Process development and optimization of apalutamide synthesis aided by the Design of Experiments (DoE)

Abstract

In this manuscript, the process of apalutamide synthesis was efficiently optimized with the guidance of Design of Experiments (DoE). By employing Definitive Screening Designs and Custom Designs, we sieved and optimized the significant factors to establish the experimental ranges for each reaction step. This approach would not only dramatically improve conversion efficiency while precisely regulating impurity levels, but also enable dynamic optimization of critical process parameters within experimental boundaries, thereby streamlining post-process monitoring requirements. Ultimately, the overall process yield for apalutamide reached 70 % with an HPLC purity of 99.97 %.