Patent GB-701683-A (GB)
Title: Process for the manufacture of 4-amino-2-hydroxybenzamides
Filed: 1949-03-10
Abstract: The invention comprises 4-aminohydroxybenzamides of the general formula <FORM:0701683/IV(b)/1> where R represents a monocyclic heterocyclic five or six memberel ring containing carbon and nitrogen atoms or carbon, nitrogen and sulphur atoms, there being one or two nuclear nitrogen atoms and having a carbon atom in the 2-position which is directly attached to the nitrogen atom of the amido group, and a process for preparing the above compounds by reducing a substituted 4-nitrosalicylamide of the general formula- <FORM:0701683/IV(b)/2> where R has the above significance and R1 represents a hydrogen atom or an alkali metal, with hydrogen in the presence of a hydrogenation catalyst, e.g., Raney nickel, and when R1 represents an alkali metal, acidifying the product.  The desired compounds may also be prepared from the required 4-nitro-2-acyloxy salicylamide by a reduction step and a hydrolysis step which may be carried out successively or simultaneously.  In the two-step process hydrolysis may be carried out using a mild alkali such as sodium or potassium carbonate followed by acidification to a pH of about 5, the product may then be dissolved in a volatile organic solvent such as methanol or ethanol and subjected to catalytic hydrogenation using as a catalyst a Group VIII metal, preferably Raney nickel.  It is preferable to carry out the reduction and hydrolysis simultaneously under mildly alkaline conditions, i.e., by treating the 4-nitro-2- acyloxy salicylamide with a slight excess of aqueous alkali and hydrogenating the reaction mixture using Raney nickel, and liberating the free compounds by adding mineral acid.  In the examples the following compounds are prepared: The 2-(41-aminosalicylamido) derivatives of pyridine, thiazole, pyrazine, pyrimidine, 4, 6-dimethylpyrinidine and 5-methyl-1, 2, 4-thiadiazole.  4- Nitro-2-substituted-benzamides of the general formula- <FORM:0701683/IV(b)/3> wherein R has the significance indicated above and R1 represents hydrogen or an acyl radical, are prepared by the reaction of 4-nitro-2-acyloxy halides, such as 4-nitro-acetyl salicylyl chloride, with the required heterocyclic amine in the presence of an acid acceptor, e.g., an excess of the heterocyclic amine or pyridine, quinoline, thiazole and their homologues, or aromatic amines such as aniline and dimethylaniline, or water-miscible organic bases.  The compounds wherein R1 represents an acyloxy radical can be converted into the compounds wherein R1 represents hydrogen by hydrolysis with a mild alkali such as sodium or potassium carbonate followed by acidification to a pH of about 5. In the examples the following compounds are prepared: The 2-(4-nitro-2-hydroxy benzamide) derivatives of pyridine, 4, 6-dimethylpyridine and 5-methyl-1, 3, 4-thiadiazole and the corresponding 2-acetoxybenzamide compounds, and the 2-(4-nitro-2-hydroxybenzamide) derivatives of thiazole, pyrazine and pyrimidine.  4- Nitro-acetylsalicylic acid is prepared by heating 4-nitro-salicylic acid with acteyl chloride or acetic anhydride with a trace of concentrated sulphuric acid.  4- Nitro-acetyl-salicylyl chloride is prepared by heating the above free acid with thionyl chloride.