FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
SYNTHESIS AND REMOVAL OF CHROMEN SULPHAMATE
IMPURITY OF ZONISAMIDE.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides synthesis and removal of chromen
sulphamate impurity of Zonisamide.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides synthesis and removal of chromen sulphamate impurity of Zonisamide.
Zonisamide, namely 3-(sulfamylmethyl)-benzo[d]isoxazole, is a known medicament belonging to the class of the sulfonamides used as antiepileptic, anticonvulsive and antineurotoxic activities, having the structure as per formula-l.
U.S. Pat. No. 4,172,896 disclosed a process for preparing zonisamide in which 4-hydroxy coumarin was reacted with hydroxylamine hydrochloride under Posner reaction conditions to give 1,2-benzisoxazole-3-acetic acid ("BOA"). BOA was brominated through the unstable bromo acid to provide zonisamide-bromide. Zonisamide-bromide was converted to 1,2-benzisoxazole-3-methane sulfonic acid sodium salt ("BOS-Na") by reaction with sodium sulfite. BOS-Na was converted in two steps into the zonisamide by first reacting BOS-Na with a halogenating agent to form benzisoxazole methane sulfonyl chloride ("BOS--CI"), which is then further reacted with ammonia in ethyl acetate to produce zonisamide.
The present invention discloses a chromen sulphamate impurity of formula-l and a process for removal of said impurity from the zonisamide, which is difficult to remove from the finish product by conventional method like crystallization. This impurity is generated during conversion of 4-hydroxy coumarin to Zonisamide. In the first step when 4-hydroxy coumarin is converted in to 1,2-benzisoxazole-3-acetic acid, the unreacted 4-hydroxy coumarin is carried forward to the next step and reacted with chlorosulphonic acid-dioxane complex and sodium hydroxide to yield sodium salt of 2-oxo-2H-chromen-4-yl-sulphate. Finally it is reacted with phosphorous oxychloride and ammonia to get above said impurity (Scheme-I).
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In one of the aspect of present invention there is disclosed an unknown impurity 2-oxo-2H-chromen-4-yl-sulphamate of formula-l,

In another aspect of present invention there is provided a synthetic route for 2-oxo-2H-chromen-4-yl-sulphamate (referred to as chromen sulphamate), which comprises of,
a) reaction of 4-hydroxy coumarin in presence of base with Chlorosulphonic acid-organic solvent mixture to form 2-oxo-2H-chromen-4-yl-sulphate.
b) conversion of 2-oxo-2H-chromen-4-yl-sulphate to 2-oxo-2H-chromen-4-yl-sulphamate by reaction with phosphorous oxychloride and ammonia.
In the first step when 4-hydroxy coumarin is converted to 1,2-benzisoxazole-3-acetic acid, the unreacted 4-hydroxy coumarin is carried forward to the next step and reacted with chlorosulphonic acid-organic solvent complex and sodium
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hydroxide to provide sodium salt of 2-oxo-2H-chromen-4-yl-sulphate. Finally it is reacted with phosphorous oxychloride and ammonia to get 2-oxo-2H-chromen-4-yl-sulphamate impurity.
In yet another aspect of the present invention, there is provided a process of removal of chromen sulphamate impurity of Zonisamide by reacting Zonisamide with hydrazine hydrate.
To a solution of hydrazine hydrate (80 %), added impure Zonisamide. Impure Zonisamide mean Zonisamide having chromen sulphamate more than 0.15% as percentage area HPLC. Stirred the reaction mass and charged organic solvent to get clear solution. To the clear solution added water under stirring to get solid. Reaction mass cooled at 0-5°C, stirred and filtered. The wet cake obtained was washed with chilled water and dried.
The non-limiting examples of organic solvents include alcohols, haloalkanes, esters, ethers, aromatic solvents or high boiling solvents. Examples of suitable solvents for practicing the invention are straight chain and branched chain C1-C6 alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, n-pentanol and the like or halo (C1-C6) alkanes such as methylene chloride, chloroform, carbon tetrachloride, 1,1,1-trichloroethylene, 1,1,2-trichloroethylene and the like or esters such as methyl acetate, ethyl acetate and the like or ethers such as tetrahydrofuran, tetrahydropyran, dioxane and the like or aromatic solvents such as benzene, toluene, xylene and the like or high boiling solvents such as dimethyl formamide, dimethyl sulphoxide and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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EXAMPLE
Process for removal of 2-oxo-2H-chromen-4-yl-sulphamate:
The Zonisamide (31.0 g, impurity chromen sulphamate 5.8%) was suspended in 80% hydrazine hydtrate (72 ml) at room temperature. The dimethyl formamide (28.0 ml) was added to get the clear solution. The product is precipitated by addition of water (400ml) and futher stirring at 0-5°C for 30 minutes. The precipitated solid was filtered, washed with water and dried to get Zonisamide free from title compound. Yield: 26 gm. Purity: 99.0 %
Process for synthesis of 2-Oxo-2H-chromen-4-yl-sulfate.
The 4-Hydroxy coumarin (25 gm) was added to dichloroethane (100 ml) followed by complex of chlorosulphonic acid -dioxane (1:2.2 (w/w), 79 gm). Reaction mass was heated at 60-65°C for 3.0 hours. After completion of reaction, reaction mixture was quenched with water and aqueous layer was separated. The aqueous layer was basified with sodium hydroxide solution to pH-11-12 and concentrated to get thick solid. The solid was then treated with phosphorus oxychloride (100 ml) at 75-80°C for 4.0 hours. Phosphorus oxychloride was distilled off under reduced pressure and then reaction mass is basified to pH 9-10 with ammonia. The product was extracted in ethyl acetate, which on concentration under reduced pressure yields title compound. Yield : 6.50 gm.
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WE CLAIM:
1. 2-oxo-2H-chromen-4-yl-sulphamate of formula-l

2. A process for 2-oxo-2H-chromen-4-yl-sulphamate (referred to as chromen sulphamate) comprises of,
c) reaction of 4-hydroxy coumarin in presence of base with Chlorosulphonic acid-organic solvent mixture to form 2-oxo-2H-chromen-4-yl-sulphate.
d) conversion of 2-oxo-2H-chromen-4-yl-sulphate to 2-oxo-2H-chromen-4-yl-sulphamate by reaction with phosphorous oxychloride and ammonia.
3. A synthesis of claim 2, wherein the organic solvents include alcohols, haloalkanes, esters, ethers, aromatic solvents or high boiling solvents.
4. A process of removal of chromen sulphamate impurity from Zonisamide by reacting Zonisamide with hydrazine hydrate.

Dated this 31ST day of Aug., 2006

For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory

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