Hydroxylamine → Acetamide, 2-(hydroxyimino)-N-phenyl-

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Reaction Steps

The starting material of 2,3-dimethyl aniline (1) was mixed and condensed with hydroxylamine and chloral hydrate to yield isonitrosoacetanilide (2), then to yield isatin (3) by acid-catalyzed cyclization and 2-amino-3,4-dimethyl-benzoic acid (4) by an oxidative ring cleavage reaction. The total yield of the first three steps was 37%. The steps involved in hydroxylamine and chloral hydrate, both of which were toxic. Additionally, the steps were a multi-phase reaction, requiring careful control on the reaction time and temperature. Under carefully-controlled conditions, 2-amino-3,4-dimethyl-benzoic acid (4) was diazotized to yield an iodide (5). The iodide was condensed with 2-hydroxyphenylacetic acid to yield 2-[2-(carboxymethyl)phenoxy]-3,4-dimethyl-benzoic acid (6), which was further cyclized to yield DMXAA. The total yield of the six steps was about 12%.

Provenance & Evidence