 2-(5-((pyrrolidin-l-ylsu1fonyl) methyl)-lH-indol-3-yl)ethanamine compound of formu1a-4,

b) reacting the 2-(5-((pyrrolidin-l-ylsu1fonyl)methyl)-lH-indol-3-yl)ethanamine compound of formu1a-4 with formalin in presence of sodiumborohydride in aqueous sodium hydroxide in methanol to provide almotriptan, which on in-situ treatment with succinic acid in ethanol provides almotriptan succinate compound of formu1a-lb,

c) treating almotriptan succinate compound of formu1a-lb with aqueous ammonia and then extracting the almotriptan with ethyl acetate, and then treating it with malic acid in methanol to provide almotriptan malate compound of formu1a-la.

6. A novel crystalline form-1 of almotriptan succinate characterized by any one of the following;

a) its power X-ray diffractogram having 20 peaks at about 9.2,14.7,16.1,16.9,18.0, 18.7, 20.3, 21.8, 22.9, 23.4, 24.7, 26.0, 29.8, 35.0 and 41.3 ± degrees 20. This crystalline form is herein designated as "form-1";

b) its IR spectrum having peaks at 3373.62, 2981.26, 2887.95, 2397.10, 1708.66, 1563.89, 1463.94, 1411.65, 1373.46, 1358.76, 1322.83, 1322.83, 1202.40, 1122.84,1015.63, 829.03, 804.79 and 656.64 cm"1;

c) its DSC thermo gram showing endothermic peak at 178.14°C.

7. A novel crystalline form-2 of almotriptan succinate characterized by any of the
following;

a) its Powder X-ray diffractogram having 20 peaks at about 6.7, 10.2, 12.2, 13.7, 14.5, 15.2, 15.8, 16.9, 17.4, 19.0, 19.9, 20.3, 21.2, 23.4, 24.4, 25.0, 26.5, 27.0, 28.5 and 32.9 ± degrees 20;

b) its IR spectrum having peaks at 3424.20, 3218.62, 3198.16, 2976.28, 2918.84, 2478.49, 1711.46, 1559.15, 1486.01, 1398.27, 1342.21, 1320.92, 1236.06, 1218.29, 1175.83, 1133.61, 986.79, 959.54, 818.70, 754.90, 667.41 and 610.17 cm"1;

c) its DSC thermo gram showing endothermic peak at 169.96°C.

8. A novel crystalline form-M of almotriptan oxalate is characterized by any one of the following;

a) its powder X-ray diffractogram having 20 peaks at about 6.5, 11.7, 12.9, 14.6, 15.9,17.8,18.4,19.9,20.3,20.7,21.9,25.5,26.6,36.0 and 39.7 ± degrees 20;

b) its IR spectrum 3418.28, 3298.26, 2927.01, 2683.12, 2512.94, 1731.28, 1631.54, 1483.10, 1434.19, 1310.03, 1196.21, 1011.26, 963.96, 805.23, 710.27 and 643.84 cm"1;

c) its DSC thermo gram showing peaks at 208.30°C and 227.33°C.

9. A process for the preparation of novel crystalline form-1 of almotriptan succinate
compound of formu1a-lb, which comprises of the following steps,

a) heating a mixture of almotriptan and succinic acid in a suitable solvent selected from a1coholic solvents; nitrile and water or mixtures thereof to reflux,

b) stirring the reaction mixture for 45 minutes at reflux,

c) cooling the reaction mixture to 25-30°C and stirring the reaction further for 2 hours,

d) filtering the solid, washing with suitable solvent,

e) drying the solid to get the crystalline form-1 of almotriptan succinate.

10. A process for the preparation of crystalline form-2 of almotriptan succinate compound of formu1a-lb, which comprises of the following steps,

a) heating a mixture of almotriptan and succinic acid in a suitable solvent selected from ester solvents; ketone solvents, hydrocarbon solvents, a1coholic solvent and water or mixtures thereof to reflux,

b) stirring the reaction mixture for 45 minutes at reflux,

c) cooling the reaction mixture to 25-30°C and stirring the reaction further for 2 hours,

d) filtering the solid, washing with suitable solvent,

e) drying the solid to get the crystalline form-2 of almotriptan succinate.