Catalysis: The pharmaceutical perspective Walter Cabri Chemistry & Analytical Development, Sigma-Tau, via Pontina km 30400, 00040 Pomezia, Roma, Italy 1. Introduction Organometallic and enzymatic catalysis are key technologies for the pharmaceutical industries for both discovery and development of new chemical entities (NCE). The discovery of NCE in the area of small molecules is centred on the design of flexible synthesis to allow a high level of chemical diversity. In spite of the increasing complexity of the molecular architecture and the increasing number of chemical steps the rapid production of molecules for screening is a must. In this context, organometallic catalysis is useful because it is a flexible technology, suitable for parallel synthesis and microwave acceleration. An aromatic halide can be subjected to several palladium-catalysed transformations (Stille, Heck, Heck/Cassar, Sonogashira, Negishi, Suzuky, Kumada, Hyama, Buchwald–Hartwig, carbonylation, reduction, cyanation, ether synthesis, etc.) generat- ing a high degree of chemical diversity. However, catalysis is even more important for the design of synthesis for the development of NCE to produce material for clinical trials and the pharmaceutical market. The popularity of chemistry among the public reached the lowest level possible 30 years ago and this economic sector is still struggling [1]. The effect of poor technical and safety design approaches to industrial processes and plants determined several accidents that completely changed the Environment Health & Safety (EH&S) laws in Europe and in the western world in general. In Europe, Flixborough (1 June 1974) and Seveso (10 July 1976) accidents were the point of no-return [2]. The new legislations increased the level of control both on safety and environmental pollution [3]. But the perception of chemistry among the public did not change: a chemical substance is bad for you and the environment. The introduction of the 12 principles of green chemistry (Fig. 1) [4] and the use of simple words improving the communication to the external world allowed several chemists to have access to public grants. However, most of the publications have a misleading approach focusing the attention on technologies that violate the main GC principles: microwaves (energy), ionic liquid (biodegradability and non-toxic products), water chemistry (water is becoming one of the most important resources world wide and the production of waste water is not ‘‘green’’), fluorous phase chemistry (biodegradability), etc. [5]. For these reasons these technologies have few or no industrial applications. The most important revolution of the 21st century are the EH&S laws made by the governments and the globalisation that forced western world industries to compete with countries like India and China with completely different cost structures. The only way to compete in the actual market is technological excellence. Thinking green is the only way to design low cost and competitive industrial processes in the western world. The violation of any of the 12 principles determines cost increases of the overall process. For process research chemists in the pharmaceutical industry, the challenge of process design is increasing. In fact, the architectural design by medicinal chemists is more complex, the number of synthetic steps and the development of enantiomeri- cally pure drugs is increasing [6]. The process chemist must use the 12 principles for the design of the synthesis from the beginning of the development process. It is worth noting that a green approach to pharmaceutical production must be focused on ‘‘taking out of the trash.’’ This was the title of an interesting paper published in 1993 by Braithwaite and Ketterman, based on the simple consideration that only a small number of atoms in a synthetic process are incorporated into the final molecule (70–80% are simply solvents) [7]. But there are other aspects that must be taken into consideration: cooling/heating agitation, filter aid, etc. (Fig. 2). Catalysis Today 140 (2009) 2–10 ARTICLE INFO Article history: Available online 21 September 2008 Keywords: Catalysis Idarubicin ST1535 Green chemistry ABSTRACT The striking impact of enzymatic and organometallic catalysis on the design of environmentally friendly processes for the discovery and production of pharmaceutical products is discussed. Four case studies namely ST1535, Idarubicin, Rubitecan and 7ACA are analysed in the context of a modern synthetic design based on the application of the 12 green chemistry principles. ß 2008 Elsevier B.V. All rights reserved. E-mail address: walter.cabri@sigma-tau.it. Contents lists available at ScienceDirect Catalysis Today journal homepage: www.elsevier.com/locate/cattod 0920-5861/$ – see front matter ß 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.cattod.2008.07.014