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

Bagley, Mark C, Davis, Terence, Dix, Matthew C, Fusillo, Vincenzo, Pigeaux, Morgane, Rokicki, Michal J and Kipling, David (2009) Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745. Journal of Organic Chemistry, 74 (21). pp. 8336-42. ISSN 1520-6904

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 29 Oct 2012 09:19
Last Modified: 29 Oct 2012 09:19
URI: http://sro.sussex.ac.uk/id/eprint/40894
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