WO2008010231A2

WO2008010231A2 - A process for the purification of topiramate

Info

Publication number: WO2008010231A2
Application number: PCT/IN2007/000211
Authority: WO
Inventors: Pandurang Balwant Deshpande; Parven Kumar Luthra; Anand Kumar Pandey; Dinesh Jayantibhai Paghdar; Bhavinkumar Prafulbhai Hamirani
Original assignee: Alembic Limited
Priority date: 2006-05-26
Filing date: 2007-05-23
Publication date: 2008-01-24
Also published as: WO2008010231A3

Abstract

The present invention provides a process for the purification of Topiramate comprising treating Topiramate with aqueous alkali solution followed by washing the aqueous alkali solution of Topiramate with water immiscible solvent and neutralizing this solution to obtain Topiramate having purity at least 99% impurity of formula (II) less than 0.1%.

Description

A PROCESS FOR THE PURIFICATION OF TQPIRAMATE

Field of Invention

The present invention relates to an improved process for the purification of Topiramate of formula (I).

Background of the invention

Topiramate is chemically known as 2, 3:4, 5-Bis-O-(1-methylethylidene)-1-O- sulfamoyl-beta-D-fructopyranose or 2, 3:4, 5-Bis-O-(1-methylethylidene)- beta-D- fructopyranose sulfamate, having molecular formula C₁₂H₂₁NO₈S and molecular weight 339.36. The current pharmaceutical product containing this drug is being sold by Ortho McNeil using the tradename Topamax^® in the form of tablets.

Topiramate is sulfamate-substituted monosaccharide derivative which are useful in the treatment of epilepsy, obesity, bipolar disorder, neuropathic pain, migraine and smoking cessation. Topiramate acts as a carbonate dehydratase inhibitor, sodium channel blocker, AMPA antagonist, GABA agonist and glutamate antagonist.

It is well known that a compound of formula (II) is used as starting material for the preparation of topiramate of formula (I) as disclosed in US 4513006. However, it has been observed by the present inventor that by preparing Topiramate as disclosed in US4513006, the resulting product always contain impurity of staring compound of formula (II) which is affecting the purity of final product.

II

There is several other purification process reported for Topiramate, for example WO2004/108732 which discloses a process of the purification of Topiramate. However, even after purification the content of impurity of formula (II) still remains more than 0.1% in final product.

US 2004/0038911 disclose processes for the preparation of Topiramate. However, this application remains silent about impurity of formula Il in final product.

US 2004/0158081 disclose continuous processes for the preparation of Topiramate. However, this application discloses that impurity of formula (II) increases after ammonolysis of compound of formula (III).

III Schematic representation for formation of impurity of formula (II) during ammonolysis of compound of formula (III) as disclosed in US 5387700,

The process for the preparation of Topiramate by utilizing a compound of formula (II) as starting material disclosed in US 5387700 which remain silent about reduction of content of impurity of formula (II) in final product.

US 2004/0215004 disclose process for the preparation of Topiramate by treating sulfamide with compound of formula (II) in presence of pyridine and O-xylene. However, the major disadvantage of this process is utilization of O-xylene as this solvent is expensive and not applicable for industrial scale. Moreover, this application remains silent about impurity of formula (II) in final product. US 2005/0203287 disclose a process for the preparation of Topiramate by utilizing a compound of formula (II) as starting material. However, this application remains silent about impurity of formula (II) in final product.

In summary, the removal of content of impurity i.e. starting material of formula (II) and preparing Topiramate with purity 99% has been an unsolved problem by the prior art.

Therefore, it is necessary to develop a process for purification of Topiramate which removes the starting material impurity of formula (II) as well as applicable for industrial scale.

Unexpectedly, present inventors found that it is indeed possible to remove the impurity of starting material i.e. formula (II) by employing a process for the purification of Topiramate comprising steps of; i) treating Topiramate with aqueous alkali solution; ii) washing the aqueous alkali solution of Topiramate obtain in step (i) with water immiscible solvent; and iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity at least 99%.

Surprisingly, the present inventors have found that this process of purification removes the starting material impurity of formula (II) up to less than 0.1 % which gives Topiramate having purity at least 99%.

Objects of the invention

It is therefore an object of the present invention is to provide an improved process for the purification of Topiramate. Another object of the present invention is to provide a process for the purification of Topiramate which is operationally simple, easy to handle and applicable at an industrial scale. Summary of the linvention According to one aspect of the present invention there is provided an improved process for the purification of Topiramate comprising steps of; i) treating Topiramate with aqueous alkali solution; ii) washing the aqueous alkali solution of Topiramate obtain in step (i) with water immiscible solvent; and iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity at least 99%

According to a further object of the present invention there is to provided an improved process for the purification of Topiramate comprising steps of; i) treating Topiramate with aqueous alkali solution; ii) washing the aqueous alkali solution of Topiramate obtain in step (i) with water immiscible solvent; and iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity at least 99% and impurity of formula (II) less than 0.1 %

According to another aspect there is provided a process for the purification of

Topiramate which comprises steps of; i) ammonolysis of compound of formula (III) in presence of base and suitable solvent to obtain Topiramate ii) treating Topiramate obtain in step (i) with aqueous alkali solution; iii) washing the aqueous alkali solution of Topiramate obtain in step (ii) with water immiscible solvent; and iv) neutralizing the solution obtain in (iii) to obtain Topiramate having purity at least

99%. Detailed description of the invention

The improved process for the purification of Topiramate is operationally simple, easy to handle and applicable at an industrial scale.

For the purpose of this specification, the meaning of the term "Topiramate" used as starting material hereinabove that include topiramate is any form, or hydrate, solvate or their mixtures, or any state of purity.

For the purpose of this specification, the meaning of the term "treating" as used hereinabove that includes suspending, dissolving, washing, mixing, crystallizing or recrystallizing Topiramate in any of the solvent described above.

For the purpose of this specification, the meaning of the term "base" as used herein above includes organic bases such as substituted or unsubstituted aliphatic amines, aromatic amines or mixture thereof.

For the purpose of this specification, the meaning of the term "suitable solvent" as used hereinabove includes substituted or unsubstituted alcoholic solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ester solvent, ether solvent, cyclic ether solvent, nitrile solvent and aqueous solvent or mixture thereof. It also includes polar or nonpolar protic solvent, polar or nonpolar aprotic solvent or mixture thereof.

For the purpose of this specification, the meaning of the term "water immiscible solvent" as used hereinabove that includes dichlorometane, ethyl acetate, toluene, dimethyl formamide, hexane, dimethyl acetamide and dimethyl sulfoxide etc. For the purpose of this specification, the meaning of the term the term "alkali" as used hereinabove that includes an alkoxide, an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali or alkaline earth metal carbonate or hydrogencarbonate salt.

Topiramate is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.

Topiramate used as starting material in the examples is prepared according to methods reported in the literature and prior art.

The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.

Example 1

2,3:4,5-bis-O-(1- methylethylidiene) - β- D- fructopyranose sulfonyl chloride (formula III) (65gm) and tetrahydrofuran (480ml) was taken in a autoclave & stirred under ammonia gas up to 1-2 kg pressure for 2-3 hr. After completion of reaction, the reaction mixture was filtered. The filterate was distilled off to get wet residue of Topiramate. 5 % sodium hydroxide solution (200 ml) was added to wet residue of Topiramate to give alkali solution of Topiramate which was washed with dichloromethane. The aqueous layer was neutralized with dilute acetic acid to crystallize pure Topiramate which was filtered, washed with water to get pure Topiramate (51 gm). Purity ~ 99.85 % (by HPLC) Content of impurity of formula Il ~ 0.06 % (by HPLC) Example 2

Topiramate (5gm) was dissolved in 3.5% sodium hydroxide solution (20 ml) and toluene (40ml). The layers were separated. The aqueous layer was washed with toluene (20ml). The aqueous layer was neutralized with dilute acetic acid to crystallize Topiramate which was filtered and washed with water to get pure Topiramate (3.8 gm). Purity ~ 99.61 % (by HPLC)

Content of impurity of formula Il ~ 0.06 % (by HPLC)

Claims

1. A process for the purification of Topiramate comprising steps of; i) treating Topiramate with aqueous alkali solution; ii) washing the aqueous alkali solution of Topiramate obtain in step (i) with water immiscible solvent; and iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity at least 99%.

2. A process for the purification of Topiramate comprising steps of, i) treating Topiramate with aqueous alkali solution; ii) washing the aqueous alkali solution of Topiramate obtain in step (i) with water immiscible solvent; and iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity at least 99% and impurity of formula (II) less than

0.1 %

II

3. A process for the purification of Topiramate comprising steps of, i) ammonolysis of the compound of formula (III) in presence of base and suitable solvent to obtain Topiramate

ii) treating Topiramate obtain in step (i) with aqueous alkali solution; Hi) washing the aqueous alkali solution of Topiramate obtain in step (ii) with water immiscible solvent; and iv) neutralizing the solution obtain in step (iii) to obtain Topiramate having purity at least 99% and impurity of formula (II) less than

0.1%

II

4. The process according to any preceding claims, wherein aqueous alkali used herein is alkoxide, an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali or alkaline earth metal carbonate or hydrogen carbonate salt and the like or mixture thereof.

5. The process according to any preceding claims, wherein water immiscible solvent used herein is dichlorometane, ethyl acetate, toluene, dimethyl formamide, hexane, dimethyl acetamide and dimethyl sulfoxide.

6. The process according to claim 3, wherein suitable solvent used herein is substituted or unsubstituted alcoholic solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ester solvent, ether solvent, cyclic ether solvent, nitrile solvent polar or nonpolar protic solvent, polar or nonpolar aprotic solvent and aqueous solvent or mixture thereof.

7. The process according to claim 3, wherein base used herein is organic bases such as substituted or unsubstituted aliphatic amines, aromatic amines or mixture thereof.

8. Topiramate having purity at least 99% and impurity of formula (II) less than 0.1%

II