Process Development of a Sonogashira Cross-Coupling Reaction as the Key Step of Tirasemtiv Synthesis Using Design of Experiments

Palladium-catalyzed coupling reactions represent an important tool for modern organic synthesis and have been extensively used in the pharmaceutical industry for the past 30 years to produce active pharmaceutical ingredients (APIs) with complex structures. A case study is discussed in which Hovione studied a palladium-catalyzed Sonogashira coupling reaction using Design of Experiments with the goal of developing an efficient, economical, and robust process to manufacture an API (tirasemtiv) at commercial scale. The most significant factors were studied, and normal operational ranges were defined, supporting risk assessment activities prior to manufacturing campaigns. As a result, API with critical quality attributes always within the required limits was obtained. Removal of residual metals was determined to be critical for the final API quality, leading to the development of an efficient strategy for residual metal removal.

Automated summary

Palladium-catalyzed coupling reactions have been widely used in the pharmaceutical industry for the past 30 years, with the goal of producing APIs with complex structures. A case study was discussed in which a palladium-catalyzed Sonogashira coupling reaction was studied to develop an efficient, economical, and robust process for manufacturing an API at commercial scale. Key factors were identified, operational ranges were defined, and a strategy for residual metal removal was developed to ensure the quality of the final API.