Microwave-Assisted Ullmann C−S Bond Formation: Synthesis of the P38α MAPK Clinical Candidate VX-745
journal contributionposted on 06.11.2009, 00:00 by Mark C. Bagley, Terence Davis, Matthew C. Dix, Vincenzo Fusillo, Morgane Pigeaux, Michal J. Rokicki, David Kipling
Microwave irradiation promotes the rapid and efficient reaction of a thiophenol and aryl or heteroaryl halide using a copper or palladium catalyst and a range of ligands, depending upon substrate. Of particular utility is the use of copper(I) iodide (5 mol %) and trans-cyclohexane-1,2-diol as ligand under basic conditions and microwave irradiation to give the corresponding sulfide in high yield. This method for C−S bond formation is applied in the four-step synthesis of the clinical candidate VX-745 in 38% overall yield. The inhibitory activity of VX-745 against p38α MAPK is confirmed in Werner syndrome dermal fibroblasts at 1.0 μM concentration by immunoblot assay.