FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
AN INDUSTRIALLY EFFICIENT PROCESS FOR THE PREPARATION 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 an industrially efficient process for the preparation of Zonisamide.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides an industrially efficient process for the preparation of zonisamide.
Zonisamide, chemically known as 1,2-benzisoxazole-3-methanesulfonamide and is a medicament belonging to the class of the sulfonamides used as antiepileptic, anticonvulsive and antineurotoxic activities, having the structure of Formula I.

S02NH2 Formula I
US Patent No. 4,172,896 disclosed a process for preparing zonisamide in which 4-hydroxy coumarin was reacted with hydroxylamine hydrochloride.
US Patent No. 6,936,720 (PCT Application No. WO 03/072552) describes a process for preparation of zonisamide via the intermediate BOS-CI. The BOS-CI is prepared by chlorinating 1,2-benzisoxazole-3-methanesulfonic acid (BOS-H) or BOS-Na with thionyl chloride (SOCI2) in an organic solvent. The BOS-CI is then reacted with ammonia to thereby obtain zonisamide.
US Patent No. 6,677,458 discloses a process for the preparation of BOS-Na salt by sulfonating BOA with chlorosulfonic acid and dioxane in methylene chloride and sodium hydroxide.
US Patent No. 7,081,539 discloses one-pot process for the preparation of 1,2-benzisoxazole-3-methanesulfonamide
2

The processes of preparation of zonisamide are also disclosed in US 6,936,720; US patent application No. US 06/069267; US 06/014814; US 06/084814 and PCT patent application No. WO 05/044808
The present inventors have surprisingly found an efficient process for the preparation of zonisamide in high purity. The process of present invention offers a cost-effective and easily scalable process for preparation of zonisamide by use of recovered solvent. The present inventors also surprisingly found that suspension of zonisamide into a mixture of alcohol and water results in increase purity of zonisamide.
In one of the aspect of the invention there is provided a process for the preparation of 1,2-benzisoxazole-3-acetic acid, wherein the said process comprises of
a) hydroxylamine hydrochloride added with sodium methoxide and 4-hydroxy coumarin,
b) heating of the reaction mass and removal of solvent,
c) extraction of reaction mass with toluene at pH 8-10 in presence of aqueous basic solution,
d) isolation of 1,2-benzisoxazole-3-acetic acid from aqueous solution of step c) at pH below 1.
In an another aspect of the present invention there is provided a process for the preparation zonisamide, wherein the said process comprises of
a) dissolving 1,2-Benzisoxazole-3-methane sodium sulphonate with
chlorinating agent,
b) distilling the reaction mass with suitable organic solvent,
c) adding ammonia to the solution of step (b) and isolation of Zonisamide
from the reaction mass thereof.
3

In another aspect of the present invention there is provided zonisamide having purity 99% or more when measured by HPLC.
The process of present invention related to preparation of zonisamide in high purity in a simple manner. Hydroxylamine hydrochloride is reacted with 4-Hydroxy coumarin in alcohol such as methanol or a like in presence of sodium methoxide. Reaction mass refluxed for 5 to 8 hours and then distilled the residue is basified by sodium bicarbonate solution. The reaction mass washed with toluene to remove the hydroxy acetophenone oxime impurity. Aqueous layer is acidified with inorganic acids such as hydrochloride, sulphuric acid to yield 1,2-Benzisoxazole-3-acetic acid.
The 1,2-Benzisoxazole-3-acetic acid converted to 1,2-Benzisoxazole-3-methane sodium sulphonate by the method known in the art.
The 1, 2-Benzisoxazole-3-methane sodium sulphonate is chlorinated using chlorinating agent such as phosphorous oxychloride or a like under stirring at temperature below 85°C for completion. Then excess of phosphorus oxychloride was distilled out and then trace of phosphorus oxychloride is removed by using toluene and ethyl acetate. To the resultant mixture added ethyl acetate and pH is adjusted to 9-10 by purging ammonia gas, reaction is workup by using water. Organic layer subjected for distillation to get crude product. The crude product is purified in organic solvent such as methanol or a like at reflux and cooled to about 0 to 5°C filtered and the wet product further suspended in alcohol and water to get zonisamide.
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.
4

EXAMPLE
Stage-I: Preparation of 1, 2-Benzisoxazole-3-acetic acid
Hydroxylamine hydrochloride (1.29 kg) was added to methanol (8 Litre) and sodium methoxide (30.05%w/w, 3.33 kg) under stirring. 4-Hydroxy coumarin (1.0 kg) was added to reaction mass and reflux the mass for 5 to 8 hours. Reaction mass was then subjected for distillation of methanol under vacuum and obtained residue was basified by using 10% sodium bicarbonate solution (10 Litre). The reaction mass obtained was extracted with toluene (6 Litre). Further acidification of aqueous layer to pH below 1 with 4N hydrochloric acid provided solid mass which was isolated by suspension in purified water, filtration and drying at 65-70°C to get title compound.
Yield = 0.767 kg
.Purity = 98.51% by HPLC
Stage-ll: Preparation of 1, 2-Benzisoxazole-3-methane sodium sulphonate
1, 2-Benzisoxazole-3-acetic acid (0.767 kg) was added to ethylene dichloride (3.15 Litre) under stirring. To the stirred solution chloro sulphonic acid and I, 4-dioxane complex (482 ml of chloro sulphonic acid and 1.54 Litre of 1,4-dioxane) was added. The resultant mass was heated to about 60-65°C for 3 to 5 hours till completion of reaction. The resultant mixture was quenched by water (2.3 Litre) and pH is adjusted to 11-12 using 25% sodium hydroxide solution (2.5 Litre) at 10-25°C. Ethylene dichloride layer was then separated and aqueous layer was distilled out under vacuum to get thick mass. The obtained product was isolated by adding acetone (4 Litre) which was filtered and dried to get title compound. Yield =1.5 kg Purity = 98.92% by HPLC
5

Stage-Ill: Preparation of zonisamide
1, 2-Benzisoxazole-3-methane sodium sulphonate (1.5 kg) was added to phosphorus oxychloride (3 Litre) and was heated to about 75-80°C for 4 to 6 hours till completion of reaction. Excess phosphorus oxychloride was distilled out under reduced pressure. Then the trace of phosphorous oxychloride was removed by addition and distillation of mixture of toluene (6 Litre) and ethyl acetate (6 Litre). To the resultant mixture was added ethyl acetate (10 Litre) and then cooled to about 0 to10°C. Ammonia gas was purged to reaction mixture to adjust the pH of 9-10 and water (4 Litre) was added. The ethyl acetate layer was separated charcolized and distillation of ethyl acetate layer yields crude product. The crude product again charcolized in methanol (9.6 Litre) at reflux and obtained filtrate was cooled to about 0 to 5°C stirred and filtered. The wet product was suspended in methanol (4.5 Litre) and water (4.5 Litre) to get Zonisamide after filtration and drying. Yield = 0.525 kg Purity = 99.49% by HPLC
6

WE CLAIM:
1. A process for the preparation 1,2-benzisoxazole-3-acetic acid, wherein the
said process comprises of
a) hydroxylamine hydrochloride added with sodium methoxide and 4-hydroxy coumarin,
b) heating of the reaction mass and removal of solvent,
c) extraction of reaction mass with toluene at pH 8-10 in presence of aqueous basic solution,
d) isolation of 1,2-benzisoxazole-3-acetic acid from aqueous solution of step c) at pH below 1.

2. The use of compound prepared as per claim 1 for preparation of Zonisamide.
3. The process of claim 1 wherein extraction of reaction mass with toluene is used to remove hydroxy acetophenone oxime impurity
4. A process for the preparation of zonisamide wherein the said process
comprises of,
a) dissolving 1,2-Benzisoxazole-3-methane sodium sulphonate with chlorinating agent,
b) distilling the reaction mass with suitable organic solvent,
c) adding ammonia to the solution of step (b) and isolation of zonisamide from the reaction mass thereof.

5. A process of claim 4 wherein chlorinating agent is phosphorous oxychloride or a like.
6. A process of claim 4 wherein organic solvent is toluene and ethyl acetate
7

7. A process of claim 4 wherein ammonia is ammonia gas.
8. A process of claim 4 wherein the zonisamide having purity 99% or more when
measured by HPLC.

Dated this 30 th day of October, 2006

For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
8