Process for the preparation of 1,2-benzisoxazole-3-acetic acid

Details Process for the preparation of 1,2-benzisoxazole-3-acetic acid Process for the preparation of 1,2-benzisoxazole-3-acetic acid

2002-03-04

2004-01-13

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06677458

ABSTRACT:

FIELD OF THE INVENTION
The field of the invention relates to the preparation of 1,2-benzisoxazole-3-acetic acid. Within that field, the present invention relates more particularly to a method for preparing 1,2-benzisoxazole-3-acetic acid comprising the step of reacting 4-hydroxy-coumarin with a hydroxyl-amine in the presence of a base.
BACKGROUND OF THE INVENTION
Zonisamide is currently avaiable as an anti-epileptic agent which possesses anti-convulant and anti-neurotoxic effects. Zonisamide is also known as 1,2-benzisoxazole-3-methane sulfonamide or 3-(sulfamylmethyl)-1,2-benzisoxazole. It has the following chemical formula:
The preparation of zonisamide is described in Japanese Pat. No. 53-77057 and Yakugaku Zasshi, 116(7), 533-47, 1996, both of which are incorporated herein by reference. These references teach a synthesis process of zonisamide that involves 4 or 5-steps, starting from 4-hydroxy-coumarin (4-HC). The synthesis of zonisamide occurs via the intermediates: namely, 1,2-benzisoxazole-3-acetic acid (BOA) and the sodium salt of benzisoxazole methane sulfonic acid (BOS—Na).
Many synthetic routes for preparing zonisamide have been described in the literature. One of the synthetic routes for preparing zonisamide is described in U.S. Pat. No. 4,172,896 and Japanese Pat. No. 53-77057 to Dainnipon. This particular synthetic route starts from 1,2-benzisoxazole-3-bromo-methane (zonisamide-bromide). The zonisamide-bromide is converted to 1,2-benzisoxazole-3-methane-sulfonic acid sodium salt (BOS—Na) in the reaction with sodium sulfite as is shown in the following scheme 1:
Zonisamide-bromide is prepared according to the literature (Chem. Pharm. Bull., (Tokyo), 24, 632, 1976) by the bromination reaction of 1,2-benzizoxazole-3-acetic acid (BOA). BOA is prepared by Posner reaction (T. Posner, Chem. Ber., 42, 2523, 0913, T.Posner, and R.Hess, Chem. Ber., 46, 3816, 1913, M. Gianella, F. Gualtieri, C. Melchiorre and A. Orlandoni, Chem. Therap., 1972, 2, 127) and starts from 4-hydroxy-coumarin in the reaction with metallic sodium as shown in the following scheme 2:
The Posner reaction for BOA preparation involves the use of metallic sodium. When metallic sodium is used in alcoholic solution, BOA is not the sole reaction product and the side-reaction product, O-hydroxy-acetophenone-oxime, is obtained in about 30%.
The high percentage of the side reaction products as well as the difficulty of using the aforementioned process on an industrial scale due to the use of metallic sodium render said process unfavorable, and thus the need for an improved process for preparing BOA and BOS—Na intermediates remains.
According to Dainnipon in the patent Japanese Pat. No. 53-77057, an alternative synthetic route for preparing zonisamide starts from 4-hydroxy-coumarin may occur via the same intermediates BOA and BOS—Na as shown in the following scheme 3:
1,2-benzizoxazole-3-acetic acid (BOA), the product of the initial step after reacting 4-HC with NH
20
H (scheme 3), is converted to the intermediate BOS—Na in the sulfonation reaction with ClSO
3
H/dioxane in ethylene chloride at room temperature for about three hours followed by about 6 hours heating at about 50° C. After the reaction is complete, water and NaOH are added and the product is isolated as sodium salt (BOS—Na) by evaporation of the aqueous layer. BOA and BOS—Na are the intermediates in the zonisamide preparation according to both synthetic schemes. All the cited references are incorporated by reference in their entireties herein.
OBJECTS AND SUMMARY OF THE INVENTION
An object of the present invention is to provide an improved process for preparing a salt of BOS (e.g., BOS—Na) with higher purity and lesser side-products.
Another object of the present invention is to provide an improved process for preparing a salt of BOS (e.g., BOS—Na) as an intermediate for the preparation of 1,2-benzisoxazole-3-methane sulfonamide (i.e., zonisamide).
Another object of the present invention is to provide an improved process for preparing a salt of BOS (e.g., BOS—Na) in which the sulfonation of BOA occurs in a solvent of methylene chloride (instead of ethylene chloride).
Another object of the present invention is to prepare 1,2-benzisoxazole-3-acetic acid (BOA) without the use of metallic sodium; and thus the process of this invention is substantially less hazardous.
Another object of the present invention is to prevent the formation of side-products, e.g., oximes; and thus, significantly increasing the yield of BOA, and substantially reducing the burden of removing the oxime side-product with ether, which by itself is hazardous.
Another yet object of the present invention is to prepare BOA or salts of BOS (e.g., BOS—Na); which are thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide (i.e., zonisamide).
The present invention provides a process for preparing 1,2-benzisoxazole-3-acetic acid (BOA), comprising the step of reacting 4-hydroxy-coumarin (4-HC) with hydroxyl-amine in the presence of a base.
In a preferred embodiment, the base is selected from the group consisting of carbonate salts, aqueous ammonia, and organic bases. In another preferred embodiment, the carbonate salt is selected from the group of sodium carbonate (Na
2
CO
3
) and potassium carbonate (K
2
CO
3
). In another preferred embodiment, the organic base is an amine. More preferably, the amine is selected from the group consisting of triethyl-amine, tributyl-amine, and diethyl-amine.
In another preferred embodiment, the present invention provides a process for preparing 1,2-benzisoxazole-3-acetic acid (BOA), comprising the step of reacting 4-hydroxy-coumarin (4-HC) with hydroxyl-amine in the presence of a base, said process occurs in the presence of an alcoholic solvent.
Preferably, the alcoholic solvent is a lower alcohol. More preferably, the lower alcohol is selected from the group consisting of ethanol, methanol, n-butanol, iso-propyl-alcohol, iso-butanol, amyl-alcohol, and iso-amyl-alcohol.
In another preferred embodiment, the present invention provides a process for preparing 1,2-benzisoxazole-3-acetic acid (BOA), comprising the step of reacting 4-hydroxy-coumarin (4-HC) with hydroxyl-amine in the presence of a base and an alcoholic solution, wherein said process occurs at a temperature between room temperature and boiling point of the alcoholic solvent.
More preferably, the temperature of the reaction is between about 40° C. and about 60° C.
The present invention also provides an improved process of preparing a salt of benzisoxazole methane sulfonic acid, comprising the steps of: 1) sulfonating 1,2-benzisoxazole-3-acetic acid (BOA) using chlorosulfonic acid and dioxane in methylene chloride and sodium hydroxide solvents; and 2) isolating the salt of benzisoxazole methane sulfonic acid.
The present invention provides an improved process for preparing a salt of BOS (e.g., BOS—Na) in which the product is isolated by precipitatation from an aqueous solvent. Preferably, the precipitation is performed by salting-out with, e.g., sodium chloride. More preferably, the precipitation is performed by salting-out and and cooling.
In another preferred embodiment, the salt of BOS (e.g., BOS—Na) is isolated by evaporation.
Preferably, the salt of BOS may be isolated as BOS-Ba or BOS—Ca.
In another preferred embodiment, the preparation of the BOS-salt (e.g., BOS—Na) occurs at about 40° C., preferably at about 55° C. Preferably, the preparation of the BOS-salt is performed for a time duration of about 4 hours. More preferably, the preparation is performed for about 3, about 3.5 and about 5 hours.
According to the present invention, the reaction was improved as the reaction (for converting BOA to BOS—Na) is faster when methylene chloride is used. In other words, the reaction rate is faster when the solvent of the reaction is changed from ethylene chloride to methylene chloride.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following abbreviations are used: 1,2-benzisoxazole-3-acetic acid (BOA); benzisoxazole methane sulfonic acid (BOS); sodium salt of benzisoxazole met

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