Pyrazinamide derivatives have been extensively studied for their biological activities, such as anti-tuberculosis activity and antiviral activities. In this work, a continuous-flow system was developed for the synthesis of pyrazinamide derivatives from pyrazine esters and amines (aliphatic amine, benzylamines and morpholine) catalyzed by Lipozyme® TL IM from Thermomyces lanuginosus, which was used for the first time. The reaction parameters including solvent, substrate ratio, reaction temperature and reaction time/flow rate were also studied in detail. A total of 23 pyrazinamide derivatives can be obtained through this method in parallel. Compared with other works, this method can be conducted at 45 °C for 20 min in a greener tert-amyl alcohol solvent and maximum yield (91.6%) was obtained as well. In brief, a more efficient and greener method for the synthesis of pyrazinamide derivatives was developed with good scalability, various substrates including aliphatic amines, benzylamines and morpholines can be applied to this method and achieve a desirable yield. Through the construction and research of amide bonds, this method provides a greener and more efficient biocatalytic continuous technology for the development of pyrazine-derived drugs, and provides a basis for the rapid synthesis of pyrazine-derived drugs in the future.
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