DESC:Field of the invention
The present invention relates to an improved process for the preparation of of sulfamate esters, more specifically to the process for pure and stable Topiramate of formula (I).

Formula (I)

Background of the invention

Topiramate is a sulfamate - substituted monosaccharide, described chemically as 2,3:4,5-bis-0-(1-methylethylidene)-p-D-fructopyranose sulfamate. Topiramate is an anti-epileptic drug which is not chemically related to any other anticonvulsant / antiepileptic drug or mood regulating medication. This active pharmaceutical ingredient differs from other anticonvulsant drugs because of its frequent effectiveness for patients who do not respond to other medications.
It is also distinctive in its side-effect profile. Topiramate distinguishes itself because it has been successful in controlling rapid cycling and mixed polar states in patients who do not benefit from other drugs like Carbamazepine, Sodium valproate etc.

Topiramate and processes for making it have been disclosed and claimed in US4513006. US4513006 discloses a number of distinct synthetic routes.

One of the general methods disclosed, provides for a method of reacting 2,3:4,5-Bis-0-(1-isopropylidene)-p-D-Fructopyranose with sulfuryl chloride to obtain a chlorosulfate compound which is then reacted with sodium azide to give the sulfamoyl azide. The azide is then reduced using either copper-methanol or hydrogenated to obtain the sulfamate. There is no specific teaching in US 4513006 of topiramate prepared by above synthetic route. Following the specific preparation details for topiramate disclosed in US 4513006, a very impure product is obtained. More particularly, US 4513006 discloses reaction of 2, 3:4, 5-Bis-0-(1-isopropylidene)-p-D-

Fructopyranose with sulfamoyl chloride to obtain topiramate. Sulfamoyl chloride is not very reactive, requires a strong base to carry out the reaction and furthermore is not readily available.

US Patent 5,387,700 claims a purification process for topiramate using alcohol and water or ethyl acetate/hexane. The product obtained by such purification process is substantially less stable and has a shorter shelf-life

A. Klockow-Beck et.al. in J. Chromatogr. B, 720 (1998) 141-151, have reported that topiramate is highly unstable under conditions of elevated temperature and humidity giving organic degradation products, insoluble polymeric products and inorganic sulfate and sulfamate anions.

Topiramate prepared according to the teachings of the prior art suffers from instability problems and also exhibits a very short shelf life. As such, it has been difficult to formulate, and store topiramate prepared further to the teaching of prior art, with storage conditions required to be below ambient conditions or under refrigeration. The instability associated with prior art topiramate has been attributed to the impurities in the final drug compound, which could at least in part be attribute to isolation thereof from a methanolic solution.

WO2004/089965 discloses the process of preparation of topiramate of formula (I) comprising hydrogenation step of azide of formula (II) in the presence of palladium on charcoal and ethyl acetate as solvent to obtain formula (I). Use of ethyl acetate for the hydrogenation generates unknown impurities, which is difficult to remove and requires further purification. This makes the process undesirable for large-scale operations.

The present inventors have focused on the problems associated with the prior art process and has developed an improved process for the preparation of Topiramate.

Object of the invention:

The object of present invention is to provide an improved process for the preparation of Topiramate of formula (I) comprising hydrogenation step of precursor azide of formula (II) in the presence of noble metal catalyst and suitably using acetone as solvent to obtain topiramate of formula (I).

The noble metal catalyst used here includes but not limited to ruthenium, rhodium, palladium, silver, osmium and iridium on carbon. The preferred one is palladium on carbon.

Detailed description of the invention:

Accordingly, present invention provides an improved process for the preparation of Topiramate formula (I)

Formula (I)

The object of present invention is to provide an improved process for the preparation of Topiramate comprising a hydrogenation step of precursor azide of formula (II) in the presence of noble metal catalyst and suitably using acetone as solvent to obtain topiramate of formula (I)

The noble metal catalyst used here includes but not limited to ruthenium, rhodium, palladium, silver, osmium and iridium on carbon.
Examples:
Example: 1
Preparation of 2,3:4,5-bis-O-(1-isopropylidene)-ß-D-fructopyranose sulfamoyl azide
Methylene dichloride (500ml), 2, 3:4, 5-bis-O-(1-methylethylidene)-ß-D-fructopyranose (100gm) and Pyridine (62.59ml) was charged at 20-25 °C and the reaction mass was cooled to 0-5°C. Sulfuryl chloride (54.51gm) in Methylene dichloride (200ml) was added to the reaction mass at 0-5°C and the temperature was raised to 20-25 °C maintained for 2-3 hrs. The reaction mass was diluted with process water (400ml) and the resultant layer was separated. The organic layer was then washed sequentially with citric acid (40gm), sodium bicarbonate (20gm) and sodium chloride (80gm). Solvent was removed by vaccum distillation at 30-35 °C and thick oily mass of chloro sulfate was obtained. Methanol (100ml) was added and distillation continued below 40 °C for complete removal of Methylene dichloride. An additional quantity of Methanol (200ml), Sodium azide (56gm) followed by Pyridine (62.4gm) was charged to residual mass,stirred for 14 hrs at 25-30 °C. After completion of reaction, water (1500ml) was slowly added to the reaction mass, stirred for 20-30mins and filtered.
The wet cake was dried under vaccum at 35-40 °C (Yield: 80-85%)

Example: 2
Preparation of 2,3:4,5-bis-O-(1-isopropylidene)-ß-D-fructopyranose sulfamate (Topiramate)
2,3 : 4, 5-Bis-O- (l-iso propylidene)-p-D-fructopyranose sulfamoyl azide (100gm) obtained further to Example 1 and Acetone (550ml) charged under stirring to obtain a clear solution. To this clear solution, palladium carbon catalyst (8. 25gm) slurry in Acetone (50ml) was charged. The filtrate was charged to hydrogenator and hydrogen gas was passed to attain a pressure of 4-5kg/cm2, stirred for 8 hours at 30-35 °C. After completion of reaction, the reaction mass was cooled to 20-25 °C. The reaction mass was washed with Acetone (50ml) and Acetone was removed by vacuum distillation below 40 °C. The reaction mass was then washed with water (800ml), stirred and filtered. (Yield: 90%)
Example: 3
Purification of 2,3:4,5-bis-O-(1-isopropylidene)-ß-D-fructopyranose sulfamate (Topiramate)
Topiramate crude (75gm) obtained further to Example 2 dissolved in Methanol (112.5ml) at room temperature. The reaction mass was stirred for 10 min at 20-25 °C till clear solution was obtained. Activated carbon (0.8gm) was charged and the reaction mass was stirred for 30 mins. The reaction mass was filtered, washed with methanol (37.5ml) and water (600ml) at 20-25 °C. The reaction mass was cooled to 0-5 °C. The reaction mass was dried under vacuum at 40-45 °C to obatain pure Topiramate. (Yield: 90-95%)

One of the embodiments of present invention is shown schematically as below.

,CLAIMS:
1. A process of preparing Topiramate of following formula (I)

Formula (I)
Wherein said topiramate of formula (I) is prepared by hydrogenation of a precursor azide of formula (II) in the presence of noble metal catalyst on carbon and suitably using acetone as solvent

Formula (II)

2. A process according to claim 1, where in the noble metal comprises of ruthenium, rhodium, palladium, silver, osmium and iridium on carbon.

3. A process according to claim 1, where in noble metal is palladium.