Details

Autor(en) / Beteiligte

• Huard, Kim
• Bagley, Scott W
• Menhaji-Klotz, Elnaz
• Préville, Cathy
• Southers, James A
• Smith, Aaron C
• Edmonds, David J
• Lucas, John C
• Dunn, Matthew F
• Allanson, Nigel M
• Blaney, Emma L
• Garcia-Irizarry, Carmen N
• Kohrt, Jeffrey T
• Griffith, David A
• Dow, Robert L

Titel

Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors

Ist Teil von

• Journal of organic chemistry, 2012-11, Vol.77 (22), p.10050-10057

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.