Synthesis 2004(8): 1211-1228  
DOI: 10.1055/s-2004-822356
PAPER
© Georg Thieme Verlag Stuttgart · New York

Dianhydrohexitole-Based Benzamidines: An Efficient Synthesis of New Factor Xa Inhibitors

Marko Voglera, Ulrich Koert*a, Klaus Harmsa, Dieter Dorschb, Johannes Gleitzb, Peter Raddatzb
a Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
Fax: Fax:+49(6421)2825677; e-Mail: E-mail: koert@chemie.uni-marburg.de;
b Merck KGaA, Preclinical Research & Development, 64271 Darmstadt, Germany
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Publikationsverlauf

Received 3 February 2004
Publikationsdatum:
03. Mai 2004 (online)

Abstract

Dianhydrohexitole-based benzamidines were synthesised as potential factor Xa inhibitors. The key steps for the synthesis of a bis-benzamidine series were nucleophilic aromatic substitutions and Mitsunobu reactions to introduce substituted phenyl ether moieties. Mono-benzamidines with an ortho-substituted biphenyl group were prepared using a Negishi-type cross coupling procedure. The benzamidines showed high biological activity and selectivity for factor Xa inhibition.

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Pd/C is preferred, since the use of Raney-nickel in MeOH-HOAc (see experimental part GP4 and GP5) leads to the formation of minor amounts of Ni(OAc)2, which is difficult to remove chromatographically.