Rapid and efficient synthesis of a novel cholinergic muscarinic M1 receptor positive allosteric modulator using flash chemistry

Org Biomol Chem. 2019 Sep 21;17(35):8166-8174. doi: 10.1039/c9ob01718f. Epub 2019 Aug 29.

Abstract

Continuous flow-flash synthesis of a 2-bromobenzaldehyde derivative 18 as a key intermediate of a novel cholinergic muscarinic M1 positive allosteric modulator 1 bearing an isoindolin-1-one ring system as a pharmacophore has been achieved using flow microreactors through selective I/Li exchange of 1-bromo-2-iodobenzene derivative 17 with BuLi and subsequent formylation at -40 °C of the highly reactive 2-bromophenyllithium intermediate using DMF, which is difficult to achieve by a conventional batch process due to the conversion of the highly reactive 2-bromophenyllithium intermediate into benzyne even at -78 °C. Late-stage cyclization to give the isoindolin-1-one ring system, through reductive amination of 18 followed by palladium-catalyzed carbonylation with carbon monoxide and intramolecular cyclization, efficiently afforded 1 for its further research and development.

MeSH terms

  • Allosteric Regulation / drug effects
  • Benzaldehydes / chemical synthesis
  • Benzaldehydes / chemistry
  • Benzaldehydes / pharmacology*
  • Cholinergic Agents / chemical synthesis
  • Cholinergic Agents / chemistry
  • Cholinergic Agents / pharmacology*
  • Humans
  • Molecular Structure
  • Receptor, Muscarinic M1 / metabolism*

Substances

  • 2-bromobenzaldehyde
  • Benzaldehydes
  • CHRM1 protein, human
  • Cholinergic Agents
  • Receptor, Muscarinic M1