Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors

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.

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

“…Reaction of 187 with either sec ‐butyllithium or tert ‐butyllithium at −78 °C followed by Boc deprotection afforded the desired spirolactam core 188 . Final amide formation reaction led to inhibitor 189 which proved to be a potent ACC inhibitor with an IC 50 value of 67 n m (Scheme ) …”

Continuous Flow Organophosphorus Chemistry

“…A 30 g scale continuous flow synthesis of an isocyanate acetyl-CoA carboxylase inhibitor precursor 317 was performed by researchers with Pfizer similarly to Ley's work [177] through a Curtius rearrangement using DPPA as the azide source. [178] The final spirolactam product 318 has a potential application in the treatment of type 2 diabetes. An excellent yield of 96 % was obtained towards 317 after 90 min of residence time at 120°C starting from carboxylic acid 316 for the continuous flow process in addition to alleviate safety concerns linked with the use of an azide derivative (Figure 83).…”

“…Continuous flow synthesis an acetyl-CoA carboxylase inhibitor precursor through a Curtius rearrangement using diphenylphosphoryl azide as the azidating agent. [178] Figure 84. Continuous flow preparation of a bromosporine analog precursor via a Curtius rearrangement using diphenylphosphoryl azide as the azide source.…”

Three-component one-pot synthesis of dihydrochromeno[4,3-b]pyrazolo[4,3-e]pyridines

“…Among the various fused systems, pyrazolopyridines show promising biological activities as antibacterial [2], antitumor [3], antiviral [4] and anti-inflammatory [5] agents, and antagonists of corticotropin-releasing factor 1 (CRF 1 ) [6], chemokine receptor type 1 (CCR1) [7] and dopamine D3 receptors antagonists [8]. They are also known to be cholesterol forming [9], acetyl-CoA carboxylase (ACC) [10], HIV reverse transcriptase [11], phosphodiesterase 3/4 (PDE3/4) cyclin-dependent 1 (CDK1) [12], and B-Raf kinase inhibitors [13]. Several methods have been devised for the synthesis of substituted pyrazolopyridines [14][15][16][17][18][19][20].…”