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Synthesis 2012; 44(23): 3598-3602
DOI: 10.1055/s-0032-1317527
paper
© Georg Thieme Verlag Stuttgart · New York

A New Route to Roflumilast via Copper-Catalyzed Hydroxylation

Feng Ni
a   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai 200040, P. R. of China
b   Shanghai Engineering Research Center of Pharmaceutical Process, 1320 West Beijing Road, Shanghai 200040, P. R. of China   Fax: +86(21)65312830   Email: li.jianqi@sipi.com.cn
,
Jianqi Li*
a   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai 200040, P. R. of China
b   Shanghai Engineering Research Center of Pharmaceutical Process, 1320 West Beijing Road, Shanghai 200040, P. R. of China   Fax: +86(21)65312830   Email: li.jianqi@sipi.com.cn
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Publication History

Received: 27 August 2012

Accepted after revision: 14 October 2012

Publication Date:
06 November 2012 (online)

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Abstract

A new route to Roflumilast, a selective phosphodiesterase type 4 (PDE 4) inhibitor, is described. The synthetic procedure starts from 4-hydroxy-3-iodobenzoic acid to access the key intermediate 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid via copper-catalyzed hydroxylation and utilizes amide coupling to accomplish the synthesis of Roflumilast in 80% overall yield.

Key words

Roflumiast - PDE4 inhibitor - preparation - hydroxylation - copper catalyzed

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis.
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