Hydroxylamine → 2-(1,2-Benzoxazol-3-yl)acetic acid

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Reaction Steps

Hydroxycoumarin (5) is treated with hydroxylamine to obtain benzo[d]isoxazol-3-yl-acetic acid (6) which is brominated at the alpha position to give benzo[d]isoxazol-3-yl-bromoacetic acid (7) from which 3-bromomethyl-benzo[d]isoxazole (8) is obtained by decarboxylation. The development of this process is limited in that the starting intermediate (1) is not commercially available and therefore the preparation of zonisamide is very complex. In fact, Posner reaction for the preparation of acid (6) requires the use of metal sodium. Moreover, when metal sodium is used in alcoholic solution, besides acid (6) also remarkable amounts of O-hydroxy-acetophenone-oxime as by-product are obtained. Furthermore, the decarboxylation reaction to give compound (8) requires drastic conditions, namely the presence of a large excess of 50% sulfuric acid and reflux temperature, and the resulting product is thus difficult to be isolated.

Provenance & Evidence