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Overcoming Problems at Elaboration and Scale-up of Liquid-Phase Pd/C Mediated Catalytic Hydrogenations in Pharmaceutical Production

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Abstract

The practical solutions for scale-up and production of intermediates or precursors of pharmaceuticals by liquid-phase Pd/C mediated hydrogenation can be of considerable interest and deserve broader attention even if they have not been the focus of previously published research due to regulations of patent law. The practical obstacles are persistent and have been known for a long time, but for the most part remained unpublished. The most important discoveries and solutions that contributed to the successful scale-up of hydrogenations for pharmaceutical production were the following: (i) the poisoning of Pd/C catalyst with Fe²⁺ ions for the selective hydrogenation of 2,6-dimethyl-1-nitrosopiperidine to the corresponding hydrazo compound; (ii) alloying of the deposited Pd metal with Cu for converting the aromatic acid chlorides into the corresponding aldehydes; (iii) alteration of the pH of the reaction mixture to basic values which enhanced the stereoselectivity of paracetamol hydrogenation; (iv) a useful modification of the catalyst preparation process, i.e., the acidification of the catalyst resulted in the hydrogenolysis of benzylic OH in a molecule containing a basic N atom; (v) use of two liquid phases, altogether a four-phase system, which permitted the hydrogenolysis of the S-S bond in a potential catalyst poisoning molecule; (vi) the preservation of the metallic Pd surface of the catalyst by saturation of the reaction mixture with hydrogen, resulting in a high H2/substrate ratio, increased the aldehyde yield in the hydrogenation of 4-chloro-butyric-acid-chloride by avoiding the unwanted poisoning effect of the hydrochloric acid. In the present article, these problems and their solutions, as they emerged during the scale-up of the processes, will be discussed in detail.

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... Polymers are superior in stabilization of metal nanoparticles compare to inorganic supports, however, application of such systems for catalytic hydrogenation have several disadvantages, including rapid nanoparticles sintering in organic reaction media under high reaction pressure and temperature [19,20]. Therefore application of traditionally used inorganic supports can be also attractive for synthesis of stable Pd nanoparticulate systems for application in catalysis [21,22]. However obtaining high dispersion of active metal became an outstanding problem for nanoparticles supported on inorganic matrix [23]. ...
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