Lewis acids in the preparation of the heterocyclic compounds: synthesis and characterization of the impurities of API

The work reported on this thesis is the result of a collaboration between the University of Camerino and the Pfizer of Ascoli Piceno. This collaboration includes, but was not limited to, the confirmation of molecular structure of reference standards. The Reference Standard's Group supports manufacturing by certifying standards which are then used in the analysis and evaluation of a new lot of an active pharmaceutical drug. Due to the potential significant impact to manufacturing, in many cases a full study is needed to confirm the structure of the standards. Another interesting scientific aspect of this collaboration has been the synthesis of impurities. It is known that the impurities in an Active Pharmaceutical Ingredients (API) may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. Then, impurities have to be monitored on the active pharmaceutical ''parent'' drug and a reference standard is often needed to determine the quantity of impurities and/or to confirm their structure without any doubt. The best approach to obtain an impurity is probably an synthetic approach which utilizes an alternative chemical pathway to get the desidered compound, and, given that it is estimated that more than 70% of all pharmaceutical products possess heterocyclic structural submits, our efforts have been focused on the development of new bond-forming reactions in the heterocyclic polyfunctionalized molecules. Parallelly, my thesis represents a contribution to the program of the research group of the Department of Organic Chemistry of the University of Camerino, that, for a long time, has focused the attention on the study of the catalytic activity of Lewis acids, such as TiCl4, and particularly the CeCl3. In fact, our research group has dedicated itself particularly to the study of new methodologies involving the use of CeCl3·7H2O-NaI system as a promoter that facilitates a variety of useful organic transformations. In many trials good results have been achieved and the procedures developed are characterized not only by the efficiency of the reactions, but also by selective processes, by a good stereochemical control, by reacting available and inexpensive reagents and in some cases from the possibility of recovering the cataliytic promoter system used through simple procedures of work-up. For this reason, we have explored the reactive possibilities of the CeCl3·7H2O-NaI system with the goal of developing some simple and efficient procedures for the synthesis of heterocyclic compounds that introduce biological activity or that can be used as building blocks for the synthesis of more complex molecules. Attention, furthermore, was focused on the use of the CeCl3·7H2O-NaI system on a silica gel surface under solvent-free conditions for the synthesis of molecules with interesting pharmacological properties.