The potential role of dimeric catalyst species on or off the catalytic cycle is considered for a case of Pd-catalyzed C−H functionalization, leading to the development of a general experimental protocol that uses the reaction itself to report on the presence and role of dimeric species in asymmetric catalytic reactions.
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.
This article details
the approach to large-scale production of
cyclobutane 2 by the continuous-flow [2 + 2] photocycloaddition
of maleic anhydride and ethylene, including (1) focused reaction optimization
and development of a robust isolation protocol, (2) the approach to
equipment design and process safety, and (3) the results of commissioning
tests and production runs delivering the target compound at throughputs
exceeding 5 kg/day.
Despite the growth of photoredox
methods in academia, application
of photoredox at scale in the pharmaceutical and fine chemical industries
has been slow. In this report, a photoredox trifluoromethylation of
a thiophenol was modified from the original literature report, and
the mechanism was investigated to define the key scale-up parameters.
The mechanistic insight was leveraged in the design and execution
of two different reactor designs: an LED-based plug flow photoreactor
and a laser-based continuous stirred tank photoreactor. In one of
the first examples of commercial-scale photoredox chemistry, the process
was scaled to provide over 500 kg of the desired intermediate and
amended to fully continuous manufacturing.
Despite the growth of photoredox methods in academia, application of photoredox at scale in the pharmaceutical and fine chemical industries has been slow. In this report, a photoredox trifluoromethylation of a thiophenol was modified from the original literature report and the mechanism was investigated to define key scale-up parameters. The mechanistic insight was leveraged in the design and execution of two different reactor designs: an LED-based plug flow photoreactor as well as a laser-based continuous stirred tank photoreactor. In one of the first examples of commercial scale photoredox chemistry, the process was scaled to provide over 500 kilograms of the desired intermediate and amended to fully continuous manufacturing.
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