This application claims priority to this Indian patent application number 1613/CHE/2013 filed on April 09,2013.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 3-(2-(dimethylamino)ethyl)-N-methy 1 -1 H-indole-5-methanesulfonamide (Sumatriptan) and its acid addition salts thereof.

BACKGROUND OF THE INVENTION

Sumatriptan is chemically designated as 3-[2-(Dimethylamino)ethyl]-N-methyl-lH-indole-5-methanesulfonamide and is being administered as succinate. Sumatriptan succinate tablets are indicated for the acute treatment of migraine attacks with or without aura in adults. Sumatriptan is represented by the following structure:
.. H
O. ,0 \ I H3C. >' ^L ^^y
H /N CH3

Sumatriptan is reported for the first time by Glaxo in patent No. US 5037845. It is found to be serotonin 5HTi-receptor agonist Sumatriptan is available in the market as Imigran or Imitrex. US 5037845, filed in 1985 and assigned to Glaxo discloses the process for the preparation of Sumatriptan succcinate by reacting 4,4-dimethylbutanamine with 4-hydrazino-N-methylbenzenemethane sulfonamide hydrochloride, to give 4-[2-[4-(dimethylamino)butylidene]hydrazine]-N-methylbenzenemethane sulphonamide, which is subjected to cyclization reaction in the presence of polyphosphate ester in chloroform. The obtained crude Sumatriptan is purified by column chromatography to give Sumatriptan base, which is treated with succinic acid in industrial methylated spirit (IMS) to give Sumatriptan Succinate. US 5103020, filed in 1991 by Glaxo group Ltd, discloses process for the preparation of 3-(2-aminoethyl)-LH-indole-5-yl]-N-methyl methane sulphonamide which is an intermediate for the preparation of Sumatriptan.

The process comprises reacting 4-Hydrazino-N-methyl Benzene methane Sulfonamide or its acid addition salt with 4-Chloro-1- hydroxy butane sulphonic acid sodium salt in the presence of acid and disodium hydrogen orthophosphate to give 3-(2-aminoethyl)-lH-indole-5-yl]-N-methyl methane sulphonamide (IV). WO 2009037718 discloses a process for the preparation of Sumatriptan benzoate and its conversion to pure Sumatriptan base as well as Sumatriptan succinate.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide an improved process for the preparation of Sumatriptan and its acid addition salts with higher yields and purity. Another object of the present invention is to provide a one pot process for the preparation of Sumatriptan acid addition salts. One aspect of the present invention provides one pot process for the preparation of Sumatriptan acid addition salts especially benzoate salt, wherein the process comprises reacting 4-Hydrazino-N-methyl Benzene methane Sulfonamide or its acid addition salt with 4-halo-l- hydroxy butane sulphonic acid or its alkaline salt in the presence of a pH modifier to give 3-[(2-aminoethyl)-lH-indole-5-yl-N-methyl]methanesulphonamide. The obtained compound is subjected to reductive methylation and converted to its benzoate salt. Another aspect of present invention provides further conversion of above obtained Sumatriptan benzoate to Sumatriptan and its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a one pot process for the preparation of Sumatriptan acid addition salts with higher yields and more purity. The main aspect of the present invention provides one pot process for the preparation of Sumatriptan benzoate salt comprising the steps of:

a) reacting 4-Hydrazino-N-methyl benzene methane Sulfonamide or its acid salt, with 4-halo-l -hydroxy butane sulphonic acid alkaline metal salt in the presence of pH modifying agent to give 3-[(2-aminoethyl)-lH-indole-5-yl-N-methyl]methanesulphonamide (IV);

b) adjusting the pH to 7.0 - 8.5;

c) adding formaldehyde and reducing agent;

d) reacting with benzoic acid to get Sumatriptan benzoate salt.

In one embodiment of present invention, reaction of 4-Hydrazino-N-methyl benzene methane sulfonamide (II) or its acid salt with 4-halo-l-hydroxy butane sulphonic acid alkaline metal salt (III) is carried out in a solvent at 50-90°C in the presence of pH modifier. The solvent used for the reaction is selected form protic organic solvents such as methanol, propanol, isopropanol, n-butanol and water or mixtures thereof. The acid salt of compound of formula II used in this reaction is preferably HC1 salt. The compound of formula HI is preferably 4-chloro-l-hydroxy butane sulphonic acid sodium salt. The pH modifying agent is selected from salts of weak acids such as salts of phosphoric, acetic, phthalic, carbonic and sulphurous acids, preferably phosphate salts and more preferably monosodium dihydrogen phosphate or disodium hydrogen orthophosphate. After completion of the reaction, reaction mass is cooled and optionally treated with activated carbon [ENOPC]. pH of the reaction mass is adjusted between 7.0 and 8.0 with a base at 10-30°C.

The base used for the pH adjustment is selected from alkali and alkaline earth metal hydroxides, carbonates and bicarbonates, preferably potassium bicarbonate. Then the resultant mixture is cooled to 5- 25 °C, preferably 14-16°C and formaldehyde solution and reducing agent solution are added. The formaldehyde solution is prepared using an alcohol preferably methanol. The reducing agent is selected from alkali or alkaline earth metal borohydrides, preferably sodium borohydride. The reducing agent solution is prepared by using water and a base, preferably alkali/alkaline metal hydroxide. Optionally pH of the resultant reaction mixture is adjusted to acidic preferably 4-6, water is added and washed with water immiscible organic solvent to remove impurities. The water immiscible organic solvent used for washing is selected from hydrocarbons, halogenated solvents, ethers, esters preferably dichloromethane. The pH of the resultant mixture is adjusted to basic preferably 10-12 and extracted with water immiscible organic solvent.

The solvent is distilled off, filtered and the crude is degassed. The water immiscible organic solvent used for extraction is selected from hydrocarbons, halogenated solvents, ethers, esters and ketones preferably dichloromethane. The obtained reaction mixture is treated with benzoic acid at 30-80°C in the presence of suitable solvents selected from alcohols, ketones, esters, ethers, halogenated solvents, hydrocarbons, and mixtures thereof, preferably acetone. The reaction mixture is filtered to isolate Sumatriptan benzoic acid salt. Another embodiment of the present invention provides a process for the preparation of pure Sumatriptan base and its acid addition salts preferably Sumatriptan succinate from Sumatriptan benzoate salt obtained in the above one pot process. The conversion of Sumatriptan benzoate to pure Sumatriptan base and Sumatriptan succinate is carried out according to the processes disclosed in WO 2007037718. The following examples illustrate the invention, which should not be construed in limiting the scope of the present invention.

Experimental procedure:

Example-1: Process for the preparation of Sumatriptan benzoate: 1200 ml of methanol was taken in a round bottom flask to this 100 gms of 4-Hydrazino-N-methyl Benzene methane Sulfonamide Hydrochloride, 90 gms of 4-Chloro-l- hydroxy butane sulphonic acid sodium salt, were added followed by 660 ml of water and 14.1 gms of disodium orthophosphate. The reaction was maintained under nitrogen purging. The temperature was raised to reflux at 75±5°C maintained for 4-6 hrs. The mass was cooled to room temperature and maintained for 1-2 hrs. The reaction mass was treated with activated carbon [ENOPC] (8gms in 10ml methanol) and filtered. Reaction mass, pH was adjusted to 7.5-7.9 using potassium carbonate. The reaction mass was cooled to 14±5°C and added freshly prepared formaldehyde (78gms of formaldehyde and 70ml of methanol) and sodium borohydride (140ml water+lgm NaOH flakes+16.5gms of sodium borohydride) solutions simultaneously.

The reaction mass was maintained for 2-4 hrs and the pH was adjusted to 2.1-2.5 with dilute hydrochloric acid. Again the pH was adjusted to 5.0-5.3 with potassium carbonate and maintained at 15±5°C. To the reaction mass water was added followed by dichloromethane. pH of the reaction mass was adjusted to 10.7-11.1 with potassium carbonate. The resultant solution was extracted with Dichloromethane. Dichloromethane layer was distilled off completely from the reaction mass. 500ml of acetone was added to the crude and the temperature was raised to 43±5°C. 50gms of benzoic acid was added to the reaction mixture. Reaction temperature was raised to 55±5°C and maintained for 20-40 min. Reaction mass was cooled and the obtained solid was filtered to yield Sumatriptan benzoate (120 gm).

Example-2: Process for the preparation of Sumatriptan base: 100 g of Sumatriptan benzoate was taken in a mixture of water (500ml) and methanol (500ml) at 30±5 °C. 2 gms of sodium dithionate and activated carbon (ENOPC) (lOg in 20ml) were added and maintained for 35±5 min. The reaction mass is filtered on hyflo bed and washed with water. pH of the filtrate is adjusted to 9.6-10.0 with aqueous sodium bicarbonate. The reaction mass was cooled to 2±2 °C and maintained for 2 hrs. The obtained solid was filtered and dried under vacuum to give 55gm of pure Sumatriptan base. ExampIe-3: Process for the preparation of Sumatriptan succinate To lOOgm of Sumatriptan base, 250ml of methanol and 50ml of water were added under nitrogen atmosphere 30±5 °C. The reaction temperature was raised to 57±5 °C. To the reaction mixture 60gm of succinic acid was added and maintained for 30 min. To this activated carbon [ENOPC] (lOg in 20ml) was added. The reaction mass was filtered, washed with methanol. Filtrate was cooled to 0-5°C and obtained solid was filtered. The solid was recrystallized in methanol to give pure Sumatriptan succinate (130 gms).

We Claim:

1. One pot process for the preparation of Sumatriptan benzoate salt comprising the steps of:

a) reacting 4-Hydrazino-N-methyl benzene methane Sulfonamide or its acid salt, with 4-halo-l-hydroxy butane sulphonic acid alkaline metal salt in the presence of pH modifying agent to give 3-[(2-aminoethyl)-lH-indole-5-yl-N-methyl]methanesulphonamide (IV);

b) adjusting the pH to 7.0 - 8.5;

c) adding formaldehyde and reducing agent;

d) reacting with benzoic acid to get Sumatriptan benzoate salt.

2. The process according to claim 1, wherein the pH modifying agent is selected from salts of phosphoric acid, acetic acid, phthalic acid, carbonic acid and sulphurous acid.

3. The process according to claim 2, wherein the pH modifying agent is monosodium dihydrogen phosphate or disodium hydrogen orthophosphate.

4. The process according to claim 1, wherein the reducing agent used in step c) is selected from alkali or alkaline earth metal borohydrides.

5. The process according to claim 4, wherein the reducing agent is Sodium borohydride.

6. The process according to claim 1, wherein obtained Sumatriptan benzoate salt is further converted into sumatriptan base or its pharmaceutically acceptable salts.

7. A process according to claim 1, wherein obtained Sumatriptan benzoate salt is further converted into Sumatriptan succinate.

8. One pot process for the preparation of Sumatriptan benzoate salt comprising the steps of:

a) reacting 4-Hydrazino-N-methyl benzene methane Sulfonamide or its acid salt, with 4-halo-l-hydroxy butane sulphonic acid alkaline metal salt in the presence of pH modifying agent to give 3-[(2-aminoethyl)-lH-indole-5-yl-N-methyl]methanesulphonamide (IV);

b) adjusting the pH to 7.0-8.5;

c) adding formaldehyde and reducing agent;

d) optionally adjusting the pH to acidic and washing with water immiscible organic solvent;

e) adjusting the pH to basic medium and extracting with water immiscible organic solvent;

f) adding benzoic acid to get Sumatriptan benzoate salt.