Commercial-Scale Visible Light Trifluoromethylation of 2-Chlorothiophenol Using CF₃I Gas

Abstract

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.

Visible-Light Photocatalysis Academic–Industrial Collaboration Retrospective: Shared Learning and Impact Analysis

“…Prior to this disclosure there had been pioneering work on the scale-up of visible-light-mediated processes from Merck, most notably for the synthesis of elbasvir . Our report and further outstanding contributions by Merck, AbbVie, , and others have clearly shown how visible light can be effectively used at manufacturing scale and in a Current Good Manufacturing Practices (cGMP) environment. Our system was operated continuously for 48 h, consuming a total of 1.2 kg of 30 to yield 31 in 60–65% assay yield.…”

Chiral Photocatalyst Structures in Asymmetric Photochemical Synthesis

“…At this early stage in the development of the field, most examples of highly asymmetric photocatalytic reactions have been proof-ofprinciple academic investigations, and these insights have yet to be translated to commercial applications. As the pharmaceutical industry in particular becomes more interested in the scale-up of photocatalytic processes, 426,427 issues concerning maximization of quantum yield and light flux 428 may become more important than they have been to date. Despite the impressive advances that have emerged in the field of asymmetric photocatalysis in recent years, many challenges remain unsolved, perhaps the most important of which is the need for generality.…”

A field guide to flow chemistry for synthetic organic chemists

“…Besides passive microreactors (which exploit the flow energy delivered by the pumps to induce mixing), active microreactors that utilize external energy are also commonly employed, particularly for scaling heterogeneous chemistry up. Multiple types of active continuous reactors have been reported, such as rotating disk reactors, 92–94 oscillatory flow reactors, 95–97 thin-film rotating reactors, 98 CSTR 99,100 and ultrasonic reactors. 101,102 To demonstrate the advantages of such flow chemistry technology, Van der Schaaf and Noël et al reported a high-throughput photochemical rotor-stator spinning disk reactor (pRS-SDR) to enhance the gas–liquid mass transfer and perform a large-scale gas–liquid photooxygenation of α-terpinene ( 19.1 ).…”