Synthesis of Substituted Azetidinones Derived from Dimer of Apremilast

Abstract

Over the past decade, design of 2-azetidinones scaffold has attracted greater interest of synthesis because of more biological and pharmacological potencies. Specifically, sulfonamide rings and their derivatives represent a medicinally and pharmaceutically important class of heterocyclic motifs that are found as the core structural skeletons in a variety of several naturally occurring alkaloids. We effectively intended 4-(3-chloro-2-oxo-4-aryllazetidin-1-yl)-2-(1-(3-ethoxy-4methoxyphenyl)-2-(methylsulfonyl)-ethyl)-2,4′-biisoindoline-1.1′3,3′-tetraones (6(a-f)). 4-Amino-2′(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-2,4′-biisoindo line-1, 1′, 3, 3′-tetraone 3 was prepared by condensation of 3-aminophthalic acid 2 with 1,3-ethoxy-4-methoxyphenyl)-2methylsutfonylethylamine 1 by a single step. Condensation of compound 3 with various aromatic aldehydes gives substituted Schiff base of 2′-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)2,4′-biisoindoline-1,1′,3,3′-tetraones (5(a-f)) which upon dehydrative annulation in the presence of chloroacetylchloride in the presence of triethylamine in DCM solvent yielded 4-(3-Chloro-2-oxo-4aryllazetidin-1-yl)-2′-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-2,4′-biisoindoline1.1′3,3′-tetraones 6(a-f). All the synthesized compounds were recognized by Infra Red-Vibrational spectroscopy, Proton Nuclear Magnetic Resonance, mass spectroscopy and their C, H, N analyses.