The polyethyleneimine-modified polymers, polystyrene–divinylbenzene-based (TAs) and polymethacrylate-based polymers (TAm), were used as palladium scavengers to eliminate residual palladium species after palladium on carbon-catalyzed Sonogashira-type coupling reaction. Since both TAs and TAm indicated relatively favorable elimination abilities toward residual palladium species in the reaction mixture, the affinities of TAs and TAm for palladium species were used as supports for palladium catalysts. The TAm-supported palladium catalyst (Pd/TAm) indicated better catalyst properties for the chemoselective hydrogenation compared to those of the corresponding TAs-supported palladium catalyst (Pd/TAs). Aromatic benzyl ethers; aromatic and aliphatic N -Cbzs; and aromatic carbonyl groups were smoothly hydrogenated in the presence of 1–5 mol % of Pd/TAm in MeOH or 2-PrOH. In contrast, the hydrogenation of aromatic ketones was selectively suppressed in morpholine which act as appropriate catalyst poison and solvent. Furthermore, Pd/TAm-catalyzed chemoselective hydrogenation was applicable to continuous-flow reaction.

The catalyst activities of various heterogeneous palladium catalysts supported by anatase-, rutile- and brookite-type titanium oxide for ligand-free Suzuki–Miyaura cross-coupling reactions of aryl chlorides were evaluated. Palladium acetate [Pd(OAc)2], supported on anatase-type titanium oxide (TiO2) via acetonitrile solution impregnation process without reduction [Pd/TiO2 (anatase-type)], demonstrated the highest catalyst activity in comparison to those of other titanium oxide (rutile- or brookite-type) supported Pd(OAc)2 without reduction and reduced Pd/TiO2 (anatase-type) [Pd(red)/TiO2 (anatase-type)]. Various aryl chloride and bromide derivatives were smoothly coupled with arylboronic acids including heteroarylboronic acids in the presence of 5–10 mol% Pd/TiO2 (anatase-type) without the addition of any ligands. Although the fresh Pd/TiO2 (anatase-type) catalyst was surprisingly comprised of ca. 1:2 mixture of palladium(II) and palladium(0) species according to X-ray photoelectron spectroscopy (XPS), in spite of no reduction process, significant further increment of palladium(0) species was observed during the Suzuki–Miyaura coupling reaction, and Pd/TiO2 (anatase-type) was converted into a catalyst, which contained palladium(0) species as the main component [ca. 1:5 mixture of palladium(II) and palladium(0) species]. Therefore, the reduction via the electron donation process to the palladium(II) species may have occurred during the reaction on anatase-type titanium oxide.

Flow reaction methods have been developed to selectively synthesize tertiary, secondary, and primary amines depending on heterogeneous platinum-group metal species under catalytic hydrogenation conditions using nitriles as starting materials. A 10 % Pd/C-packed catalyst cartridge affords symmetrically substituted tertiary amines in good to excellent yields. A 10 % Rh/C-packed catalyst cartridge enables the divergent synthesis of secondary and primary amines, with either cyclohexane or acetic acid as a solvent, respectively. Reaction parameters, such as the metal catalyst, solvent, and reaction temperature, and continuous-flow conditions, such as flow direction and second support of the catalyst in a catalyst cartridge, are quite important for controlling the reaction between the hydrogenation of nitriles and nucleophilic attack of in situ-generated amines to imine intermediates. A wide variety of aliphatic and aromatic nitriles could be highly selectively transformed into the corresponding tertiary, secondary, and primary amines by simply changing the metal species of the catalyst or flow parameters. Furthermore, the selective continuous-flow methodologies are applied over at least 72 h to afford three different types of amines in 80-99 % yield without decrease in catalytic activities.

Herein, a continuous-flow deuteration methodology for various aromatic compounds is developed based on heterogeneous platinum-catalyzed hydrogen-deuterium exchange. The reaction entails the transfer of a substrate dissolved in a mixed solvent of 2-propanol and deuterium oxide into a catalyst cartridge packed with platinum on carbon beads (Pt/CB). Pt/CB could be continuously used without significant deterioration of catalyst activity for at least 24 h. Deuteration proceeded within 60 s of the substrate solutions being passed through the Pt/CB layer in the Pt/CB-packed cartridge.

conditions and is suitable as an API for manufacture in solid formulations. The phosphorus K-edge XANES spectra differed among form I, the amorphous form, and form II, which may be ascribed to the difference in the coordinate bond schemes between the phosphate moieties and sodium ions. The results demonstrated that the phosphorus K-edge XANES spectroscopy could be applied to the identification or the discrimination of crystal forms of the APIs containing phosphate moieties. Conclusions Acquired information about physical properties are crucial for manufacturing of solid formulations of disodium etidronate. XANES spectroscopy is a promising alternative method for evaluating the solid-state forms of APIs. KEY WORDSbisphosphonates • crystal structure • etidronate • physical properties • X-ray absorption near-edge structure spectroscopy ABBREVIATIONS API Active pharmaceutical ingredient DSC Differential scanning calorimetry DVS Dynamic vapor sorption RH Relative humidity TG Thermal gravimetry XANES X-ray absorption near-edge structure XRPD X-ray powder diffraction