Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745.

Abstract

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.

• Authors: Mark C Bagley, Terence Davis, Matthew C Dix, Vincenzo Fusillo, Morgane Pigeaux, Michal J Rokicki, David Kipling
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 74 Issue 21 Pg. 8336-42 (Nov 06 2009) ISSN: 1520-6904 [Electronic] United States
• PMID: 19778055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyridazines
• Pyrimidines
• p38 Mitogen-Activated Protein Kinases
• VX-745

Topics

• Magnetic Resonance Spectroscopy
• Protein Kinase Inhibitors (chemical synthesis, pharmacology)
• Pyridazines (chemical synthesis, pharmacology)
• Pyrimidines (chemical synthesis, pharmacology)
• Spectrometry, Mass, Electrospray Ionization
• Spectrophotometry, Infrared
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)