2.5- dihydroxyterephthalic acid

The requisite 2,5-dihydroxyterephthalic acid (DHTA) was initially prepared by bromine oxidation of commercially available diethyl succinylosuccinate (DDS also known as diethyl 1,4-cyclohexanedione-2,5-dicarboxylate) in cold sulfuric acid, followed by alkaline hydrolysis. It was later found that a more convenient and facile preparation of DHTA involved the aromatization of DSS using elemental sulfur as the hydrogen acceptor in the presence of a catalytic amount of Pd/C in boiling diethylbenzene (DEB), (see figure 8). 

C2H5O —C—C — OC2H5 diethyl ester of 2,5-dihydroxyterephthalic acid... 

Dihydroxyterephthalic acid (DHTA) is described (Scheme 9.3) in the literature as the product of bromine/sulfuric acid mediated aromatization [29] of diethyl succinoylsuccinate, a commercial product, followed by hydrolysis. The aromatization can also be effected with sulfur succinoyl succinate is boiled with slight excess of sulfur in NMP for 20-30 min as the temperature rises from about 150°C (H S evolution) to about 200°C. Dilution with water precipitates dimethyl dihydroxyterephthalate which is hydrolyzed with hot aqueous NaOH. Alternatively, aromatization can be done with S and a Pd/C catalyst [17-20]. Sikkema et al. found a convenient and non-noxious procedure in aromatizing the succinoylsuccinate in acetic acid at reflux with 30% aqueous hydrogen peroxide with... 

Succinosuccinic ester was discovered by Fehling and investigated by Remsen. It was synthesised and its conversion into p-dihydroxyterephthalic acid observed by F. Herrmann. Baeyer synthesised terephthalic acid from succinosuccinic acid, and with W. A. Noyes synthesised succinosuccinic acid by reducing dihydroxyterephthalic acid. Baeyer found that phloroglucinol forms an oxime, and hence can function as triketohexamethylene as well as trihydroxybenzene, a recognition of tautomerism. He introduced the de-colorisation of alkaline permanganate solution as a test for unsaturation. 

A most important property of any sequestering agent to be used in chelation therapy is oral activity. One of the few agents to show any oral efficacy as an iron removal drug is 2,3-dihydroxybenzoic acid u4). Therefore, the 2,3-dihydroxyterephthalate conjugates of spermine and spermidine have been synthesized 115) according to the general scheme outlined above. While the neutral catechol derivative is insoluble in water, the carboxylate derivative shows increased water solubility and lower toxicity. 

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