Patent GB-743912-A (GB)
Title: X-ray diagnostic agent and process for manufacturing same
IPC: C07C59/56
Filed: 1953-01-23
Abstract: The invention comprises compounds of formula <FORM:0743912/IV(a)/1> or non-toxic alkali metal, alkaline earth metal or amine salts thereof, wherein R is an alkyl radical of 1, 2 or 3 carbon atoms. The compounds are prepared (1) by condensing 3-hydroxy benzaldehyde with an appropriate aliphatic carboxylic acid or salt thereof (preferably a mixture of the alkali metal salt and the corresponding acid anhydride), hydrogenating the resulting cinnamic acid derivative (e.g. with a Raney nickel aluminium alloy in alkaline solution, or using a Raney nickel or platinum oxide catalyst), and tri-iodinating the resulting hydrocinnamic acid derivative (e.g. with iodine monochloride or iodine and potassium iodide); (2) by reacting meta-nitrobenzaldehyde with, for example, butyric anhydride and sodium butyrate to form a -ethyl-meta-nitrocinnamic acid, hydrogenating this to a -ethyl-b -(3-aminophenyl)-propionic acid which, upon treatment with iodine monochloride, gives a -ethyl-b -(2,4,6-triiodo-3-aminophenyl) propionic acid, the amino group of the latter compound being converted to hydroxyl by subsequent diazotization and hydrolysis; (3) by tri-iodinating meta-amino- or meta-hydroxybenzaldehyde and reacting the product with, for example, butyric anhydride and sodium butyrate to form a -ethyl-3-amino- or 3 , hydroxy - 2,4,6 - triiodo - cinnamic acid, which may be subsequently reduced with hydroiodic acid and red phosphorus, the 3-amino product being subjected to diazotization and hydrolysis either before or after the reduction step; (4) by condensing meta-methoxybenzaldehyde with diethyl malonate to form diethyl meta-methoxybenzal-malonate, reducing this to diethyl meta-methoxybenzyl-malonate, which gives on treatment with ethyl bromide and sodium ethoxide, diethyl 1-(21,41,61-triiodo-11-hydroxyphenyl) - butane - 2,2 - dicarboxylate, and subsequently hydrolysing this compound with caustic potash; (5) by condensing meta-chloromethylphenyl benzyl ether with diethyl malonate to form diethyl 1-meta-benzyloxyphenylbutane - 2,2 - dicarboxylate, which is then treated as for the meta-methoxyphenyl-butanedicarboxylate in (4); (6) by condensing b -metabenzyloxyphenyl-propionitrile with ethyl bromide in presence of sodamide to form a -ethyl-b -meta-benzyloxyphenyl - propionitrile, hydrogenating this to form a -ethyl-b -metahydroxyphenylpropionitrile, which may either be hydrolysed with caustic potash and acidified to give a -ethyl - b  - 3 - hydroxyphenylpropionic acid, which is subsequently tri-iodinated, or triiodinated to give a -ethyl-b -(2,4,6-triiodo-3-hydroxyphenyl) - propionitrile, which is subsequently hydrolysed with hydrochloric acid or caustic potash; (7) by reacting meta-methoxy-benzyl bromide with butyronitrile in presence of sodamide to give a -ethyl-b -meta-methoxyphenylpropionitrile, treating this with pyridine and hydrobromic acid to give a -ethyl-b -meta-hydroxyphenyl - propionitrile, which is subsequently tri-iodinated and hydrolysed as in (6).  The examples describe the preparation of a -methyl-, a -ethyl-, a -isopropyl- and a -n-propyl-b  - (2,4,6 - triiodo - 3 - hydroxyphenyl) - propionic acid.  a  - Methyl - and a  - ethyl - 3 - hydroxycinnanic acid are prepared as intermediates using method (1).ALSO:An X-ray diagnostic agent comprises a non-toxic pharmaceutical carrier and an acid of formula <FORM:0743912/VI/1> or a non-toxic alkali metal (e.g. lithium, sodium and potassium), alkaline earth metal (e.g. calcium and magnesium) or amine (e.g. mono-, di-, and tri-ethanolamine or propanolamine) salt thereof, wherein R is an alkyl radical of 1, 2 or 3 carbon atoms.  The free acids or salts may be incorporated in tablets containing, for example, starches, sugars, gums and soaps, or may be dissolved or suspended in milk, water or orange juice.  The aqueous suspensions of the free acids may also contain pectin, methyl cellulose or kaolin, and the free acids are also stated to be soluble in sodium bicarbonate solution and in lower fatty alcohols.  a -ethyl-b -(2, 4, 6-triiodo-3-hydroxyphenyl) propionic acid is a preferred active constituent.