Chemical Reactions and Synthesis Design

In 1967, work was presented from a Sheffield group on indexing chemical reactions for database budding. In 1969, a Harvard group presented its first steps in the development of a system for computer-assisted synthesis design. Soon afterwards, groups at Brandeis University and TU Munich, Germany, presented their work in this area. 

---

We are mainly concerned with the development of EROS (Elaboration of Reactions for rganic Synthesis), a program system for the prediction of chemical reactions and the design of organic syntheses (Jj- 3). This system does not rely on a database of known reactions. Instead, reactions are generated in a formal manner by breaking and... 

Reaction prediction treats chemical reactions in their forward direction, and synthesis design in their backward, retrosynthetic direction,... 

Structural chemistry is an essential part of modern chemistry in theory and practice. To understand the processes taking place during a chemical reaction and to render it possible to design experiments for the synthesis of new compounds, a knowledge of the structures of the compounds involved is essential. Chemical and physical properties of a substance can only be understood when its structure is known. The enormous influence that the structure of a material has on its properties can be seen by the comparison of graphite and diamond both consist only of carbon, and yet they differ widely in their physical and chemical properties. 

A New Treatment of Chemical Reactivity Development of EROS, an Expert System for Reaction Prediction and Synthesis Design... 

We have already emphasized our view that the evaluation of chemical reactions and synthetic pathways is of preeminent importance in any system for computer-assisted synthesis design or reaction prediction. The quality of the evaluation process will determine to a large extent the overall quality of such a system. 

As these reagent systems are anchored on a solid, they also allow the simultaneous use of multiple reagents to achieve one-pot transformations where, because of incompatibility of the reagents, no solution-phase equivalent exists or would require intermediate isolation. Many examples of this are illustrated in the following sections where it can be seen that these concepts add a new dimension to how one can think about organic synthesis and will certainly have important ramifications on the design and implementation of new chemical reactions and processes in the future. 

Now I would like to turn to some of the issues of operations within the manufacturing process itself and speak to certain process controls that are expected. In a chemical synthesis sequence, as I mentioned above, intermediates will need to be fully characterized. That characterization will then lead to a set of specifications for the intermediate, that is, its level of purity, its form, etc. Test procedures that demonstrate that the intermediate meets specifications must be established. Some intermediates are deemed to be more important than others and are given specific designation, such as pivotal, key, and final intermediates. In those cases, it is necessary to demonstrate that the specific and appropriate structure is obtained from the chemical reaction and that the yield of the intermediate is documented and meets the expected yield to demonstrate process reproducibility and control. Purity of the substance is to be appropriately documented. And, finally, in reactions which produce pivotal, key, and final intermediates, side products or undesirable impurities are identified and their concentrations measured and reduced by appropriate purification procedures so that the intermediate meets in-process specifications. Thus, those important intermediates become focuses of the process to demonstrate that the process is "under control" and functioning in a reproducible and expected manner. All of these activities ultimately are designed to lead to the production of the actual active ingredient which is referred to then as a "bulk pharmaceutical agent." That final product will need to be completely characterized which then will document that it meets a set of specifications ("Final Product Specifications") for qualification as suitable for pharmaceutical use. 

A second novel aspects approach is substrate directed synthesis. The point of this aspect is that wild-type enzymes could be used to generate more diversity without engineering the enzyme. Therefore acceptor substrates were designed which allow the control of linkage specificity by the enzyme and further chemical reactions and... 

The position of the radionuclide in the molecule of interest is also critical as it will affect the biological behavior of the radiopharmaceutical. Chemical reactions must be designed to be stereospecific in many cases, as the production of a mixture of different stereoisomers complicates the purification of the final radiopharmaceutical. Synthesis procedures must also be easy to automate, as very elevated activities are used for the synthesis of PET radiopharmaceuticals (several curies usually) and appropriate radiation protection systems must be used. 

Gasteiger J, Hutchings HG, Christoph B, Gann L, Hiller C, Low P, Marsili M, Sailer H, Yuki K (1987) A new treatment of chemical reactivity Development of EROS, an expert system for reaction prediction and synthesis design, Top Curr Chem 137 19... 

---