The talk covers computational chemistry methods currently applied to study chemical reactions involved in drug substances syntheses. The theoretical concepts, behind computational chemistry methods applied to model chemical reactions, are briefly explained, highlighting the most used for mechanistic studies of chemical reactions. Mechanistic modeling of chemical reactions is based on the transition state theory and uses measurable parameters like reactions’ barrier energy and overall energy balance to predict the course of small molecules syntheses. Knowledge on the mechanisms of the reactions under study is required to develop accurate models with computational chemistry methods. A brief description of the pros and cons of the most used models is included, illustrated with examples. After presenting fundamental concepts, six case studies developed for the synthesis of active pharmaceutical substances are described. The case studies describe real-world problems encountered on the development of active substances manufacturing processes. Examples like how to clarify which one of two plausible mechanisms a specific hydrogenation reaction follows, or how to select the best route of synthesis for a product, or how to select the best reagents for reactions involved on the synthesis of active pharmaceutical substances, or how to predict the impact of process parameters like solvent or temperature on the reaction outcome, or how to understand unexpected issues related to the formation of high levels of side products, found during the development of processes for the manufacture of active pharmaceutical substances. Six case studies on the application of computational chemistry to the development of drug substances manufacturing processes are presented. On one case, the challenges encountered during the synthesis of an intermediate of vilanterol trifenatate synthesis are presented. In this case it was possible to clarify which of the two possible mechanisms an isoxazolidinone ring opening reaction follows, enabling to select the most favorable reagent to improve the completeness and the selectivity of the reaction. Another case related to reaction mechanisms, shows how it was realized that the synthesis of sancycline, an intermediate on minocycline synthetic route, follows a hydrogenolysis mechanism rather than a hydrogenation path, while providing a rational for the formation of a major impurity. The successful synthesis of novel salts of doxycycline, after selecting one of two possible pathways based on energetics driving factors, is also presented. The selection of best reagents to run the transesterification reaction on the synthesis of tioptropium bromide precursor, together with the understanding on the formation of the major process impurity, are explained. Selectivity problems found in reactions involved in the manufacturing processes of aclidinium bromide and umeclidinium bromide, related to the formation of major impurities in a transesterification reaction and in a nucleophilic substitution reaction, respectively, are described. Take-home messages are listed in the last slides, to convey relevant items on the application of the methodology.
Learning Objectives:
Upon completion of the presentation, participants will be able to theorize about computational chemistry methods applied to model the syntheses of active pharmaceutical substances.
Upon completion of the presentation, participants will be able to design major elements required to apply computational chemistry methods to select best conditions to test in experiments.
Upon completion of the presentation, the participants will be able to explore the potential of computational chemistry to accelerate experimental process development work.
