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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;
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Publikationsverlauf

Received 31 May 2007
Publikationsdatum:
10. Oktober 2007 (online)

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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

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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.