Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors

摘要

The synthesis of 4′,6′-dihydrospiro[piperidine-n4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one-based acetyl-CoAncarboxylase inhibitors is reported. The hitherto unknown N-n2 tert-butyl pyrazolospirolactam core was synthesized fromnethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-nstep synthesis requiring only one chromatography procedure.nThe described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates.nKey steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement undernboth conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-typencyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropylnlactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification ofnpotent analogues.