Medicinal Chemical Studies on Antiplasmin Drugs. VI. Aza Analogs of 4-Aminomethylbenzoic Acid

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Four aza analogs of 4-aminomethylbenzoic acid (1) were prepared as part of a search for new antiplasmin drugs. 5-Aminomethylpyridine-2-carboxylic acid (5) was prepared by the hydrogenation of methyl 5-cyanopyridine-2-carboxylate (4), followed by alkaline hydrolysis. Similarly, 6-aminomethylpyridine-3-carboxylic acid (7) was prepared from ethyl 6-cyanopyridine-3-carboxylate (6). 5-Aminomethylpyrimidine-2-carboxylic acid (12) was obtained from methyl 5-methylpyrimidine-2-carboxylate (8) via the phthalimido derivative (10). 2-Aminomethylpyrimidine-5-carboxylic acid (25) was obtained by the reaction of benzyloxycarbonylaminoacetamidine (22) with ethoxycarbonylmalonaldehyde (18) in acetic acid, followed by deblocking of the protected groups. Treatment of benzoylaminoacetamidine (14) with acetylacetone (15) in acetic acid provided 2-benzoylaminomethyl-4, 6-dimethylpyrimidine (16), whereas in the presence of K₂CO₃, 2-amino-3-benzoylamino-4, 6-dimethylpyridine (17) was obtained together with a trace of 16. No compound showed more potent antiplasmin activity than tranexamic acid (2), but 5 was more active than 1.