通过靛红(isatin)合成多取代邻氨基苯甲酸

Synthesis of lanthranilic acid via oxidative opening of isatin

Chloral hydrate (90 g, 0.54 mol) and anhydrous Na₂SO₄ (453 g, 3.2 mol) were added to water (1.5 L) with rapid stirring. A slurry of hydroxylamine sulfate (410 g, 2.5 mol) and 2,3-dimethylaniline (58.1 g, 0.48 mol) in water (500 mL) containing concentrated HC1 (50 mL) was then added, and the stirred mixture was heated slowly to 45 °C over 90 min,to 52 °C over 45 min, and finally to 75 °C for 60 min. After cooling, the precipitate was collected, washed with water followed by petroleum ether, and dried to give the crude isonitroso compound (80.2 g, 87%).

Crude, powdered, isonitroso compound (60.0 g, 0.31 mol) was added in portions to stirred CH₃SO₃H (240 mL) at 70-80 °C. The cooled mixture was poured onto ice and diluted with water, and the precipitate was collected and dissolved in excess 1 N aqueous NaOH. Neutralization with AcOH precipitated impurities which were removed by filtration, and acidification (HCl) of the clarified solution gave isatin as an orange-red solid (35.8 g, 65%).

A solution of 6,7-dimethylisatin (37.8 g, 0.22 mol) in water (400 mL) containing NaOH (14.0 g) and KCl (35 g) was vigorously stirred and treated dropwise at 8-10 °C with 35% H₂O₂ (ca. 45 g) over 45 min. The reaction mixture was then stirred at 20 °C until TLC analysis indicated complete reaction. Addition of AcOH precipitated the crude anthranilic acid, which was washed with water and dried (23.2g, 65%).

J. Med. Chem. 1991, 34, 217-222

标签： isatin