Development and Proof of Concept for a Large-Scale Photoredox Additive-Free Minisci Reaction

Abstract

New route development activities toward ceralasertib (AZD6738) have resulted in the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding resulting from LED-NMR reaction profiling, quantum yield measurements, and Stern−Volmer quenching studies have enabled optimization of the catalyst system, resulting in a significant enhancement in the rate of reaction. A large-scale continuous photoflow process has been developed, providing encouraging proofof-concept data for the future application of this technology in the clinical manufacture of ceralasertib.

Commercial-Scale Visible-light Trifluoromethylation of 2-Chlorothiophenol using CF3I gas.

“…While the reaction had been optimized using laser-based reactor configurations, laser equipment was not available to Asymchem within the desired timeframe (1-2 months) so efforts were directed towards scaling the reaction using LEDs as the light source in conjunction with a plug flow reactor (PFR). [34][35][36][37] Asymchem had previous success scaling similar reactors using UV LEDs 10,11 and several different research groups have reported success using such reactions on scales up to 1 kg but greater scales were not known at the time but have been reported since. 34,37 After an LED-PFR system was selected, the focus became identifying stable feed solutions for the initial scale-up.…”

Practical and Scalable Installation of Neglected S(VI) Functionality with Applications to the Enantiospecific Synthesis of Pharmaceuticals

“…Longer term it would be beneficial to have a more convergent approach with a higher yielding route". 32 During the development of our sulfonimidoyl SNAr method, AZ's process team disclosed an improved route (Scheme 3A, middle left) 33 and an attempt at a photocatalyzed flow approach via a Minisci reaction (Scheme 3A, middle right) 34 . The newly developed process route to 1 (Scheme 3A, middle left) addressed the issue of installing a cyclopropyl methyl sulfide moiety from 129 and 130 in a single step, while still relying on an enantioselective enzymatic oxidation.…”

Practical and Scalable Installation of Neglected S(VI) Functionality with Applications to the Enantiospecific Synthesis of Pharmaceuticals

“…Longer term it would be beneficial to have a more convergent approach with a higher yielding route". 32 During the development of our sulfonimidoyl SNAr method, AZ's process team disclosed an improved route (Figure 5A, middle left) 33 and an attempt at a photocatalyzed flow approach via a Minisci reaction (Figure 5A, middle right) 34 . The newly developed process route to 1 (Figure 5A, middle left) addressed the issue of installing a cyclopropyl methyl sulfide moiety from 129 and 130 in a single step, while still relying on an enantioselective enzymatic oxidation.…”