Optimized Kilogram-Scale Synthesis and Impurity Identification of Clascoterone

Clascoterone is a first-in-class topical androgen receptor inhibitor for acne treatment. We describe an optimized three-step kilogram-scale synthesis of clascoterone. By optimizing the reaction parameters, we developed a new strategy that utilizes NH 4 Cl or Lewis acids to mediate the site-selective hydrolysis to solve the issues of acyl migration and overhydrolysis pathways. This process utilizes the selective coordination of the Lewis acid with the substrate to precisely activate its cyclic ketal structure, thereby significantly suppressing the formation of Impurity 5 (from C-21 propionyl isomerization) and Impurity 2 (from 17,21-dihydroxy hydrolysis). As a result, both impurities were consistently maintained below 0.1%. Eight process-related impurities were synthesized and characterized, including four previously unreported impurities, and corresponding control strategies were established. Validated at the 10 kg scale, the process delivered a 72.9% overall yield and API with ≥99.5% HPLC purity, meeting ICH Q6A specifications. The optimized process has mild reaction conditions, simple postprocessing, high yield, high purity, quality control, and cost-effectiveness and is suitable for large-scale industrial production.