FIELD OF INVENTION
[001] The invention relates to a process for the preparation and purification of topiramate, and more particularly to the preparation and purification of topiramate from azido sulphonate precursor compound.

BACKGROUND OF INVENTION

[002] Topiramate is a sulphamate - substituted monosaccharide, chemically known as 2,3:4,5-Bis-O-(l-methylethylidene)-beta-D-fructopyranose sulfamate. It has earlier been used to treat epilepsy, migraines, bipolar disorder, neuropathic pain andalcoholism, among others.

[003] Topiramate's activities include; blockage of voltage-dependent sodium channels, augmentation of gamma-aminobutyrate acid activity, antagonism of AMPA, and inhibition of the carbonic anhydrase enzyme.

[004] US 5387700 claims a purification process for topiramate using alcohol and water, or ethyl acetate/hexane. It is observed that the product obtained by such purification process is unstable.

[005] Further, WO2007099388 provides a process for the manufacture of Topiramate by subjecting 2,3:4,5-bis-0-(l-methylethylidene)-P-D-fructopyra-nose to a sulfamoylation reaction with sulfamoyl halide in a suitable solvent, in presence of a suitable organic base.

[006] Furthermore, WO2004089965 (hereinafter refered to as v965) provides a process for the preparation of topiramate from the precursor azide compound of formula (a)

[007] Topiramate in ‘965 is prepared by the hydrogenation of the precursor azide compound, in the presence of a metal catalyst such as palladium on charcoal catalyst and ethyl acetate as solvent. Purification of topiramate in the reference ‘965 is performed using conventional methods. The catalyst, palladium on charcoal, used in ‘965 is expensive and therefore the process is not viable for production of topiramate at an industrial scale.

[008] The present invention provides a process for the preparation of pure Topiramate. The process provides the preparation of Topiramate from an azido sulphonate precursor using an easily available catalyst, thereby making the process simple and easy. The process further provides a purification step which yields pure and stable Topiramate. The process of the present invention is, therefore, economical and commercially viable.

OBJECT OF INVENTION

[009] The principal object of this invention is to provide a process for the preparation of Topiramate from an azido sulphonate precursor.

[0010] Another object of the invention is to provide a process for the purification of topiramate from crude topiramate.

STATEMENT OF INVENTION

[0011] Accordingly the invention provides a process for the preparation of topiramate from an azido sulphonate precursor.

[0012] There is also provided a process for the purification of topiramate from crude topiramate.

[0013] An aspect of the invention provides a process for the preparation of crude Topiramate from 2,3:4,5-bis-0-(l-methylethylidene)-b-D-fructopyranose-1-azido sulphonate by hydrogenation in the presence of Raney nickel catalyst. Further, crude topiramate is separated from the reaction mixture, on completion of hydrogenation, using acetone and cyclohexane.

[0014] Another aspect of the invention provides a process for purification of topiramate from crude topiramate, wherein the crude Topiramate is purified using charcoal, acetone and cyclohexane.

[0015] These and other aspects of the embodiments herein will be better appreciated and understood when considered in conjunction with the following description and the accompanying drawings. It should be understood, however, that the following descriptions, while indicating preferred embodiments and numerous specific details thereof, are given by way of illustration and not of limitation. Many changes and modifications may be made within the scope of the embodiments herein without departing from the spirit thereof, and the embodiments herein include all such modifications.

DETAILED DESCRIPTION OF INVENTION

[0016] The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying drawings and detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0017] In one embodiment of the invention, the process for the preparation of topiramate comprises of preparation of crude Topiramate by hydrogenation of 2,3:4,5-bis-0-(l-methylethylidene)- b-D-fructopyranose-1-azido sulphonate, wherein, 2,3:4,5-bis-0-(l- methylethylidene)-b-D-fructopyranose-l-azido sulphonate is hydrogenated in the presence of Raney nickel catalyst and acetone. Raney nickel is introduced to a mixture of 2,3:4,5-bis-O-(l-methylethylidene)-b-D-fructopyranose-l-azido sulphonate and acetone, under vacuum. The hydrogen gas is introduced pressurizing the reaction mixture in the range of 7-10 kg/cm2, preferably at 7.5 kg/cm2. On completion of the reaction the reaction mixture is filtered and topiramate is extracted using acetone and cyclohexane, sequentially, to obtain crude topiramate.

[0018] In another embodiment of the invention, the process for the preparation of topiramate comprises of purification of topiramate by refluxing

crude topiramate with acetone to obtain a clear solution. Purification of topiramate is further continued by introducing charcoal into the reaction mixture and refluxing the reaction mixture. The reaction mixture is then filtered, concentrated and treated with cyclohexane to obtain topiramate in its pure form.

[0019] The invention is further defined by reference to the following example. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLE:

Stage-1: Preparation of crude Topiramate. Representation of the reaction at

Stage 1 is as follows:

Representation of the reaction at Stage 1 is as follows:

[0020] Procedure: 6.0 L of acetone and 1.0 Kg of 2,3:4,5-bis-O-(l-methylethylidene)-b-D-fructopyranose-l-azido sulphonate is charged into a 10L autoclave. 150g of Raney nickel catalyst (type BTCOI) is then introduced into the autoclave by applying vacuum. The internal vacuum is nullified by

applying nitrogen which is in turn replaced by hydrogen to a pressure of 7.5 kg/cm2. The hydrogenation is allowed to proceed and the temperature of the reaction is recorded every 2h. The pressure is maintained at 7.5 kg/cm2 and the hydrogen in the autoclave is replaced with fresh hydrogen every 2h. This operation is repeated until the reaction is complete, as monitored by Infrared spectroscopy (IR).On completion of the reaction, the reaction mixture is filtered through hyflo bed and the solids are washed with 600 ml of acetone. Acetone is later distilled out from the combined filtrate at a vapour temperature of below 70°C, until 1 L of solvent remains in the flask. The reaction mass is then cooled to 25°C -30°C, and 2.4 L of cyclohexane is then charged slowly under stirring. The resultant mixture is stirred for 1 h at 25°C -30°C and further chilled to 10°C-15°C for 1 h. The mixture is filtered and washed with 600 ml cyclohexane to obtain a solid, which is dried under vacuum. Wet weight of the crude product is 920 g and dry weight is 860 g (93%).
Stage-2: Purification of Topiramate from crude Topiramate.

[0021] Procedure: 1.7 L of acetone and 860 g of crude topiramate (obtained from stage 1) is charged into a 5 L Round bottom flask and refluxed under stirring to get a clear solution. 50 g of charcoal is then added and the mixture is refluxed for about 15-20 min. The mixture is then filtered over a hyflo bed and the residue is washed with 250 ml of acetone. The combined filtrate is then concentrated under vacuum at a temperature below 50°C until 900 to 950 ml of the solvents remains in the flask. The reaction mass is cooled to around 25°C -30°C and 1.7 L of fresh cyclohexane is charged slowly with stirring. The resultant mixture is further stirred for about 1 h at around 25°C-30°C and

then chilled to 10°C -12°C for about 1 h. The mixture is then filtered and washed with about 200-300 ml of cyclohexane in order to obtain a solid which is suction dried. Further, the solid is dried in hot air oven at 50°C -55°C for about 2-3 h to achieve a constant weight. Wet weight of the product is 800g and dry weight 780 g (90.7%).

[0022] The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

STATEMENT OF CLAIMS

We claim:

1, A process for the preparation of Topiramate comprising:

(a) hydrogenating 2,3:4,5-bis-0-( 1 -methylethylidene)-b-D-fructopyranose-1- azido sulphonate in the presence of Raney nickel catalyst;

(b) extracting erode topiramate with extraction solvents; and

(c) purifying topiramate from crude topiramate.

2. The process for the preparation of Topiramate as claimed in claim 1,
wherein said hydrogenation of step (a) is carried out with hydrogen gas
at a pressure in the range of 7-10 Kg/cm2, preferably at 7.5 Kg/cm2.

3. The process for the preparation of Topiramate as claimed in claim 1,
wherein said extraction solvents of step (b) are acetone and cyclohexane,

4. The process for the preparation of Topiramate as claimed in claim 1,
wherein purification of step (c) includes:

(a) refiuxing acetone and crude Topiramate to obtain a clear solution;

(b) refiuxing said clear solution in the presence of charcoal; and

(c) extracting Topiramate with cyclohexane.