Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors

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• 作者：Kim Huard ; Scott W. Bagley ; Elnaz Menhaji-Klotz ; Cathy Pr茅ville ; James A. Southers ; Jr. ; Aaron C. Smith ; David J. Edmonds ; John C. Lucas ; Matthew F. Dunn ; Nigel M. Allanson ; Emma L. Blaney ; Carmen N. Garcia-Irizarry ; Jeffrey T. Kohrt ; David A. Griffith ; Robert L. Dow
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：November 16, 2012
• 年：2012
• 卷：77
• 期：22
• 页码：10050-10057
• 全文大小：385K
• 年卷期：v.77,no.22(November 16, 2012)
• ISSN：1520-6904

文摘

The synthesis of 4鈥?6鈥?dihydrospiro[piperidine-4,5鈥?pyrazolo[3,4-c]pyridin]-7鈥?2鈥?i>H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues.