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Synthesis 2010(19): 3363-3373  
DOI: 10.1055/s-0030-1257864
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 1,5,6,7-Tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as Conformationally Constrained Pyrazole Analogues of Histamine

Darja Žerovnika, Uroš Grošelja, David Kralja, Črt Malavašiča, Jure Bezenšeka, Georg Dahmannb, Katarina Starea, Anton Medena, Branko Stanovnika, Jurij Svete*a
a Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P.O. Box 537, 1000 Ljubljana, Slovenia
b Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Chemical Research, 88397 Biberach, Germany
Fax: +386(1)2419220; e-Mail: jurij.svete@fkkt.uni-lj.si;
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Received 21 April 2010
Publikationsdatum:
22. Juli 2010 (online)

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Erratum zu diesem Artikel:

Synthesis of 1,5,6,7-Tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as Conformationally Constrained Pyrazole Analogues of HistamineSynthesis 2010; 2010(19): e4-e4
DOI: 10.1055/s-0030-1258257

Abstract

Three synthetic methods for the preparation of 1,5-disubstituted 1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as heterocyclic histamine analogues were developed. The first method starts from easily available methyl 5-(2-aminoethyl)-1H-pyrazole-4-carboxylates, which were N-alkylated and the resulting secondary amines were cyclised in the presence of a base to give the title compounds in 17-92% yields (method A). Alternatively, the amines were first cyclised to the 5-unsubstituted pyrazolo[4,3-c]pyridin-4-ones. Subsequent N-benzylation afforded three of the title compounds in 36-49% yields (method B). The third method comprises a six-step transformation of methyl acrylate into 1-benzylpiperidine-2,4-dione. Treatment of the latter with N,N-dimethylformamide dimethylacetal (DMFDMA) followed by acid-catalysed cyclisation of the formed enaminone with methyl-, phenyl- and tert-butylhydrazine afforded the same three title compounds in 79-87% yields (method C).

Key words

enaminones - cyclisation - alkylation - pyrazolo[4,3-c]pyridine - histamine

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Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 770933 (4a) and CCDC 770934 (4i). These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html.