1260118-25-9Relevant academic research and scientific papers
Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation?
Verzijl, Gerard K. M.,De Vries, Andre H. M.,De Vries, Johannes G.,Kapitan, Peter,Dax, Thomas,Helms, Matthias,Nazir, Zarghun,Skranc, Wolfgang,Imboden, Christoph,Stichler, Juergen,Ward, Richard A.,Abele, Stefan,Lefort, Laurent
, p. 1531 - 1539 (2014/01/06)
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.
PROCESS FOR THE PREPARATION OF AN ENANTIOMERICALLY PURE TRISUBSTITUTED 1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVE
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Page/Page column 16-17, (2011/02/24)
The present invention relates to a process for the preparation of the compound of formula 7, which process comprises: the asymmetric transfer hydrogenation of the compound of formula 4 * HX: wherein HX is as decribed in the description; in the presence of
