Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745.
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 p38alpha MAPK is confirmed in Werner syndrome dermal fibroblasts at 1.0 microM concentration by immunoblot assay.
Bagley
Mark C
MC
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff CF10 3AT, UK. bagleymc@cf.ac.uk
Davis
Terence
T
Dix
Matthew C
MC
Fusillo
Vincenzo
V
Pigeaux
Morgane
M
Rokicki
Michal J
MJ
Kipling
David
D
D009682:Magnetic Resonance Spectroscopy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C464966:VX-745