Synthesis of unsymmetrical biaryl ureas from N-carbamoylimidazoles: kinetics and application |
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Authors: | Tristan Rawling Andrew M McDonagh Bruce Tattam Michael Murray |
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Institution: | 1. Pharmacogenomics and Drug Development Group, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia;2. Institute for Nanoscale Technology, University of Technology Sydney, NSW 2007, Australia;3. Thomas R. Watson Mass Spectroscopy Facility, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia |
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Abstract: | N-Carbamoylimidazoles dissociate in solution to yield imidazole and an isocyanate that may be reacted with another aryl amine to form an unsymmetrical biaryl urea. This paper investigates the reaction kinetics and the influence of electron withdrawing/donating substituents on the reaction of N-carbamoylimidazoles with aniline. The overall reaction mechanism involves two zwitterionic intermediates, formed during dissociation and upon reaction of the liberated isocyanate with aniline. The rate limiting step for the reaction is a base catalysed proton transfer from the second zwitterionic intermediate. Although electron withdrawing substituents on the aryl group hinder dissociation, they significantly increase reaction rates compared to compounds bearing electron donating substituents. The imidazole liberated upon dissociation catalyses the rate determining step so that reactions of dissociated N-carbamoylimidazoles proceed more rapidly than those involving only isocyanates. In addition, the imidazole eliminates the need for anhydrous reaction conditions. The N-carbamoylimidazole methodology was demonstrated by preparing sorafenib, a biaryl urea kinase inhibitor, in good yield and excellent purity. |
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