Pharmaceutical Technology - October 2021


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56 Pharmaceutical Technology APIs, EXCIPIENTS, AND MANUFACTURING eBOOK 2021 P h a r mTe c h . c o m Development for increasing yields and selectivity in these types of reactions. The work of Alcázar and coworkers (10) demonstrates this well, combining continuous flow synthesis with solid materials, for instance, zinc, for the light-induced conversion of in-situ formed organo- metallic intermediates and innovative analytical tools for process control. While these reagents may be com- mercially available, they are dangerous to handle and can be air and moisture sensitive, meaning that the purity is different every time they are used, which makes it difficult to reproduce the results. A photoinduced Negishi coupling over two-steps is described, with the formation of the organozinc reagent in flow followed by coupling with the aryl- halide halide in the presence of blue LEDs, a nickel catalyst, and ligand (Figure 2) (10). These cross-coupling reactions traditionally use a transition metal catalyst; however, recent research dem- onstrates the desired transformation being achieved in the absence of a catalyst by using only light in a flow photoreactor. The obvious advantage of this workflow is further limiting the amount of material used and wasted. Late-stage C–H activation. The di- rect C–H functionalization of het- erocycles has become an increas- ingly valuable tool in modern drug discovery, but there are relatively few methodologies for synthesiz- ing complex organic molecules. More recently, late-stage alkyla- tion—ethylation, methylation, and cyclopropanation—of biologically active heterocycles, such as the po- tent vasodilator, Fasudil, has been successfully achieved using stable organic peroxides activated by vis- ible light photoredox catalysis (450 nm blue LEDs and an iridium or ruthenium photocatalyst) (11). Increasing complexity. Flow photochemistry has seen an increase in researchers developing novel method- ologies that combine several transformations into a single step reaction, allowing for shorter reaction times and higher product yields compared to batch synthesis, and improved safety profiles. For example, tetrahydro- β-carbolines were coupled with α-keto vinyl azides through a visible light-mediated photocascade strategy involving photosensitization, photoredox catalysis, and a [3 + 2] cycloaddition reaction (Figure 3) (12). The mi- croreactor was fed with the substrates and a solution of the catalyst, and the reaction was triggered by incidence of white light, resulting in 18 examples with 62–81% iso- lated yields, obtained in a residence time of 43 minutes. The future is bright The vision of continuous flow photochemistry is to have a broad portfolio of reactions that can be seam- lessly implemented, while meeting the key trends Figure 2. An automated flow system for a light-mediated Negishi cross- coupling reaction. NMR is nuclear magnetic resonance. BPR is back pressure regulator.

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