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.

中文翻译：

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沃罗孢素的合成与结晶研究

在这项研究中，设计了一种合成和结晶 Voclosporin 的增强方法。选择乙酸异丙酯作为乙酰化反应的溶剂，使反应时间从4天大幅缩短至15小时。选择试剂( E )-三甲基(3-(4,4,5,5-四甲基-1,3,2-二氧硼杂硼烷-2-基)丙-1-烯-1-基)硅烷( 8 )用于Peterson反应，转​​化率超过90%。随后，采用1,8-二氮杂双环[5,4,0]十一碳7-烯(DBU)作为水解试剂进行脱乙酰化，得到97:3的E / Z比。此外，使用乙醇/水混合物作为结晶溶剂有利于以结晶形式生产沃罗孢素，从而无需柱分离和纯化步骤。综上所述，成功实现了沃罗孢素的四步生产工艺，总收率达到 50%，高效液相色谱纯度为 98.8%。研究了 Voclosporin 的晶型，获得了相当大的晶体，并记录了 Voclosporin 的晶体结构。我们的数据对于增进对 Voclosporin 的合成方法和晶体稳定性的理解具有重要价值。