通过离心分配色谱实现外消旋伏立康唑的规模化对映体分离：过程强化实现连续操作

亮点

• 离心分配色谱（CPC）能够实现伏立康唑的工业规模对映体分离，并具有高生产效率。
• 以间歇式CPC为基准，进一步强化为循环连续叠加进样CPC模式。
• 多重双模式（MDM）CPC可实现连续进样和双出口产品收集。
• 与传统的非连续分离方式相比，MDM CPC的强化工艺带来了约25倍的生产效率提升。
• 通过重复循环利用溶剂相，连续CPC减少了溶剂和手性选择剂的用量。

Abstract
In industrial practice, enantiopure (2R,3S)-voriconazole is commonly produced by classical resolution with (1R)-(−)-10-camphorsulfonic acid, a reliable approach that remains constrained by batch operation and downstream cleavage/work-up. Here, rac-voriconazole was selected as a demanding model mixture to demonstrate that cyclodextrin (CD)-mediated centrifugal partition chromatography (CPC) can provide a scalable, support-free alternative when the primary objective is high productivity under intensified operation. A rapid batch CPC baseline separation was established and then intensified into two continuous solutions: (i) a cyclic continuous stacked-injection workflow enabling repeated use of the selector-rich stationary phase, and (ii) a continuous multiple dual mode (MDM) CPC workflow that sustains chiral discrimination under repeated mode switching with dual-outlet collection. Because the CD selector is confined to the aqueous phase while the target enantiomer is recovered in the organic stream, the collected product is essentially CD-free and does not require a dedicated selector-removal step. Preservation and reuse of the selector-rich phase further enable solvent and CD recycling. To improve process economics, sulfobutyl ether-β-cyclodextrin (SBE-β-CD) was replaced with lower-cost randomly methylated β-cyclodextrin (RM-β-CD) without compromising the partitioning and selectivity required for MDM operation. Continuous MDM CPC afforded (2R,3S)-voriconazole at ≥99.8% optical purity and 99.9% enantiomeric excess (ee), with 81% isolated yield and 6.0 g·L−1·h−1 productivity (∼25-fold higher than classical resolution and 7.5-fold higher than stacked injection). Collectively, these results position CD-mediated CPC as a manufacturing-oriented alternative to conventional resolution, combining streamlined downstream processing with productivity-driven continuous operation and strong potential for favorable process economics.

摘要

在工业实践中，光学纯的(2R,3S)-伏立康唑通常通过经典的(1R)-(−)-10-樟脑磺酸拆分法生产，该方法虽然可靠，但仍受限于间歇操作及后续的裂解和后处理步骤。本研究选择外消旋伏立康唑作为一个具有挑战性的模型混合物，旨在证明当以强化操作下的高生产效率为首要目标时，环糊精（CD）介导的离心分配色谱（CPC）可作为一种可规模化、无需固体载体的替代方案。首先建立了快速的间歇式CPC基线分离，然后将其强化为两种连续操作模式：（i）循环连续叠加进样CPC流程，可实现富含手性选择剂的固定相的重复利用；（ii）连续多重双模式（MDM）CPC流程，在重复切换运行模式并进行双出口收集的过程中，维持手性识别能力。由于环糊精选择剂被限制在水相中，而目标对映体在有机相中被回收，收集到的产品基本上不含环糊精，无需专门的选择剂去除步骤。富含选择剂相的保存和重复利用，进一步实现了溶剂和环糊精的循环使用。为改善工艺经济性，本研究用成本更低的随机甲基化-β-环糊精（RM-β-CD）替代了磺丁基醚-β-环糊精（SBE-β-CD），且未影响多重双模式操作所需的分配行为和选择性。连续MDM CPC工艺获得的(2R,3S)-伏立康唑光学纯度≥99.8%，对映体过量（ee）为99.9%，分离收率为81%，生产率为6.0 g·L⁻¹·h⁻¹（比经典拆分法高约25倍，比叠加进样模式高7.5倍）。综上所述，这些结果确立了环糊精介导的CPC作为一种面向生产的传统拆分替代方案的地位，它将简化的下游处理与高生产率的连续操作相结合，并展现出实现良好工艺经济性的巨大潜力。