Patent GB-466185-A (GB)
Title: Manufacture of substituted pyridine-ortho-dicarboxylic acid amides
Filed: 1935-11-28
Abstract: Amides of pyridine o-dicarboxylic acids, substituted with alkyl groups on the amide nitrogen atoms, are prepared (1) by reacting a pyridine-o-dicarboxylic acid or a derivative thereof, such as a salt, ester, halide or anhydride, with a primary or secondary aliphatic amine or a salt thereof, or (2) by reacting a salt of a pyridine-o-dicarboxylic acid with a mono- or di-alkylcarbamyl halide in the presence or absence of a solvent.  The term aliphatic amine includes cyclic compounds such as piperidine in which a group NH is attached to different carbon atoms of a single alkylene group.  When a pyridine-o-dicarboxylic acid is taken as such or as its anhydride, the reaction is effected in the presence of a water-binding agent, e.g. a phosphorus halide, thionyl chloride, phosgene, or phosphorus pentoxide, and in the presence or absence of a solvent; in other cases falling under (1) above, the reaction is effected in the presence or absence of a solvent and a water-binding or acid-binding agent.  The two carboxylic groups may be amidated in different stages, products differently substituted on the amide nitrogen atoms being thus obtainable. In the examples, (1) pyridine - 2 : 3 : dicarboxylic acid dichloride and diethylamine are reacted in cold benzene solution to yield pyridine-2 : 3-dicarboxylic acid bis-diethylamide; pyridine-2 : 3-dicarboxylic acid bis-diallylamide is similarly obtainable; (2) pyridine-2 : 3-dicarboxylic acid dichloride is heated with diethylamine hydrochloride to yield pyridine-2 : 3-dicarboxylic acid bis-diethylamide; the same product is obtainable from the sodium or calcium salt of the acid and diethylcarbamyl chloride; (3) pyridine-2 : 3-dicarboxylic acid is added to diethylamine, and the salt produced is heated with phosphorus oxychloride (or phosphorus pentoxide, thionyl chloride or phosgene); pyridine-2 : 3-dicarboxylic acid bis-diethylamide is again obtained; (4) pyridine-2 : 3-dicarboxylic anhydride is mixed with diethylamine to yield the diethylamine salt of 2-carboxypyridine-3-carboxylic acid diethylamide, which is heated with phosphorus oxychloride to yield pyridine-2 : 3-dicarboxylic acid bis-diethylamide; (5) pyridine-2 : 3-dicarboxylic acid dichloride and di-n-butylamine, in the presence of caustic soda, yield pyridine-2 : 3-dicarboxylic acid bis-di-n-butylamide; (6) pyridine-2 : 3-dicarboxylic acid dichloride and piperidine, in the presence of caustic soda, yield pyridine-2 : 3-dicarboxylic acid dipiperidide; (7) pyridine-2 : 3-dicarboxylic acid dimethyl ester, heated with ethylamine and methyl alcohol, yield pyridine-2 : 3-dicarboxylic acid bis-ethylamide; the product is also obtainable from the dichloride of the acid and ethylamine; (8) pyridine-2 : 3-dicarboxylic acid dichloride and dimethylamine, reacted in ethereal or aqueous solution, yield pyridine-2 : 3-dicarboxylic acid bis-dimethylamide; (9) 2-carboxypyridine-3-carboxylic acid diethylamide (made by treating its diethylamine salt, described in example 4, with hydrochloric acid), is mixed in toluene suspension with di-n-propylamine, and the mixture is heated with phosphorus oxychloride; pyridine-2-carboxy di - n - propylamide - 3 - carboxydiethylamide is obtained; (10) pyridine - 3 : 4-dicarboxylic acid dichloride (from the acid and phosphorus pentachloride) is treated with diethylamine in ethereal solution to yield pyridine - 3 : 4 - dicarboxylic acid bis-diethylamide; pyridine - 3 : 4 - dicarboxylic acid bis - di - n - propylamide is similarly obtainable. The products are of therapeutic value.