Synthesis of N,N′-diaryl unsymmetrical urea via diphenyl carbonate (DPC) based N-aryl-O-phenyl carbamate

Urea derivatives have wide scope in drug design, medicinal chemistry and many other pharmaceutical applications. Traditionally, urea-containing compounds have been synthesized by the reaction of amines with phosgene, carbon monoxide, or isocyanates. However, these synthetic procedures involve safety and environmental issues because of the toxicity and hazards associated with the reagents used. Efficient, practical synthesis of N,N′-diarylureas derivatives via water-assisted synthesis of N-aryl-O-phenyl carbamates have been achieved in a manner that is free from the problems associated with previously reported methods. The process involved preparation of N-aryl-O-phenyl carbamates using diphenyl carbonate in aqueous-organic medium and did not require the use of hazardous reagents, and has shown a broad substrate scope with good to excellent yields of urea derivatives. N,N′-diaryl unsymmetrical ureas were synthesized using a strong base in refluxing solvents via the generation of an isocyanate intermediate followed by trapping of the intermediate with another aryl amine. Further supported the mechanistic investigation using ¹⁹F NMR spectra which clearly showed that the reaction proceeded via base-catalyzed elimination of phenoxide to yield an isocyanate. Further this protocol was employed in an improved synthesis of Sorafenib, Regorafenib and MBX-4132 that, entails the present procedure is operationally simple, potentially scalable, and environmentally benign for the synthesis of important urea motifs.