Microwave-Assisted Ullmann C-S Bond Formation: Synthesis of the P38α MAPK Clinical Candidate VX-745

被引：63

作者：

Bagley, Mark C. ^{[1
]}

Davis, Terence ^{[2
]}

Dix, Matthew C. ^{[1
]}

Fusillo, Vincenzo ^{[1
]}

Pigeaux, Morgane ^{[1
]}

Rokicki, Michal J. ^{[2
]}

Kipling, David ^{[2
]}

机构：

[1] Cardiff Univ, Sch Chem, Cardiff CF10 3AT, S Glam, Wales

[2] Cardiff Univ, Sch Med, Dept Pathol, Cardiff CF14 4XN, S Glam, Wales

来源：

JOURNAL OF ORGANIC CHEMISTRY | 2009年 / 74卷 / 21期

基金：

英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

CROSS-COUPLING REACTIONS; PALLADIUM-CATALYZED SYNTHESIS; ORGANIC-SYNTHESIS; ARYL HALIDES; KINASE INHIBITORS; WERNER-SYNDROME; P38; INHIBITORS; NUCLEOPHILIC-SUBSTITUTION; LIGAND-FREE; THIOLS;

D O I：

10.1021/jo9017155

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Microwave irradiation promotes the rapid and efficient reaction of I thiophenol and aryl or heteroaryl halide using it copper or palladium catalyst and it 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% over-all yield. The inhibitory activity of VX-745 against p38 alpha MAPK is confirmed in Werner syndrome dermal fibroblasts at 1.0 mu M concentration by immunoblot assay

引用

页码：8336 / 8342

页数：7

共 76 条

[1] Microwave chemistry: Out of the kitchen [J].

Adam, D .

NATURE, 2003, 421 (6923) :571-572

[2] Rapid synthesis of VX-745: p38 MAP kinase inhibition in Werner syndrome cells [J].

Bagley, Mark C. ;

Davis, Terence ;

Dix, Matthew C. ;

Rokicki, Michal J. ;

Kipling, David .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (18) :5107-5110

[3] Microwave-assisted synthesis of N-pyrazole ureas and the p38α inhibitor BIRB 796 for study into accelerated cell ageing [J].

Bagley, Mark C. ;

Davis, Terence ;

Dix, Matthew C. ;

Widdowson, Caroline S. ;

Kipling, David .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2006, 4 (22) :4158-4164

[4] Rapid Ullmann-type synthesis of aryl sulfides using a copper(I) catalyst and ligand under microwave irradiation [J].

Bagley, Mark C. ;

Dix, Matthew C. ;

Fusillo, Vincenzo .

TETRAHEDRON LETTERS, 2009, 50 (26) :3661-3664

[5] A general method for the formation of aryl-sulfur bonds using copper(I) catalysts [J].

Bates, CG ;

Gujadhur, RK ;

Venkataraman, D .

ORGANIC LETTERS, 2002, 4 (16) :2803-2806

[6]

Bemis G. W., 2000, US, Patent No. [6147080, 6147080 A1]

[7]

Bemis GW., 1998, patent, Patent No. [WO9827098, 9827098]

[8] Cross Coupling of Bromo Sydnones: Development of a Flexible Route toward Functionalized Pyrazoles [J].

Browne, Duncan L. ;

Taylor, John B. ;

Plant, Andrew ;

Harrity, Joseph P. A. .

JOURNAL OF ORGANIC CHEMISTRY, 2009, 74 (01) :396-400

[9] Copper-catalyzed Ullmann coupling under ligand- and additive-free conditions. Part 2: S-arylation of thiols with aryl iodides [J].

Buranaprasertsuk, Pongchart ;

Chang, Joyce Wei Wei ;

Chavasiri, Warinthorn ;

Chan, Philip Wai Hong .

TETRAHEDRON LETTERS, 2008, 49 (12) :2023-2025

[10] MICROWAVE-ASSISTED ORGANIC-REACTIONS [J].

CADDICK, S .

TETRAHEDRON, 1995, 51 (38) :10403-10432

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