Patent GB-664991-A (GB)
Title: Process for the production of acyl derivatives of aminohydroxybenzene carboxylic acids
Filed: 1948-07-02
Abstract: A process for the production of a salt of hippuryl- or a substituted hippurylamido hydroxy - benzoic acid having the general formula <FORM:0664991/IV (b)/1> in which X is a benzoyl or substituted benzoyl group and Y is hydrogen or an alkyl group or a salt thereof, comprises treating an aminohydroxy-benzoic acid or a salt thereof with a hippuryl or substituted hippuryl halide having the general formula XNH.CHY.COZ in which X and Y are as above defined and Z is halogen, in the presence of an acid acceptor.  To an aqueous solution of a water soluble salt, e.g. an alkali metal salt, of the aminohydroxy-benzoic acid diluted with a water soluble organic solvent, e.g. acetone, methyl ethyl ketone or dioxane, is added the acid halide which may be dissolved in the same solvent, the reaction mixture being maintained neutral or slightly alkaline by additions of alkali.  Substantially stoichiometric amounts of acid halide and alkali may be added substantially simultaneously to the reaction mixture.  Sodium and potassium metal salts are preferred and the added alkali is preferably a caustic alkali, e.g. sodium or potassium hydroxide.  Alternatively the acyl halide may be added to a solution of the aminohydroxy-benzoic acid in an organic base such as pyridine or a picoline, the product being taken up in water and purified as an alkali metal salt by treatment with alkali or with an aqueous solution of a salt thereof with a weak or readily displaceable acid. The free acid may be obtained by treating the reaction mixture with an acid, preferably a mineral acid, to bring the pH to about 3.  The aminohydroxy-benzoic acid employed may be 3-, 4-, or 5-amino-salicylic acid, 2-, 4- or 6-amino-3-hydroxy-benzoic acid or 4-hydroxy-3-aminobenzoic acid and the acylating agent may be an hippuryl halide such as hippuryl chloride, a nuclear substituted hippuryl halide such as p-nitrohippurylchloride, a p-halogeno-hippuryl halide or a p-acylamido-hippuryl halide such as p-acetamidohippuryl chloride or an acid halide derived from an acid in which a hydrogen atom or the a -carbon atom of hippuric acid is replaced by an alkyl group as in the corresponding benzoyl and substituted benzoyl derivatives of alanine, leucine, isoleucine and valine.  In examples: (1) 4-aminosalicylic acid is dissolved with sodium hydroxide and the solution diluted with acetone, hippuryl chloride and sodium hydroxide are added to maintain a pH of 8-8.5 and after removal of acetone the free acid is obtained by addition of hydrochloric acid; (2) 4-(p-chloro-hippuramido) - salicylic acid is obtained by treating 4-amino-salicylic acid in pyridine with p-chlorohippuryl chloride, obtained by the action of phosphorus pentachloride and acetyl chloride on p-chlorohippuric acid, converting this to the sodium salt by treating with sodium bicarbonate, in boiling water and acidifying with hydrochloric acid to obtain the free acid. 4-(p-Nitrohippuramido)-salicylic acid is similarly obtained from p-aminosalicylic acid and p-nitrohippuryl chloride, prepared by treating p-nitrohippuric acid with phosphorus pentachloride and acetyl chloride.