Multiphase Catalysis in Industry

During the past two decades a variety of transition-metal catalyzed reactions have been introducedin synthetic organic chemistry. Among the most popular examples are asymmetric oxidations and reductionsand a variety of cross-coupling reactions to form C − C and C-heteroatom bonds. Examples are the Heck reaction, Suzuki–Kumadaand Sonagashira coupling reactions and the aryl-aminations introduced by Buchwald and Hartwig. These reactions are homogeneously catalyzed using a metal complex containing expensive metalsand ligands many of which are difficult to synthesize. In most cases the catalysts are very efficient,therefore quite often only millimolar amounts or less are applied. This portfolio of new reactions wasintroduced into lab-scale synthesis within a few years of their discovery and is today frequently usedfor first syntheses of active pharmaceutical ingredients and other high-value fine chemicals. Protocolsfor the use of these reactions in very small-scale combinatorial synthesis have been developed and moreand more hits and later on development products resulted from these efforts. Pharmaceutical products need,because of the intensive and time-consuming clinical development, up to ten years until the first industrial-scaleproduction has to be scheduled. As part of the process development a method to fully separate thecatalyst components from the products after the reaction has to be worked out. Only extremely small residuesof metals or of ligands are tolerated in active pharmaceutical ingredients (APIs). The concentration ofmetals such as Pt, Pd, Ir, Rh, Ru or Os has been limited to 5 ppm by the recommendations of the EuropeanAgency for the Evaluation of Medicinal Products (EMEA) [1].A variety of methods can be applied to fulfil these requirements (as exemplified for palladium in [2] ). Besides environmental and health criteria, cost considerations also motivate the development of processeswhich enable the separation and reuse of the catalyst complex after the reaction. Chiral ligands or ligandsfrequently used for cross-coupling reactions are difficult to synthesize and only some ten's of kilogramsare needed even for the production of many tons of a final product. Both the demanding synthesis andthe production in kg-labs or small pilot plants makes these ligands very expensive. Prices ranging from2000 to 100000 $/kg and more are quite common [3].Both ecological and economical constraints force chemical and pharmaceutical industries to establish proces