Process Development for the Synthesis of a Selective M₁ and M₄ Muscarinic Acetylcholine Receptors Agonist

Abstract

A practical and chromatography-free synthetic process to selective M1 and M4 muscarinic acetylcholine receptors agonist was developed and demonstrated on a several hundred gram scale. The key feature of this route is N,N-dimethylcarbamoylation of the anilinic nitrogen on the spiro 7-azaindoline structure via intermolecular migration of the N,N-dimethylcarbamoyl group. The resulting compound 1 was prepared in 43% overall yield with a chemical purity >99% via six steps starting with (2-chloropyridin-3-yl)­acetonitrile.

Efficient Azacycle Formations Developed in Japanese Pharmaceutical Industries: Elegancy, Logistics, and Training (ELT) “Sandwich” for Process Chemists

“…A research group at Sumitomo Dainippon established a practical and chromatography-free process to obtain the selective M 1 /M 4 muscarinic acetylcholine receptor agonist 125 that effectively utilizes the cyano functionality of the raw material 121 to conduct cycloalkylation by KOH/DMSO at the α-position and a subsequent reductive cyclization by LiAlH­(O t -Bu) 3 to give dihydropyrrolo­[2,3- b ]­pyridine intermediate 123 , as shown in Scheme . The obtained intermediate was converted to the API 125 through four reaction steps, including an intermolecular migration reaction of the N , N -dimethylcarbamoyl moiety to afford 124 .…”