| Autor: |
Emma L. Blaney, David A. Griffith, Jeffrey T. Kohrt, Cathy Préville, James A. Southers, Scott W. Bagley, David J. Edmonds, Aaron C. Smith, Kim Huard, Matthew F. Dunn, Elnaz Menhaji-Klotz, Nigel M. Allanson, Robert L. Dow, Carmen N. Garcia-Irizarry, John C. Lucas |
| Rok vydání: |
2012 |
| Předmět: |
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| Zdroj: |
The Journal of organic chemistry. 77(22) |
| ISSN: |
1520-6904 |
| Popis: |
The synthesis of 4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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