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.
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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)
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Chemical References |
- Protein Kinase Inhibitors
- Pyridazines
- Pyrimidines
- p38 Mitogen-Activated Protein Kinases
- VX-745
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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)
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