Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility. However, for over half a century, pharmaceutical manufacturing has used batch systems because the synthesis of complex molecules such as drugs has been difficult to achieve with continuous-flow systems. Here we describe the continuous-flow synthesis of drugs using only columns packed with heterogeneous catalysts. Commercially available starting materials were successively passed through four columns containing achiral and chiral heterogeneous catalysts to produce (R)-rolipram, an anti-inflammatory drug and one of the family of γ-aminobutyric acid (GABA) derivatives. In addition, simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with the opposing enantiomer, we obtained antipole (S)-rolipram. Similarly, we also synthesized (R)-phenibut, another drug belonging to the GABA family. These flow systems are simple and stable with no leaching of metal catalysts. Our results demonstrate that multistep (eight steps in this case) chemical transformations for drug synthesis can proceed smoothly under flow conditions using only heterogeneous catalysts, without the isolation of any intermediates and without the separation of any catalysts, co-products, by-products, and excess reagents. We anticipate that such syntheses will be useful in pharmaceutical manufacturing.

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The effect of solvents on the reduction of esters was examined with readily available sodium borohydride which is known to be incapable of reducing such functional groups. In mixed solvents of t-butyl alcohol–methanol or tetrahydrofuran–methanol, various carboxylic esters and lactones were found to be reduced by sodium borohydride to the corresponding alcohols or diols in high yields. Slow addition of methanol to the refluxing mixture of ester and sodium borohydride in t-butyl alcohol or tetrahydrofuran was essential to achieve effective reduction. On the other hand, each individual solvent, methanol or t-butyl alcohol, was not effective for the reduction. The procedure provided a practical method for the functional group selective reduction of esters in the presence of chloro, cyano, carboxylato, carbamoyl, carboxy or nitro groups, which can not usually be performed by lithium aluminium hydride.

Polysilane-supported Pd and Pt catalysts have been prepared for the first time, and used successfully in hydrogenation, Suzuki and Sonogashira reactions, and hydrosilylation respectively: the reactions proceeded in high yields, and the catalysts could be recovered almost quantitatively by simple filtration and reused.

We developed poly(dimethyl)silane-supported Pd catalysts that are readily prepared from Pd(OAc) 2 ,p oly(dimethyl)silane, and Al 2 O 3 .T he immobilization was achieved for the first time with as upport that does not contain benzene rings. The Pd catalyst thus prepared was found to have higher hydrogenation activity than Pd/C. Furthermore,t he catalystw as used in continuous-flow hydrogenation with various substrates, including simple liquid substrates (neat) and dissolved solid substrates. Vegetable oils, squalenes, and phosphatidylcholine were successfully hydrogenated on gram to kilogram scales.Catalytic hydrogenation is one of the most important methods for organic synthesis in both academia and industry. [1] It is widely used for the synthesis of natural products,b iologically important compounds, active pharmaceutical ingredients, and many intermediate compounds. The hydrogenation of fats, phospholipids,a nd squalenesi sp erformed to prevent oxidation of their unsaturated bonds, which causes coloration or odor. [2] The hydrogenated products thus prepared are used as emulsifiers, compoundinga gents, and so on. Hydrogenation of lecithin is an important process for the preparation of emulsifiers. Catalytic hydrogenation by using Pd/C has been used in ab atch system for this process;h owever,arelativelyh igh loading of Pd/C is required and subsequentr emoval of Pd by filtration is time consuming.M oreover,t he recovered Pd has low activity.T oa ddress thesei ssues, alternative catalyst systems have been investigated, and among the variousc atalysts tested, polysilane-supported Pd (Pd/PSi) was found to have high activity.W ed eveloped this methodology further, and herein, we describe ac ontinuous-flow hydrogenation process by using an ovel Pd/PSisystem as the catalyst.We previously prepared poly(methylphenyl)silane-supported Pd (Pd/MPPSi)a nd used it as ac atalyst for severalr eactions. [3] Poly(methylphenyl)silane was chosen as an analogue of polystyrene, because in microencapsulated [4] and polymer-incarcerated [5] catalysts with polystyrenes as polymer backbones, it is assumed that the benzene rings of the backbone are important for the immobilization of the metal catalysts through electronic interactions (p electrons). This reasoning led us to assumet hat benzene rings would also be important for immobilization of polysilane-supported catalysts, and poly(methylphenyl)silane was chosen accordingly.H owever,t he availability of poly(methylphenyl)silane is relatively limited. In contrast, poly(dimethyl)silane is readily available; [6] therefore, we examined the use of poly(dimethyl)silane in place of polystyrenes or poly(methylphenyl)silane as ab ackbone fors upported catalysts.We began our study by exploring the preparation of ap oly(dimethyl)silane-supported palladium/alumina hybrid catalyst [Pd/(DMPSi-Al 2 O 3 )] according to the method shown in Scheme 1. This methodw as based on ap rocedure that was used previously to preparet he Pd/MPPSi catalyst. [3] Unexpectedly,t he Pd loading of the catalyst (56.6...