5 research outputs found
Structural studies of peri-interactions and bond formation between electron-rich atomic centres and N-phenylcarboxamides or nitroalkenyl groups
Short Synthesis of a Proline Amide Orexin Receptor Antagonist on the Pilot Plant Scale
A three-step
fully telescoped synthesis of an <i>N</i>-sulfonyl proline
amide, a nonpeptide antagonist of human orexin
receptors, is described. The process development from the medicinal
chemistry route up to the 240 kg production of <b>1</b> is discussed
with a focus on an economical and efficient amide bond formation and
identification of a new polymorph. The routes are compared using green
metrics
Alternative pig liver esterase (APLE) - cloning, identification and functional expression in Pichia pastoris of a versatile new biocatalyst
Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation?
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.