Modular, automated synthesis of spirocyclic tetrahydronaphthyridines from primary alkylamines

  • Commun Chem. 2023 Oct 4;6(1):215. doi: 10.1038/s42004-023-01012-2.
Qiao Cao  1 ,  Joshua D Tibbetts  1 ,  Gail L Wrigley  2 ,  Adam P Smalley  3 ,  Alexander J Cresswell  4
Affiliations
  • 1. Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
  • 2. Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK.
  • 3. UCB, 216 Bath Road, Slough, SL1 3WE, UK.
  • 4. Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK. [email protected].
PMID: 37794068 DOI: 10.1038/s42004-023-01012-2
Abstract

Spirocyclic tetrahydronaphthyridines (THNs) are valuable scaffolds for drug discovery campaigns, but access to this 3D chemical space is hampered by a lack of modular and scalable synthetic methods. We hereby report an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines ("1,8-THNs"), in addition to their regioisomeric 1,6-THN analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated vinylpyridines is sequenced in combination with intramolecular SNAr N-arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a palladium-catalysed C-N bond formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting Materials, using the same bond disconnections. The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core of Pfizer's MC4R Antagonist PF-07258669.

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