The present invention provides processes for the purification of torsemide.
Background of the Invention

Torsemide, its pharmaceutically acceptable salts thereof and process for their preparation were first disclosed in U.S. Patent No. 4,018,929 (herein after refer to '929 patent). Torsemide is chemically, N-[[(l-methylethyl)amino]carbonyl]-4-[(3- methylphenyl)amino]pyridine-3-sulfonamide. Torsemide is represented by the following structure.

Torasemide (USAN) is a pyridine-sulfonyl urea type loop diuretic mainly used in the management of edema associated with congestive heart failure. It is also used at low doses for the management of hypertension. It is marketed under the brand name Demadex'^'. Torsemide is a loop diuretic that has been found to be particularly effective for the treatment of edema associated with chronic renal failure.

According to the '929 patent described a process for the preparation of torsemide which comprises 3-sulfonamido-4-(3-methylbenzyl)amino-pyridine with N- butylisocyanate in the presence of triethylamine by heating at 85 to 95*^0 during 10 hours to obtain residue. To the residue was added ethanol and sodium hydroxide, acidified with acetic acid. The mixture was treated with a solution of sodium bicarbonate in a mixture (3:1) of water and ethanol during 1 hour, and isolating to obtain torsemide.

US patent no. 4,244,950 described a process for the preparation of torsemide which comprises reacting 3-sulfonamido-4-(3-methylbenzyl)amino-pyridine with isopropylisocyanate in the presence of triethylamine and dichloromethane at room temperature for 20 hours, acidified with acetic acid and isolating to obtain torsemide.

EP patent application no. 1,433,784 disclosed a process for the preparation of torsemide which comprises providing a reactive mixture comprising 4-(3- niethylphenylamino)-3-pyridine-sulphonamide, acetone and sodium hydroxide, and adding isopropyhsocyanate and optionally water to the mixture. Then the reaction mixture was acidified with acetic acid and isolating to form torsemide.

EP patent application no. 1,741,429 disclosed a process for the preparation of torsemide which comprises reacting 3-sulfonylamide-4-(3'-methylphenyl)- aminopyridine with isopropyhsocyanate in the presence of triethyl amine in a solvent selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate and butyl acetate, and mixtures thereof.

U.S. patent no. 7,378,527 disclosed a process for the preparation of torsemide which comprises reacting 3-sulfonylamide-4-(3'-methylphenyl)-aminopyridine with isopropyl isocyanate in the presence of an alkali carbonate or bicarbonate such as sodium carbonate and potassium carbonate and acetone to form alkali torsemide mixture. The alkali torsemide mixture was dissolved in water and then added acetic acid, the resulting suspension was stirred for 2 hours and isolating to obtain torsemide.

Torsemide is purified with ethanol and water in ethanol to water ratio of 1:3. This method failed to effectively reduce 4-((3-methylphenyl)amino)-3-pyridinesulfonamide from the torsemide.
4-((3-methylphenyl)amino)-3-pyridinesulfonamide and 4-[(N-(3-methylphenyl)- N-4-((3-methylphenyl)amino)-3-pyridinesulfonyl)amino]-3-pyridinesulfonamide are common impurities of the torsemide and it has been found that is very difficult to remove these impurities of the torsemide contaminated with the impurities. The present invention is intended to enhance the purity of torsemide, in particular, the present invention is directed to reduce or remove 4-((3-methylphenyl)amino)-3- pyridinesulfonamide and 4-[(N-(3-methylphenyl)-N-4-((3-methylphenyl)amino)-3- pyridinesulfonyl)amino]-3-pyridinesulfonamide impurities from the pure torsemide.

Thus, an object of the present invention is to provide processes for the purification of torsemide.

Detailed Description of the Invention

According to one aspect of the present invention, there is provided a process for the purification of torsemide, which comprises:

a. maintaining torsemide with solvent system comprising ethanol and water at
below 50"C; and

b. isolating torsemide in the solvent system.

The said process is characterized in that the ratio of ethanol to water is 2:1 to 4:1. Preferably the ratio of ethanol to water may be 2.5:1 to 3.5:1 and more preferably the ratio is 3:1.

The maintenance in step (a) may preferably be carried out at below 40°C and more preferably at below 20 to 30°C.

Preferably maintenance may be carried out under stirring for at least 30 minutes.

Isolation of torsemide may preferably be carried out by methods known such as filtration or centrifugation.

The purification method of the invention enhances the purity of torsemide, particularly by reducing or removing 4-((3-methylphenyl)amino)-3-pyridinesulfonamide impurity.

According to another aspect of the present invention, there is provided a process for the purification of torsemide, which comprises:
a. suspending or dissolving torsemide in acetone;
b. heating the contents to an elevated temperature; and
c. isolating torsemide from the contents.
The term "elevated temperature" refers to temperature at above 25°C. Preferably the contents are heating in step (b) at reflux.

Isolation of torsemide may preferably be carried out by methods known such as filtration or centrifugation.

The purification method of the invention enhances the purity of torsemide, particularly by reducing or removing 4-[(N-(3-methylphenyl)-N-4-((3- methylphenyl)amino)-3-pyridinesulfonyl)amino]-3-pyridinesulfonamide impurity.

The contents of torsemide and the impurities are determined by High performance liquid chromatography (HPLC). HPLC conditions for analysis are:
Column : Zodiac 120-7-C18 shield; 150 mm x 4.6 mm, 7 |am or
equivalent
Flow rate : 1.5 mL/min
Detector wavelength : 288 mm
Column oven temperature : 25°C
Injection volume : 20 µL
Run time : 70 minutes.

The chemical formula of 4-((3-methylphenyl)amino)-3-pyridinesulfonamide may be represented as:

The chemical formula of 4-[(N-(3-methylphenyl)-N-4-((3-methylphenyl)amino)- 3-pyridinesulfonyl)amino]3-pyridine sulfonamide may be represented as:

The two purification methods of the invention can be performed sequencely in any order to obtain torsemide in highly pure form.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples

Example 1:

Preparation of Torsemide

4-((3-methylphenyl)amino)-3-pyridinesulfonamide (100 gm), dichloromethane (1000 ml) and triethylamine (54 ml) are added and stirred for 10 minutes at room temperature. To the reaction mass was added isopropyl isocynate (64 gm) for 1 hour and the temperature of the reaction mass was raised to reflux. The reaction mass was maintained for 4 hours at reflux and distilled off the solvent completely under vacuum at below 50"C. Water (800 ml) was added to the reaction mass and cooled to 20®C. The pH of the reaction mass was adjusted to 12.0 with sodium hydroxide solution (40%, 200 ml). The aqueous layer was treated with carbon and the pH was adjusted to 6.0 to 6.5 by using acetic acid (90 ml), and stirred for 2 hours at room temperature. The separated solid was filtered and dried at 50 to 55'^C for 4 hours to obtain 132 gm of torsemide (HPLC Purity: 98.9%)

Example 2:

Purification of Torsemide

Torsemide (125 gm; HPLC Purity: 98.9%) as obtained in example 1 was added to ethanol (750 ml) and stirred for 10 minutes at 30°C. To the reaction mass was added water (250 ml) and stirred for 1 hour at 30''C, filtered. The solid obtained was dried at 50 to 55"C for 5 hours to obtain 116 gm of torsemide. Torsemide: 99.6%;
4-((3-methylphenyl)amino)-3-pyridinesulfonamide: 0.05%); 4-[(N-(3-methylphenyl)-N-4-((3-methylphenyl)amino)-3-pyridinesulfonyl)amino]-3- pyridinesulfonamide (dimmer impurity): 0.3%i.

Example 3:

Purification of Torsemide

Torsemide (12 gm; HPLC Purity: 98.9%) was added to ethanol (75 ml) and stirred for 10 minutes at 40°C. To the reaction mass was added water (25 ml) and stirred for 1 hour at 30"C, filtered. The solid obtained was dried at 50 to 55°C for 5 hours to obtain 10.5 gm of torsemide. Torsemide: 99.55%; 4-((3-methylphenyl)amino)-3-pyridinesulfonamide: 0.06%; Dimmer impurity: 0.31%.

Example 4:

Purification of Torsemide

Torsemide (100 gm; HPLC Purity: 98.9%) was added to ethanol (600 ml) and water (200 ml) at 30°C. The reaction mass was stirred for 1 hour at 30°C, filtered, dried at 50 to 55°C for 6 hours to obtain 91 gm of torsemide. Torsemide: 99.65%;
4-((3-methylphenyl)amino)-3-pyridinesulfonamide: 0.04%; Dimmer impurity: 0.29%.

Example 5:

Purification of Torsemide

Torsemide (125 gm; HPLC Purity: 98.9%) was added to ethanol (625 ml) and stirred for 10 minutes at 25 to 30°C. To the reaction mass added water (250 ml) and stirred for 1 hour at 25 to 30°C. The separated solid was filtered and dried at 50 to 55°C for 6 hours to obtain 115 gm of torsemide.

Torsemide: 99.63%; 4-((3-methylphenyl)amino)-3-pyridinesulfonamide: 0.05%; Dimmer impurity: 0.3%.

Example 6:

Purification of Torsemide

Torsemide (110 gm; HPLC Purity: 98.9%) as obtained in example 1 was suspended in acetone (550 ml) and stirred for 10 minutes at room temperature. The contents were heated to reflux and maintained for 30 minutes at reflux. The reaction mass was cooled to room temperature and stirred for 30 minutes at room temperature, filtered. The solid obtained was dried at 50 to 55°C for 5 hours to obtain 100 gm of torsemide. Torsemide: 99.61%; 4-((3-methylphenyl)amino)-3-pyridinesulfonamide: 0.3%; Dimmer impurity: 0.05%.

Example 7:

Purification of Torsemide

Torsemide (10 gm; HPLC Purity: 98.9%) was suspended in acetone (50 ml) and stin-ed for 10 minutes at room temperature. The contents were heated to 40°C and maintained for 1 hour at 40°C. The reaction mass was cooled to room temperature and stirred for 30 minutes at room temperature. The separated solid was filtered and dried at 50 to 55"C for 5 hours to obtain 8.5 gm of torsemide. Torsemide: 99.6%; 4-((3-methylphenyl)amino)-3-pyridinesulfonamide: 0.3%; Dimmer impurity: 0.06%).

Example 8:

Purification of Torsemide

Torsemide (100 gm; HPLC Purity: 99.6%) as obtained in example 2 was suspended in acetone (500 ml) and stirred for 10 minutes at room temperature. The contents were heated to reflux and maintained for 30 minutes at reflux. The reaction mass was cooled to room temperature and stirred for 30 minutes at room temperature, filtered. The solid obtained was dried at 50 to 55°C for 6 hours to obtain 97 gm of pure torsemide.

Torsemide: 99.87%; 4-((3-methylphenyl)amino)-3-pyridinesulfonamide: 0.04%; Dimmer impurity: 0.06%.

Example 9:

Purification of Torsemide

Torsemide (50 gm; HPLC Purity: 99.61%) as obtained in example 6 was added to ethanol (300 ml) and stirred for 10 minutes at 30°C. To the reaction mass was added
water (100 ml) and stirred for 1 hour at 30°C, filtered. The solid obtained was dried at 50 to 55°C for 6 hours to obtain 48 gm of pure torsemide.

Torsemide: 99.88%; 4-((3-methylphenyl)amino)-3-pyridinesulfonamide: 0.05%; Dimmer impurity: 0.05%.

We claim:

1. A process for the purification of torsemide, which comprises:

a. maintaining torsemide with solvent system comprising ethanol and water at below 50V; and

b. isolating torsemide in the solvent system.

2. The process according to the claim 1, wherein the maintenance in step (a) is carried out at below 40°C.

3. The process according to the claim 2, wherein the maintenance at below 20 to 30°C.

4. The process according to the claim 1, wherein the maintenance is carried out under stirring for at least 30 minutes.

5. The process according to claim 1, wherein the process is characterized in that the ratio of ethanol to water is 2:1 to 4:1.

6. The process according to the claim 5, wherein the ratio of ethanol to water is 2.5:1 to 3.5:1.

7. The process according to the claim 6, wherein the ratio of ethanol to water is 3:1.

8. A process for the purification of torsemide, which comprises:

a. suspending or dissolving torsemide in acetone;

b. heating the contents to an elevated temperature; and

c. isolating torsemide from the contents.

9. The process according to claim 8, wherein the contents are heating in step (b) at above 25V.

10. The process according to claim 9, wherein the contents are heating at reflux.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by
reference.