Nanomaterial assisted bulk scale synthesis of 2-methyl-6-nitroquinoline

Abstract

Quinolines are an interesting class of moieties with various medicinal chemistry uses. The most prominent is their ability to be used as the last line of therapy for bacterial and viral infections including recent COVID-19. The synthesis of quinoline is through a cyclization reaction and overall reaction yields are about 20%. The bulky ring and the associated crowding of functional groups limit the catalyst options. In this publication, the use of Fe₃O₄@SiO₂ for enhancing yield improvements, especially for heterocyclics is reported. The use of the 40 nm sized silica functionalized magnetite nanoparticles seems to help in both condensation and cyclization steps of representative 2-methyl-6-nitroquinoline. Reaction time reduction due to surface enabled catalysis of nanoparticles is 110 min to 80 min. The reaction yield has doubled due to the presence of catalyst and the mechanism suggests this drastic result is due to stabilization of unstable intermediate on the acidic surface of the silica coating. This near homogeneous catalysis of 40 nm sized, silica functionalized, magnetite nanoparticles have far reaching applications in bulk drug industry for drugs like chloroquine & hydroxychloroquine, the two essential drugs for prophylactic use for COVID-1.

Keywords: 2-methyl-6-nitroquinolin; Bulk Scale Synthesis; Fe3O4@SiO2; Quinoline; Silica functionalized Magnetic Nanoparticles (SMNP).

Scheme 1

Antimalarial quinolone structures a) Cholroquine, b) Amodiaquine, c) Quinine) d) Mefloquine.

Fig. 1

Diagrammatic representation of Fe₃O₄@SiO₂ Synthesis: Synthesis of nanoparticles using ferrous sulphate heptahydrate, NaNO₃ as starting materials and sodium hydroxide as reducing agent. The NaNO₃ in equilibrium with FeSO₄ generates in situ which allows nanoparticle formation.

Fig. 2

SEM analysis of silica functionalized magnetic nanoparticles.

Fig. 3

IR spectra of silica functionalized magnetic nanoparticles of different batches and compared with non-silanized magnetic nanoparticles.

Scheme 2

Synthesis scheme of quinoline derivative: The conjugative addition, cyclization, and aromatization reactions happened in situ of the reaction.

Scheme 3

Mechanism for synthesis of 2-methyl-6-nitroquinoline: The reaction mechanism with silica functionalized magnetic nanocatalyst for the synthesis of 2-methyl-6-nitroquinoline.

Fig. 4

Reduction of reaction time via the Fe₃O₄@SiO₂ catalyst: The graph shows the relation between the reaction yields versus reaction time. This the proof that of Fe₃O₄@SiO₂ catalyst will reduce the reaction and essential improvement in product yield (Green peak). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)