No abstract

Spirocycles; Tetramates; Antibacterial Highly functionalised spirocyclic tetramates were prepared via a sequential Knoevenagel reaction and [1,5]-prototropic shift (Treaction) of bicyclic tetramates. While these compounds isomerise in solution, stable analogues can be prepared via appropriate choice of substituents. Further modification of these compounds allows for introduction of aromatic groups, making them suitable as skeletons suitable for application in medicinal chemistry.

Synthetic routes to drug products typically introduce several potentially mutagenic impurities (PMIs) which require controlling to a safe level in the final drug substance, generally directed by the control options within the ICH M7 guideline. These impurities are most commonly introduced due to their specific synthetic utility; however, the formation of a PMI can also occur indirectly from a combination of otherwise nonmutagenic sources, as was the case for NDMA within valsartan. Identifying these formation risks currently relies on manually assessing the synthetic route, a process requiring extensive knowledge and potentially liable to oversight. Herein we report on the development of functionality within an in silico risk assessment tool to facilitate the identification of synthetic stages which introduce the risk of formation of PMIs for industrial and/or regulatory users.