HSD-016

We report a Pd-catalyzed stereospecific α-arylation of optically pure 2,3-epoxy-1,1,1-trifluoropropane (TFPO). This method allows for the direct and reliable preparation of optically pure 2-CF₃-2-(hetero)aryloxiranes, which are precursors to many CF₃-substituted tertiary alcohols. The use of continuous-flow methods has allowed the deprotonation of TFPO and subsequent zincation at higher temperature compared to that under traditional batch conditions.

Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11β-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11β-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.