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Verzijl G.K.M.,Royal DSM | De Vries A.H.M.,Royal DSM | De Vries J.G.,Royal DSM | Kapitan P.,DSM Fine Chemicals Austria | And 10 more authors.
Organic Process Research and Development | Year: 2013

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. © 2013 American Chemical Society.

Alsters P.L.,Royal DSM | Jary W.,DSM Fine Chemicals Austria | Nardello-Rataj V.,Lille University of Science and Technology | Aubry J.-M.,Lille University of Science and Technology
Organic Process Research and Development | Year: 2010

We describe the development of a scalable process for the "dark" singlet oxygenation of β-citronellol as a key step in the manufacture of the fragrance compound, rose oxide. This process, based on catalytic disproportionation of hydrogen peroxide into singlet oxygen and water, has been carried out on production scale in 10 m3 reactors. © 2010 American Chemical Society.

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