Download PDF
Synthesis 2007(21): 3301-3308  
DOI: 10.1055/s-2007-990823
PAPER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of New Pyridazinone Derivatives: 2,6-Disubstituted 5-Hydroxy-3(2H)-pyridazinone-4-carboxylic Acid Ethyl Esters

Lian-Sheng Li, Yuefen Zhou*, Jingjing Zhao, Peter S. Dragovich, Nebojsa Stankovic, Thomas M. Bertolini, Douglas E. Murphy, Zhongxiang Sun, Chinh V. Tran, Benjamin K. Ayida, Frank Ruebsam, Stephen E. Webber
Anadys Pharmaceuticals, 3115 Merryfield Row, San Diego, CA 92121, USA
Fax: +1(858)5303644; e-Mail: yzhou@anadyspharma.com;
Further Information

Publication History

Received 31 May 2007
Publication Date:
10 October 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

2,6-Disubstituted 5-hydroxy-3(2H)-pyridazinone-4-carboxylic acid ethyl esters were synthesized from α-keto esters via an efficient three-step sequence including hydrazone formation, acylation with ethyl malonyl chloride, and subsequent Dieckmann cyclization.

Key words

α-keto esters - acylation - hydrazones - Dieckmann cyclization - pyridazinones

    References

  • 1 Costantino L. Rastelli G. Vescovini K. Gignarella G. Vianello P. Del Corso A. Cappiello M. Mura U. Barlocco D. J. Med. Chem.  1996,  39:  4396 
    CrossrefGoogle Scholar
  • 2a Corsano S. Vezza R. Scapicchi R. Foresi S. Strappaghetti G. Nenci GG. Gresele P. Eur. J. Med. Chem.  1995,  30:  627 
    CrossrefGoogle Scholar
  • 2b Thyes M. Lehmann HD. Gries J. König H. Kretzschmar R. Kunze J. Lebkücher R. Lenke D. J. Med. Chem.  1983,  26:  800 
    CrossrefGoogle Scholar
  • 3 Betti L. Zanelli M. Giannaccini G. Manetti F. Schenone S. Strappaghetti G. Bioorg. Med. Chem.  2006,  14:  2828 ; and references cited therein
    CrossrefGoogle Scholar
  • 4 Yamada T. Nobuhara Y. Shimamura H. Tsukamoto Y. Yoshihara K. Yamaguchi A. Ohki M. J. Med. Chem.  1983,  26:  373 
    CrossrefGoogle Scholar
  • 5 Stevenson TM. Crouse BA. Thieu TV. Gebreysus C. Finkelstein BL. Sethuraman MR. Dubas-Cordery CM. Piotrowski DL. J. Heterocycl. Chem.  2005,  42:  427 
    CrossrefGoogle Scholar
  • 6a Al-Omran F. El-Khair AA. J. Chem. Res., Synop.  2006,  6 ; and references cited therein
    CrossrefGoogle Scholar
  • 6b Keshk EM. Heteroat. Chem.  2004,  15:  85 
    CrossrefGoogle Scholar
  • 6c Al-Shiekh MA. Salah El-Din AM. Hafez EA. Elnagdi MH. J. Heterocycl. Chem.  2004,  41:  647 
    CrossrefGoogle Scholar
  • 6d Sayed SM. Khalil MA. Ahmed MA. Raslan MA. Synth. Commun.  2002,  32:  481 ; and references cited therein
    CrossrefGoogle Scholar
  • 6e Schnell B. Kappe T. J. Heterocycl. Chem.  2000,  37:  911 ; and references cited therein
    CrossrefGoogle Scholar
  • 6f Erian AW. Araki VF. Aziz SI. Sherif SM. Monatsh. Chem.  1999,  130:  661 
    CrossrefGoogle Scholar
  • 6g El-Kousy S. El-Sakka I. El-Torgoman AM. Roshdy H. Elnagdi MH. Collect. Czech. Chem. Commun.  1990,  55:  2977 
    CrossrefGoogle Scholar
  • 6h Estevez I. Coelho A. Raviña E. Synthesis  1999,  1666 
    CrossrefGoogle Scholar
  • 6i Schober BD. Megyeri G. Kappe T. J. Heterocycl. Chem.  1990,  27:  471 
    CrossrefGoogle Scholar
  • 6j Bruché L. Garanti L. Zecchi G. J. Heterocycl. Chem.  1989,  26:  619 
    CrossrefGoogle Scholar
  • 6k Schmidt P. Druey J. Helv. Chim. Acta.  1954,  37:  134 
    CrossrefGoogle Scholar
  • 6l McElavain SM. Jelinek A. J. Am. Chem. Soc.  1943,  65:  2236 
    CrossrefGoogle Scholar
  • 7 Fusco R. Sannicolò F. J. Org. Chem.  1982,  47:  1691 
    CrossrefGoogle Scholar
  • 10 The alkyl hydrazine oxalic acid salts can be prepared by a reported procedure: Anderson FE. Kaminsky D. Dubnick B. Klutchko SR. Cetenko WA. Gylys J. Hart JA. J. Med. Chem.  1962,  5:  221 
    CrossrefGoogle Scholar
  • 11 Haddad N. Baron J. Tetrahedron Lett.  2002,  43:  2171 
    CrossrefGoogle Scholar
  • 12 Compound 1a made by this method was further transformed into its 5-methoxy analogue to confirm the assigned structure of the corresponding pyrazole compound (1-substituted 5-hydroxy-1H-pyrazole), see our previous publication: Dragovich PS. Bertolini TM. Ayida BK. Li L.-S. Murphy DE. Ruebsam F. Sun Z. Zhou Y. Tetrahedron  2007,  63:  1154 
    CrossrefGoogle Scholar
  • 15 The described preparation is based on a modified literature procedure: Dondoni A. Fantin G. Fogagnolo M. Medici A. Pedrini P. J. Org. Chem.  1988,  53:  1748 
    CrossrefGoogle Scholar
  • 16 The described preparation is based on a modified literature procedure using Rieke reagents: Zhu L. Wehmeyer R. Rieke R. J. Org. Chem.  1991,  56:  1445 
    CrossrefGoogle Scholar
  • 17 The described preparation is based on a literature method: Nelson TD. LeBlond CR. Frantz DE. Matty L. Mitten JV. Weaver DG. Moore JC. Kim JM. Boyd R. Kim P.-Y. Gbewonyo K. Brower M. Sturr M. McLaughlin K. McMasters DR. Kress MH. McNamara JM. Dolling UH. J. Org. Chem.  2004,  69:  3620 
    CrossrefGoogle Scholar
8

No attempt was made to separate the Z/E-isomers formed in the reaction because the pure isomer slowly isomerizes to a mixture of two isomers as evident from 1H NMR analysis. In fact, the Z- and E-isomers show sufficiently large R f differences on TLC, so that they can be separated by chromatographic purification, if desired. It is noteworthy that the ratio of two isomers observed during purification sometimes is not the same as suggested by analysis of the reaction mixture, which indicates that the isomerization can take place on the silica gel during the purification.

9

The isoamylhydrazine was prepared by treatment of 1-bromo-3-methylbutane with a large excess of NH2NH2 in refluxing EtOH, followed by a basic aqueous work-up.

13

The α-keto esters which were not commercially available were synthesized based on modified literature methods.15-17 Representative procedures are provided in the experimental section.

14

We observed ring-opened side products by LC-MS analysis when the hydrazone intermediate (R1 = cyclopropyl, R2 = isoamyl) was treated with ethyl malonyl chloride without a base in 1,4-dioxane at r.t., probably due to the HCl generated in situ from the acylation reaction. As expected, under basic conditions (NaH), this acylation reaction proceeded smoothly.