Facile formation of amide bonds between fragments containing unmasked imidazole‐ring systems. Synthesis of N‐[N‐[[[(5‐methyl‐4‐imidazolyl)methyl]thio]acetyl]‐L‐methionyl]histamine

Abstract

AbstractThe synthesis is reported of the optically pure title compound [α20 −2.31 l·mol−1·dm−1] from a sequence of reactions involving 5‐methyl‐4‐imidazolemethanol, mercaptoacetic acid and (L‐methionyl)histamine. The development of a suitable synthetic route, using N‐benzyl‐2‐[[(5‐methyl‐4‐imidazolyl)methyl]thio]acetamide as a model compound, and the problems associated with the presence of imidazole ring systems in the reagents are discussed. The main problem of the synthesis, i.e., the formation of amide bonds between reagents that contain unmasked imidazole functions, is overcome by using an N,N′‐dicyclohexylcarbodiimide‐activated and N‐hydroxybenzotriazole‐moderated coupling procedure.The present method seems generally applicable and yields gram quantities in an overall yield of more than 30%, without the need for chromatography techniques.