Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation?

Gerard K. M. Verzijl, Andre H. M. de Vries, Johannes G. de Vries, Peter Kapitan, Thomas Dax, Matthias Helms, Zarghun Nazir, Wolfgang Skranc, Christoph Imboden, Juergen Stichler, Richard A. Ward, Stefan Abele*, Laurent Lefort

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Scopus)
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Abstract

Several methods are presented for the enantioselective synthesis of the tetrahydroisoquinoline core of almorexant (ACT-078573A), a dual orexin receptor antagonist. Initial clinical supplies were secured by the Noyori Ru-catalyzed asymmetric transfer hydrogenation (Ru-Noyori ATH) of the dihydroisoquinoline precursor. Both the yield and enantioselectivity eroded upon scale-up. A broad screening exercise identified TaniaPhos as ligand for the iridium-catalyzed asymmetric hydrogenation with a dedicated catalyst pretreatment protocol, culminating in the manufacture of more than 6 t of the acetate salt of the tetrahydroisoquinoline. The major cost contributor was TaniaPhos. By switching the dihydroisoquinoline substrate of the Ru-Noyori ATH to its methanesulfonate salt, the ATH was later successfully reduced to practice, delivering several hundreds of kilograms of the tetrahydroisoquinoline, thereby reducing the catalyst cost contribution significantly. The two methods are compared with regard to green and efficiency metrics.

Original languageEnglish
Pages (from-to)1531-1539
Number of pages9
JournalOrganic Process Research & Development
Volume17
Issue number12
DOIs
Publication statusPublished - Dec-2013
Externally publishedYes

Keywords

  • ENANTIOSELECTIVE SYNTHESIS
  • CYCLIC IMINES
  • EFFICIENT
  • LIGANDS
  • KETONES
  • COMPLEX
  • DIAMINE
  • WATER
  • SOLIFENACIN
  • ALKALOIDS

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