Synthesis of 2-Oxopropanethioamide for the Manufacture of Lanabecestat: A New Route for Control, Robustness, and Operational Improvements

A new route to 2-oxopropanethioamide, a key intermediate in the synthesis of lanabecestat (AZD3293/LY3314814), is described by employing commercially available 2,2-diethoxypropionitrile as a raw material. In contrast to the previous route, this work offers several advantages; for example, the raw material is safer to manufacture and handle, highly toxic hydrogen sulfide gas is no longer required as a reagent, and in situ FTIR spectroscopy monitoring has provided manufacturing controls and robustness. Additionally, this route offers a hold- and control-point by virtue of an isolable crystalline intermediate, which in turn provides improved quality that is evident in the downstream synthesis. An extensive design-of-experiment analysis was undertaken to understand multifactor interdependencies, build a model, visualize factor relationships, map the process parameter reaction space, identify potential process operating conditions, and predict their performance.