Hydroxycinchoninic Acid

Submitted by Thomas L. Jacobs, S. Winstein, Gustave B. Linden, Jean H. Robson, Edward F. Levy, and Dexter Seymour. Checked by R. T. Arnold and F. M. Robinson. 

N-Acetylisalin. In a 3-1. three-necked flask equipped with a mercury-sealed stirrer and reflux condenser are placed 600 g. (4.1 moles) of isatin (Note 1) and 1390 ml. (14.7 moles) of acetic anhydride (Note 2). This mixture is refluxed for 4 hours over a free flame with constant stirring. The solution is allowed to cool slowly to room temperature with stirring and is then cooled to about 10° (Note 3). The slurry of crystals is collected on a 12-in. 

Buchner funnel and washed with five 17S-ml. portions of ether or until the washings are light red. The yield of crude air-dried N-acetylisatin, m.p. 141-142° (cor.), is 635 to 643 g. (82-83%) (Note 4). 

Commercial isatin, m.p. 199.0-200.5° (cor.), was obtained from the National Aniline and Chemical Company. 

Acetic anhydride obtained from the Carbide and Carbon Chemicals Corporation was employed. Redistillation of this reagent did not increase the yield. 

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B. 3-Hydroxycinchoninic acid. A 3-1., four-necked flask (Note 1) is equipped with a sealed mechanical stirrer, gas inlet tube, gas outlet consisting of a 1-mm. capillary (Note 7), and thermometer. The flask is charged with a freshly prepared solution containing 448 g. (8 moles) of reagent grade (85% minimum assay) potassium hydroxide and 900 ml. of water. The solution (hot from dissolution of potassium hydroxide) is stirred and 147 g. (1 mole) of isatin (Note 8) is introduced. The solid quickly dissolves to give an orange-yellow solution. 

C. 3-Hydroxyquinoline. A 1-1. beaker is fitted with a thermometer and mechanical stirrer and clamped firmly on an efficient electric heater (Note 14). Diethyl succinate (400 ml.) (Note 15) is placed in the beaker and heated to boiling (215-220°) with stirring. 3-Hydroxycinchoninic acid (part B) (94.6 g., 0.5 mole) is added in portions to the boiling solution by means of a metal spoon or Scoopula. Care is taken to prevent too vigorous evolution of carbon dioxide. The addition requires 2-3 minutes, during which time a temperature drop is noted unless good heating is maintained. 

Hydroxycinchoninic acid of this purity is adequate for decarboxylation. A sample recrystallized from dimethylform-amide or SiV hydrochloric acid decomposes at 224° when observed as described before. 

The procedure described for the preparation of 3-hydroxycin-choninic acid is adapted from that reported. This synthesis is successful when bromopyruvic acid or its ethyl ester is substituted for chloropyruvic acid. The reaction of isatin with chloropyruvic acid to produce 3-hydroxycinchoninic acid has been reported however, no details or physical properties were given. This method offers a decided advantage over the method involving diazotization of the difficultly accessible 3-aminocinchoninic acid. ... 

Until recent years the only syntheses of 3-hydroxy quinoline involved multistep processes, the last step of which consisted of the conversion of 3-aminoquinoline to 3-hydroxyquinoline via the diazonium salt. " Small quantities of quinoline have been oxidized to 3-hydroxyquinoline in low yields by using oxygen in the presence of ascorbic acid, ethylenediaminetetraacetic acid, ferrous sulfate, and i)hosi)halc buffer. The decarboxylation of 3-hydroxycinchoninic, acid in boiling nitrobenzene has been re-... 

N,N-Diethyl-N -phenyI-2,2-dichloro-acetamidine, 41, 23 Diethyl succinate, for synthesis of tri-ethyl oxalylsucdnate, 44, 67 reaction with 3-hydroxycinchoninic acid to yield 3-hydroxyquinoline, 40,56... 

Hydroxycinchoninic acid, 40, 55 reaction with diethyl succinate to yield 3-hydroxyquinoline, 40, 56... 

Isatin, reaction with chloropyruvic add to yield 3-hydroxycinchoninic acid, 55... 

Hydroxycinchoninic acid has been prepared by the rearrangement of N-acetylisatin in alkali, -by the treatment of isatin with malonic acid in glacial acetic acid, and by heating cinchoninic acid with concentrated potassium hydroxide. ... 

Karrer and Schmid have examined the water-soluble constituents in poppy straw after extraction of the alkaloids, and have recorded the presence of -hydroxybenzaldehyde, vanillin, -hydroxystyrene, meconin and the following acids fumaric, dZ-lactic, benzoic, -hydroxycinnamic, p-hydroxybenzoic, 2-hydroxycinchoninic, vanillic, phthalic, hemipinic and m-hemipinic, with a more highly unsaturated, carboxylic acid J, b.p. 170-570-02 mm., and three unidentified substances Fa , m.p. 271-2° Wx, m.p. 310° (dec.) and Q, m.p. 260° the two latter are free from nitrogen and contain no methoxyl. 

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