Synthesis of 7-Oxo-dihydrospiro[indazole-5,4鈥?piperidine] Acetyl-CoA Carboxylase Inhibitors

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• 作者：Scott W. Bagley ; James A. Southers ; Shawn Cabral ; Colin R. Rose ; David J. Bernhardson ; David J. Edmonds ; Jana Polivkova ; Xiaojing Yang ; Daniel W. Kung ; David A. Griffith ; Scott J. Bader
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：February 3, 2012
• 年：2012
• 卷：77
• 期：3
• 页码：1497-1506
• 全文大小：369K
• 年卷期：v.77,no.3(February 3, 2012)
• ISSN：1520-6904

文摘

Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50鈥?5 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.