Mechanistic Understanding Guides Impurity Control Strategy for CELMoD API Reaction

Cereblon modulators are prevalent throughout BMS’s portfolio, including IMiDs^® and CELMoDs^®. These molecules bind to cereblon through a glutarimide ring, which is responsible for the highly-potent nature of these compounds. To minimize the number of high-potent steps, the synthetic sequence of these compounds has been designed to install the glutarimide ring in the final chemical transformation via an acid-catalyzed deprotection and cyclization.

In this presentation we will highlight reaction studies on model systems utilizing in-situ process analytical technologies (PAT) coupled with kinetic analysis and design of experiments (DoEs) to gain a mechanistic understanding of the desired and undesired reactions.

Key findings from these studies indicate that the deprotection has a second-order dependence on catalyst concentration and that the undesired reactions largely stem from accumulation of isobutylene. Controlling the fate of isobutylene is critical for the development of a robust impurity control strategy. We utilized these findings to build predictive models based on mechanistically-derived equations for various portfolio assets, enabling a robust strategy to control isobutylene-related impurity formation to ensure API meets quality standards