Patent GB-396414-A (GB)
Title: The manufacture of water-soluble pyridine derivatives for use as contrast media in x-ray photography
Filed: 1931-12-18
Abstract: 3 : 5-Dihalogen-g -pyridones, in which the halogen is bromine or iodine or both and which contain a solubility-conferring group attached to the N-atom, are prepared by introducing the said group into a 3 : 5-dihalogen-g -pyridone or by brominating or iodizing a g -pyridone possessing a solubility-conferring group attached to the N-atom.  The groups conferring solubility comprise an alkyl group substituted by a salt-forming group, e.g. a carboxylic, sulphonic, amino or alkylamino group, or by a quaternary amino group.  In the form of their salts the products are water-soluble and are useful as contrast media in the X-ray photography of animal organs.  According to the examples, (1) 3 : 5-diiodo-g -pyridone (see Specification 394,387) is heated with chloracetic acid and the resulting 3 : 5-diiodo-4-pyridone-N-acetic acid converted into its sodium salt; the contrast effect of this salt in X-ray photography is twice that obtained with the corresponding monoiodo compound; (2) N-diethylaminoethyl-3 : 5-diiodo-4-pyridone is obtained by treating 3 : 5-diiodo-4-pyridone with diethylaminoethyl chloride; (3) 3 : 5-diiodo-4-pyridone is first heated with chlorethylalcohol, the resulting N-(b -hydroxyethyl) compound then treated with thionyl chloride to give the N-(b -chlorethyl) body, which is finally heated with sodium sulphite to produce 3 : 5-diiodo-4-pyridone-N-ethanesulphonic acid; the same compound is obtained by reacting with ethylene bromide upon 3 : 5-diiodo-4-pyridone and treating the product with sodium sulphite, or by direct interaction of 3 : 5-diiodo-4-pyridone with b -chlorethanesulphonic acid; (4) N-diethylaminoethyl-3 : 5-diiodo-4-pyridone is converted into its quaternary compound with dimethyl sulphate; (5) 3 : 5-dibromo-4-pyridone, prepared by brominating 4-pyridone, is treated with chloracetic acid to give its N-acetic acid derivative; (6) a solution of 4-pyridone in caustic soda is heated with chloracetic acid ethyl ester; saponification of the ester product takes place and the resulting 4-pyridone-N-acetic acid is then brominated in caustic soda solution, yielding a product identical with that of (5). Specification 355,017 is referred to. The Specification as open to inspection under Sect. 91 describes also the conversion of g -pyridone into its 3 : 5-dihalogen derivatives by direct halogenation, the halogenation of g -aminopyridine and the diazotization of the products to form the corresponding pyridones, the production of g -pyridone by heating g -pyridylpyridinium chloride with water followed by halogenation of the reaction solution, and the attachment of acetamide and alkyl groups to the N-atom of 3 : 5-dihalogen-g -pyridones.  The following examples are also included:--(1) 3 : 5-diiodo-4-pyridone is prepared by treating g -pyridone with iodine chloride in hydrochloric acid solution; (2) 3 : 5-diiodo-4-pyridone is treated with chloracetamide to give the N-acetamide compound; the N-methyl derivative is prepared in an analogous manner using methyl iodide or dimethyl sulphate and N-(b , g -dioxypropyl)-3 : 5-diiodo-4-pyridone by means of monochlorhydrin; (3) N-methylchelidamic acid is treated with iodine chloride, and the acidic product heated to form N-methyl-3 : 5-diiodo-4-pyridone with elimination of carbon dioxide; the same acidic product is obtained by converting diiodochelidamic acid with dimethyl sulphate into the N-methyl compound and saponifying; (4) 4-aminopyridine is treated with iodine chloride, the 3 : 5-diiodo4-aminopyridine then separated from the accompanying 3-iodo-4-aminopyridine and converted into 3 : 5-diiodo-4-pyridone by diazotizing and heating the solution; (5) 3 : 5-diiodo-4-pyridone is prepared by treating pyridine with thionyl chloride, heating the product with water, and again after the addition of a mixture of potassium iodide and iodate; (6) N-allyl-3- : 5-diiodo-4-pyridone is obtained by interaction of 3 : p 5-diiodo-4-pyridone with allyl bromide.  This subject-matter does not appear in the Specification as accepted.  Reference has been directed by the Comptroller to Specification 361,437.ALSO:3 : 5-Dihalogen-g -pyridones, in which the halogen is bromine or iodine or both and which contain a solubility-conferring group attached to the N- atom, are employed in the form of their salts as contrast media in the X-ray photography of animal organs.  The groups conferring solubility comprise an alkyl group substituted by a salt-forming group, e.g. a carboxylic, sulphonic, amino or alkylamino group, or by a quaternary amino group.  Compounds specified are 3 : 5-diiodo-4-pyridone-N-acetic acid (the contrast effect of the sodium salt of which is stated to be twice that obtained with the corresponding mono-iodo compound), N-diethylaminoethyl - 3 : 5 - diiodo 4-pyridone, 3 : 5 - diiodo - 4 - pyridone - N - ethanesulphonic acid and 3 : 5-dibromo-4-pyridone-N-acetic acid.  The Specification as open to inspection under Sect. 91 also refers to the following compounds: 3 : 5-diiodo-4-pyridone-N-acetamide, N-methyl-3 : 5-diiodo-4-pyridone, N-(b , g -dioxypropyl)-3 : 5-diiodo-4-pyridone and N-allyl-3 : 5-diiodo-4-pyridone.  This subject-matter does not appear in the Specification as accepted.  Reference has been directed by the Comptroller to Specification 361,437.