Patent GB-467946-A (GB)
Title: Process for the manufacture of iodised hydroxy derivatives of 2-phenylquinoline-4-carboxylic acid
IPC: C07D215/52
Filed: 1936-06-18
Abstract: Iodized hydroxy derivatives of 2-phenylquinoline-4-carboxylic acid are manufactured by condensing 3 : 5-diiodo-4-hydroxyacetophenone, its homologues or their substitution products, including derivatives substituted in the hydroxy group by alkyl, oxyalkyl, alkoxyalkyl, alkylcarboxylic acid, or other residues, with isatins, preferably iodoisatins. The condensation may be effected by the action of aqueous or alcoholic alkali, e.g. potash, alcoholic potash lye being preferably used in the case of diiodohydroxyacetophenones in which the hydroxy group is substituted by hydroxyalkyl residues, since with aqueous potash lye an isomeric product is first obtained which must be further treated with alcoholic potash lye to yield the final product of direct treatment with alcoholic potash lye. In the manufacture of the substitution products, the substitution of the hydroxy group may alternatively be effected after the condensation. The products are suitable as X-ray contrast agents, particularly for making the gall visible.  In examples: (1) 3 : 5-diiodo-4-hydroxyacetophenone is heated with 5-iodoisatin in the presence of potash lye and alcohol, producing 2-(3<1> : 5<1>-diiodo - 4<1> - hydroxyphenyl) - 6 - iodoquinoline - 4-carboxylic acid; (2) 3 : 5-diiodo-4-methoxyacetophenone (obtainable by treating the sodium salt of 3 : 5-diiodo-4-hydroxyacetophenone with methyl iodide in alcoholic solution) similarly yields 2-(3<1> : 5<1>-diiodo-4<1>-methoxyphenyl) - 6 - iodoquinoline - 4 - carboxylic acid; (3) 3 : 5-diiodo-4-ethoxyacetophenone (obtainable by treating the sodium salt of 3 : 5-diiodo-4-hydroxyacetophenone with ethyl iodide) similarly yields the corresponding ethoxy compound; (4) 3 : 5-diiodo-4-hydroxyacetophenone methoxymethyl ether (obtainable by treating the sodium salt of the corresponding hydroxy compound with chloromethyl ether in benzene solution) similarly yields 2-(3<1> : 5<1>-diiodo - 4<1> - methoxymethoxyphenyl) - 6 - iodoquinoline - 4 - carboxylic acid; (5) 3 : 5 - diiodo - 4-hydroxyethoxyacetophenone (obtainable by treating the sodium salt of the corresponding hydroxy compound with ethylene chlorhydrin) similarly yields 2-(3<1> : 5<1> - diiodo - 4<1> - hydroxyphenyl) - 6 - iodo - 3 - (b  - hydroxyethyl) - quinoline - 4 - carboxylic acid; alternatively the condensation is effected with aqueous potash lye and the initial product is isomerized by treatment with alcholic potash lye; (6) the same product is obtained by condensing 3 : 5-diiodo - 4 - hydroxy - 1 - (g - hydroxy) - butyrophenone (obtainable by iodizing 4-hydroxy-1-(g -hydroxy)-butyrophenone, obtained by the action of aluminium chloride on g -bromobutyrophenol made from phenol and bromobutyryl chloride) with 5-iodoisatin in the presence of aqueous potash lye; (7) 3 : 5-diiodo-1-aceto-4-phenoxyacetic acid similarly yields (6<1>-iodo-4<1>-carboxyquinolyl - 2<1>) - 3 : 5 - diiodo - 4 - phenoxyacetic acid; (8) isatin is employed in place of its 5-iodo derivative in the process of (7) to produce (4<1>-carboxyquinolyl-2<1>)-3 : 5-diiodo-4-phenoxyacetic acid; (9) 3 : 5-diiodo-4-ethoxy-acetophenone is heated with 5-methylisatin and alcoholic potash lye, producing 2-(3<1> : 5<1>-diiodo-4<1> - ethoxyphenyl) - 6 - methylquinoline - 4 - carboxylic acid.  Other starting materials specified are 3 : 5-diiodo-4-hydroxy-1-propiophenone and -1-butyrophenone (obtainable by introducing iodine into 4-hydroxy-1-propiophenone and -1-butyrophenone respectively).  Specification 458,640 is referred to.