Download PDF
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;
Further Information

Publication History

Received 21 April 2010
Publication Date:
22 July 2010 (online)

    Permissions and Reprints All articles of this category

Corrected by:

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

    References

  • 1a Wells JA. McClendon CL. Nature (London)  2007,  450:  1001 
    Google Scholar
  • 1b Lee GM. Craik CS. Science (Washington, D.C.)  2009,  324:  213 
    Google Scholar
  • 1c Robinson JA. DeMarco S. Gombert F. Moehle K. Obrecht D. Drug Discovery Today  2008,  13:  944 
    Google Scholar
  • 2a Hanessian S. McNaughton-Smith G. Lombart H.-G. Lubell WD. Tetrahedron  1997,  53:  12789 
    Google Scholar
  • 2b Cluzeau J. Lubell WD. Biopolymers  2005,  80:  98 
    Google Scholar
  • 2c Maison W. Prenzel AHGP. Synthesis  2005,  1031 
    Google Scholar
  • 2d Vagner J. Qu H. Hruby VJ. Curr. Opin. Chem. Biol.  2008,  12:  292 ; and references cited therein
    Google Scholar
  • 3a Patrick GL. In An Introduction to Medicinal Chemistry   3rd ed.:  Oxford University Press; Oxford: 2005. 
    Google Scholar
  • 3b Kazuta Y. Hirano K. Natsume K. Yamada S. Kimura R. Matsumoto S.-i. Furuichi K. Matsuda A. Shuto S. J. Med. Chem.  2003,  46:  1980 
    Google Scholar
  • 3c Liebscher J. Patzel M. Synlett  1994,  471 
    Google Scholar
  • 4a Paillet-Loilier M. Fabis F. Lepailleur A. Bureau R. Butt-Gueulle S. Dauphin F. Lesnard A. Delarue C. Vaudry H. Rault S. Bioorg. Med. Chem. Lett.  2007,  17:  3018 
    Google Scholar
  • 4b Pullagurla M. Dukat M. Roth BL. Setola V. Glennon RA. Med. Chem. Res.  2005,  14:  1 
    Google Scholar
  • 5a Elguero J. Pyrazoles, In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Elsevier Science Ltd.; Oxford: 1996.  p.1 
    Google Scholar
  • 5b Stanovnik B. Svete J. Pyrazoles, In Science of Synthesis, Houben-Weyl Methods of Organic Transformations   Vol. 12:  Neier R. Georg Thieme Verlag; Stuttgart: 2002.  p.15 
    Google Scholar
  • 6a Svete J. In (4R*,5R*)-4-Benzoylamino-5-phenyl-3-pyrazolidinone - A Useful Building Block in the Synthesis of Functionalized Pyrazoles, In Stereochemistry Research Trends   Horvat MA. Golob JH. Nova Science Publishers, Inc.; New York: 2008.  p.129 ; open access item: https://www.novapublishers.com/catalog/product_info.php?products_id=16416
    Google Scholar
  • 6b Pezdirc L. Stanovnik B. Svete J. Aust. J. Chem.  2009,  62:  1661 ; and references cited therein
    Google Scholar
  • 7a Stanovnik B. Svete J. Chem. Rev.  2004,  104:  2433 
    Google Scholar
  • 7b Svete J. ARKIVOC  2006,  (vii):  35 ; and the references cited therein
    Google Scholar
  • 8 Baškovč B. Bevk D. Stanovnik B. Svete J. J. Comb. Chem.  2009,  11:  500 ; and references cited therein
    CrossrefGoogle Scholar
  • 9 Kralj D. Grošelj U. Meden A. Dahmann G. Stanovnik B. Svete J. Tetrahedron  2007,  63:  11213 
    CrossrefGoogle Scholar
  • 10 Kralj D. Novak A. Dahmann G. Grošelj U. Meden A. Svete J. J. Comb. Chem.  2008,  10:  664 
    CrossrefGoogle Scholar
  • 11 Kralj D. Friedrich M. Grošelj U. Kiraly-Potpara S. Meden A. Wagger J. Dahmann G. Stanovnik B. Svete J. Tetrahedron  2009,  65:  7151 
    CrossrefGoogle Scholar
  • 12 Verardo G. Geatti P. Pol E. Giumanini AG. Can. J. Chem.  2002,  80:  779 
    CrossrefGoogle Scholar
  • 13a Takano S. Yuta K. Hatakeyama S. Ogasawara K. Tetrahedron Lett.  1979,  369 
    Google Scholar
  • 13b Ibenmoussa S. Chavignon O. Teulade J.-C. Viols H. Debouzy J.-C. Chapat J.-P. Gueiffier A. Heterocycl. Commun.  1998,  4:  317 
    Google Scholar
  • 13c Chang D. Feiten H.-J. Witholt B. Li Z. Tetrahedron: Asymmetry  2002,  13:  2141 
    Google Scholar
  • 13d Asahi K. Nishino H. Heterocycl. Commun.  2005,  11:  379 
    Google Scholar
  • 13e Asahia K. Nishino H. Tetrahedron  2005,  61:  11107 
    Google Scholar
  • 14a Yeom C.-E. Kim MJ. Kim BM. Tetrahedron  2007,  63:  904 
    Google Scholar
  • 14b Gill HS. Freeman S. Irwin WJ. Wilson KA. Eur. J. Med. Chem.  1996,  31:  847 
    Google Scholar
  • 14c Chen XS. Jin SZ. Wu J. Zhang P. Synthesis  2008,  3931 
    Google Scholar
  • 15 Lima PG. Sequeira LC. Costa PRR. Tetrahedron Lett.  2001,  42:  3525 
    CrossrefGoogle Scholar
  • 16a De Michelis C. Rocheblave L. Priem G. Chermann JC. Kraus JL. Bioorg. Med. Chem.  2000,  8:  1253 
    Google Scholar
  • 16b Bezencon O, Bur D, Corminboeuf O, Grisostomi C, Remen L, Richard-Bildstein S, and Weller T. inventors; PCT Int. Appl.; WO  2007102127.  ; Chem. Abstr. 2007, 147, 365397
  • 16c Kong T. Syed S. Urwyler S. Bertrand S. Bertrand D. Reymond J.-L. ChemMedChem  2008,  3:  1520 
    Google Scholar
  • 17a Brooks DW. Lu LD.-L. Masamune S. Angew. Chem.  1979,  91:  76 
    Google Scholar
  • 17b Hashiguchi S. Kawada A. Natsugari H. Synthesis  1992,  403 
    Google Scholar
  • 17c Moreau RJ. Sorensen EJ. Tetrahedron  2007,  63:  6446 
    Google Scholar
  • 18 Collect Software   Nonius BV. Delft; The Netherlands: 1998. 
    Google Scholar
  • 19 Otwinowski Z. Minor W. Methods Enzymol.  1997,  276:  307 
    PubMedGoogle Scholar
  • 20 Altomare A. Burla MC. Camalli M. Cascarano GL. Giacovazzo C. Guagliardi A. Moliterni AGG. Polidori G. Spagna R. J. Appl. Crystallogr.  1999,  32:  115 
    CrossrefGoogle Scholar
  • 21 Hall SR. King GSD. Stewart JM. The Xtal3.4 User’s Manual   University of Western Australia; Lamb/Perth: 1995. 
    Google Scholar
  • 22 Wang H. Robertson BE. Structure and Statistics in Crystallography   Wilson AJC. Adenine Press; New York: 1985. 
    Google Scholar
  • 23 Burnett MN. Johnson CK. In ORTEP-III: Oak Ridge Thermal Ellipsoid Plot Program for Crystal Structure Illustrations   Oak Ridge National Laboratory Report ORNL-6895; 1996. 
    Google Scholar
24

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.