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DOI: 10.1055/s-0030-1257864
Synthesis of 1,5,6,7-Tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as Conformationally Constrained Pyrazole Analogues of Histamine
Publication History
Publication Date:
22 July 2010 (online)
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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
-
1a
Wells JA.McClendon CL. Nature (London) 2007, 450: 1001 -
1b
Lee GM.Craik CS. Science (Washington, D.C.) 2009, 324: 213 -
1c
Robinson JA.DeMarco S.Gombert F.Moehle K.Obrecht D. Drug Discovery Today 2008, 13: 944 -
2a
Hanessian S.McNaughton-Smith G.Lombart H.-G.Lubell WD. Tetrahedron 1997, 53: 12789 -
2b
Cluzeau J.Lubell WD. Biopolymers 2005, 80: 98 -
2c
Maison W.Prenzel AHGP. Synthesis 2005, 1031 -
2d
Vagner J.Qu H.Hruby VJ. Curr. Opin. Chem. Biol. 2008, 12: 292 ; and references cited therein -
3a
Patrick GL. In An Introduction to Medicinal Chemistry 3rd ed.: Oxford University Press; Oxford: 2005. -
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 -
3c
Liebscher J.Patzel M. Synlett 1994, 471 -
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 -
4b
Pullagurla M.Dukat M.Roth BL.Setola V.Glennon RA. Med. Chem. Res. 2005, 14: 1 -
5a
Elguero J. Pyrazoles, In Comprehensive Heterocyclic Chemistry II Vol. 3:Katritzky AR.Rees CW.Scriven EFV. Elsevier Science Ltd.; Oxford: 1996. p.1 -
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 -
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 TrendsHorvat 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 -
6b
Pezdirc L.Stanovnik B.Svete J. Aust. J. Chem. 2009, 62: 1661 ; and references cited therein -
7a
Stanovnik B.Svete J. Chem. Rev. 2004, 104: 2433 -
7b
Svete J. ARKIVOC 2006, (vii): 35 ; and the references cited therein - 8
Baškovč B.Bevk D.Stanovnik B.Svete J. J. Comb. Chem. 2009, 11: 500 ; and references cited therein - 9
Kralj D.Grošelj U.Meden A.Dahmann G.Stanovnik B.Svete J. Tetrahedron 2007, 63: 11213 - 10
Kralj D.Novak A.Dahmann G.Grošelj U.Meden A.Svete J. J. Comb. Chem. 2008, 10: 664 - 11
Kralj D.Friedrich M.Grošelj U.Kiraly-Potpara S.Meden A.Wagger J.Dahmann G.Stanovnik B.Svete J. Tetrahedron 2009, 65: 7151 - 12
Verardo G.Geatti P.Pol E.Giumanini AG. Can. J. Chem. 2002, 80: 779 -
13a
Takano S.Yuta K.Hatakeyama S.Ogasawara K. Tetrahedron Lett. 1979, 369 -
13b
Ibenmoussa S.Chavignon O.Teulade J.-C.Viols H.Debouzy J.-C.Chapat J.-P.Gueiffier A. Heterocycl. Commun. 1998, 4: 317 -
13c
Chang D.Feiten H.-J.Witholt B.Li Z. Tetrahedron: Asymmetry 2002, 13: 2141 -
13d
Asahi K.Nishino H. Heterocycl. Commun. 2005, 11: 379 -
13e
Asahia K.Nishino H. Tetrahedron 2005, 61: 11107 -
14a
Yeom C.-E.Kim MJ.Kim BM. Tetrahedron 2007, 63: 904 -
14b
Gill HS.Freeman S.Irwin WJ.Wilson KA. Eur. J. Med. Chem. 1996, 31: 847 -
14c
Chen XS.Jin SZ.Wu J.Zhang P. Synthesis 2008, 3931 - 15
Lima PG.Sequeira LC.Costa PRR. Tetrahedron Lett. 2001, 42: 3525 -
16a
De Michelis C.Rocheblave L.Priem G.Chermann JC.Kraus JL. Bioorg. Med. Chem. 2000, 8: 1253 -
16b
Bezencon O,Bur D,Corminboeuf O,Grisostomi C,Remen L,Richard-Bildstein S, andWeller 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 -
17a
Brooks DW.Lu LD.-L.Masamune S. Angew. Chem. 1979, 91: 76 -
17b
Hashiguchi S.Kawada A.Natsugari H. Synthesis 1992, 403 -
17c
Moreau RJ.Sorensen EJ. Tetrahedron 2007, 63: 6446 - 18
Collect Software
Nonius BV. Delft; The Netherlands: 1998. - 19
Otwinowski Z.Minor W. Methods Enzymol. 1997, 276: 307 - 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 - 21
Hall SR.King GSD.Stewart JM. The Xtal3.4 User’s Manual University of Western Australia; Lamb/Perth: 1995. - 22
Wang H.Robertson BE. Structure and Statistics in CrystallographyWilson AJC. Adenine Press; New York: 1985. - 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.
References
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.