Enzymatic aminolysis in continuous flow: an efficient strategy for the synthesis of salicylamide derivatives

Salicylamide derivatives with different amine substitutions demonstrate potent biological activities such as anti-tumor, antibacterial and neuroprotective properties. In this work, a green and efficient strategy for the synthesis of salicylamide derivatives catalyzed by Lipozyme®TL IM from Thermomyces lanuginosus in continuous flow microreactors was developed. Enzymatic aminolysis from methyl salicylate and amines (cyclic and linear aliphatic amines, aryl alkyl amines, tryptamines) in a continuous-flow microreactor was used for the synthesis of salicylamide derivatives. Reaction parameters were optimized, and continuous flow was compared with conventional batch methods using space-time yield (STY). This strategy showed broad substrate applicability, enabling the synthesis of 34 salicylamide derivatives with ideal yields. It provides a novel sustainable approach for precise modification of the salicylamide skeleton, offering valuable compounds for drug screening and structure-activity relationship studies.