This book describes the development of two kinds of continuous-flow transformation using heterogeneous catalysts, and explains how they can be applied in the multistep synthesis of active pharmaceutical ingredients. It demonstrates and proves that fine chemicals can be synthesized under continuous-flow conditions using heterogeneous catalysis alone. Importantly, the book also proposes a general concept and strategy for achieving multistep flow synthesis and developing heterogeneous catalysts, and shows that commercially available anion exchange resin can be used as a water-tolerant strong base catalyst for various types of continuous-flow aldol-type reaction. Reviewing the state of the art in heterogeneous catalysis in flow chemistry – a “hot topic” and rapidly developing area of organic synthesis – the book will provide readers with a deeper understanding of fine chemical flow synthesis and its future prospects.
We, synthetic chemists, deeply rely on flasks as reaction environments. They have been used since the era of alchemy and most of the modern organic syntheses are still performed using conventional glassware. Such a manufacturing method is called batch synthesis, where reagents, reactants, catalysts, and solvent are charged in a reaction vessel at once to perform target organic transformations. Because it is reliable and is a well-established method from a laboratory to industry, almost all fine chemicals such as active pharmaceutical ingredients (APIs), agrochemicals, and functional organic materials are synthesized by repeating this method. However, this method has several drawbacks, especially for mass production.
Continuous-flow hydrogenation is an important technology component to achieve multistep flow synthesis. Especially, hydrogenation of functional groups with high oxidation states such as nitrile, nitro, and carbonyl compounds are essential chemical transformations in my aldol-hydrogenation strategy (Scheme 3.1). To establish this method, I first focused on the hydrogenation of nitriles to primary amines as a target reaction.
Continuous-flow aldol-type reactions are the other essential part of the aldol-hydrogenation strategy (Scheme 4.1). In Chap. 2, flow aldol condensation between nitromethane and aldehyde using amine-functionalized SiO2 catalyst was described. To expand the scope of nucleophiles and to access both aldol compounds and dehydrated compounds selectively, I decided to investigate different types of heterogeneous catalysts.
Venlafaxine hydrochloride is a commonly used antidepressant agent. It inhibits the reuptake of serotonin and norepinephrine [Harvey et al. in Arch Gen Psychiatry 57:503, 2000]. It was first developed by Wyeth, a pharmaceutical company in the U.S., in 1993 and is now marketed by Pfizer. It was the sixth most used antidepressant in the U.S. in 2007 with >17 million prescriptions.
Yuki Saito
Backmatter
Metadaten
Titel
Multistep Continuous Flow Synthesis of Fine Chemicals with Heterogeneous Catalysts
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