Microwave-assisted N-formylation of active pharmaceutical ingredients (APIs) and intermediates, and screening of their N-formylated derivatives towards anti-bacterial potential

Abstract

We report a robust and sustainable approach for the selective N-formylation of API and their intermediates containing primary or secondary amine (both aliphatic and aromatic) in the presence of DMF and catalytic AcOH under microwave irradiation. The optimized conditions were established via N-formylation of Lopinavir intermediate-I and various marketed drugs (e.g. Duloxetine, Atomoxetine, Nebivolol, Desloratadine, Valaciclovir, Phenylephrine, Memantine, Vortioxetine, Tamsulosin, Palbociclib and Crizotinib) were employed subsequently. The other substrates include multi-functionalized API intermediates possessing various substituents or groups in addition to chiral centers in some cases. Generally, the N-formylation proceeded smoothly affording the corresponding product in good to acceptable yield. All the reactions were performed in gram scale and the methodology does not require the use of expensive and cumbersome column chromatographic purification of products. The selectivity, eco-friendly nature, low cost, operational and isolation/purification simplicity along with the access to several valuable drug impurities are the key features of the current protocol. When tested for anti-bacterial activities in vitro against several S. aureus strains along with E. coli, the low to good inhibition was noted for compound 2d and 2e against S. aureus.