Synthesis of spiropiperidine lactam acetyl-CoA carboxylase inhibitors

J Org Chem. 2012 Nov 16;77(22):10050-7. doi: 10.1021/jo3014808. Epub 2012 Nov 5.

Abstract

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.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Acetyl-CoA Carboxylase / chemistry*
  • Alkylation
  • Cyclization
  • Lactams / chemical synthesis*
  • Lactams / chemistry*
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry*
  • Pyrazoles / chemistry*
  • Pyridones / chemical synthesis*
  • Pyridones / chemistry*
  • Stereoisomerism

Substances

  • 4',6'-dihydrospiro(piperidine-4,5'-pyrazolo(3,4-c)pyridin)-7'(2'H)-one
  • Lactams
  • Piperidines
  • Pyrazoles
  • Pyridones
  • ethyl 3-amino-1H-pyrazole-4-carboxylate
  • Acetyl-CoA Carboxylase