Microwave-assisted Ullmann C-S bond formation: synthesis of the P38 alpha MAPK clinical candidate VX-745

Bagley, Mark Christopher, Davis, Terence ORCID: https://orcid.org/0000-0003-2780-0262, Dix, Matthew Charles, Fusillo, Vincenzo, Pigeaux, Morgane, Rokicki, Michal Jaroslaw and Kipling, David Glyn 2009. Microwave-assisted Ullmann C-S bond formation: synthesis of the P38 alpha MAPK clinical candidate VX-745. Journal of Organic Chemistry 74 (21) , pp. 8336-8342. 10.1021/jo9017155

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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
Date Type:	Publication
Status:	Published
Schools:	Schools > Chemistry
Subjects:	Q Science > QD Chemistry
Publisher:	American Chemical Society
ISSN:	0022-3263
Last Modified:	14 Dec 2022 02:14
URI:	https://orca.cardiff.ac.uk/id/eprint/23857

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