Kurt Püntener

The presentation gives an insight into “the past, the current & the future set-up”, as well as a  general overview of the role of catalysis & conti processing at Synthetic Molecules Technical Development / Roche Basel – namely in supporting the development of new drug substance process applying state-of-the-art methodologies / technologies to install chemical bonds and chiral centers with high selectivity. As demonstrated for Ipatasertib^1,2, the built-up of the three stereocenters and the 5-membered ring greatly relied on asymmetric metal and enzyme catalysis, resp. conti processing as enabling technologies which alltogether allowed for the speedy development of a robust, cost-efficient and sustainable commercial drug substance process.

Five selected snap-shot / case studies are presented in more detail, wherein asymmetric hydrogenation, Buchwald/Hartwig coupling, ring-closing-metathesis and transition metal catalyzed oxidation play a key role – namley for:

1)    the Ru-catalyzed hydrogenation of methyl 3-oxotetradecanoate affording (R)-3-hydroxy-tetradecanoate as first chiral intermediate in a 2nd generation process of Roche’s anti-obesity drug Orlistat³

2)    the enabling of the synthesis of Danoprevir¹ (a peptidomimetic HCV protease inhibitor) via RCM

3)    the employment of a double catalyst system to efficiently access (2R,4R)-4-(4-chlorophenyl)-butane-1,2,4-triol – the key chiral building block in the synthesis of Genentech`s TrpA1 inhibitor GDC-6599⁴

4)    a safe and highly cost-efficient access to (S)-1,1,1-trifluoroisopropanol – a key building block for Bitopertin⁵ – a potent Glyt-1 inhibitor in clinics at DiscMedicine

5)    a streamlined, safe and sustainable process for Gemlapodect⁶ – an efficient PDE10A inhibitor in clinics at Noema