Initial synthesis of UK-427,857 (Maraviroc)

doi:10.1016/j.tetlet.2005.05.082

Tetrahedron Letters

Volume 46, Issue 30, 25 July 2005, Pages 5005-5007

https://doi.org/10.1016/j.tetlet.2005.05.082 Get rights and content

Abstract

The initial synthesis of UK-427,857 (Maraviroc) is described including the preparation of 4,4-difluorocyclohexanoic acid and amide coupling utilizing a polymer supported reagent.

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Acknowledgements

The authors wish to thank Andy Fowler for supplying and recommending the polymer supported reagent and Torren Peakman for his assistance with analysis of the ¹H spectra.

References and notes (10)

T.W. Greene et al.
Protective Groups in Organic Synthesis
(1999)
E. De Clercq
J. Med. Chem.
(2005)
D.A. Price et al.
Synlett
(2005)
C.G. Wermuth
F.H. AbdulJ. Cochran
Chem. Eng. News
(1979)
W.J. Middleton
Chem. Eng. News
(1979)
P.A. Messina et al.
J. Fluorine Chem.
(1989)

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Initial synthesis of UK-427,857 (Maraviroc)

Abstract

Graphical abstract

Section snippets

Acknowledgements

J. Med. Chem.

Synlett

Chem. Eng. News

Chem. Eng. News

J. Fluorine Chem.