Synthesis and Crystallization Research of Voclosporin

Abstract

In this study, an enhanced methodology for the synthesis and crystallization of Voclosporin was devised. Isopropyl acetate was selected as the solvent for the acetylation reaction, resulting in a substantial reduction in the reaction duration from 4 days to 15 h. The reagent (E)-trimethyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)silane ( 8) was chosen for the Peterson reaction, achieving a conversion rate exceeding 90%. Subsequently, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) was employed as the hydrolysis reagent for deacetylation, yielding an E/Z ratio of 97:3. Moreover, the use of an ethanol/water mixture as the crystallization solvent facilitated the production of Voclosporin in its crystalline form, obviating the need for column separation and purification steps. In summary, a successful four-step process for producing Voclosporin was achieved, yielding a 50% overall yield with a high-performance liquid chromatography purity of 98.8%. The crystal form of Voclosporin was investigated, resulting in the acquisition of a sizable crystal, and the crystallographic structure of Voclosporin was documented. Our data hold significant value for advancing the understanding of both the synthetic methodology and the crystal stability of Voclosporin.