Continuous Flow Asymmetric Hydrogenation with Supported Ionic Liquid Phase Catalysts Using Modified CO2 as the Mobile Phase: from Model Substrate to an Active Pharmaceutical Ingredient,ACS Catalysis

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Continuous Flow Asymmetric Hydrogenation with Supported Ionic Liquid Phase Catalysts Using Modified CO2 as the Mobile Phase: from Model Substrate to an Active Pharmaceutical Ingredient
ACS Catalysis ( IF 11.3 ) Pub Date : 2018-03-16 00:00:00 , DOI: 10.1021/acscatal.8b00216
Daniel Geier ₁ , Pascal Schmitz ₁ , Jędrzej Walkowiak ₁ , Walter Leitner _{1,

2} , Giancarlo Franciò ₁

Affiliation

The continuous flow asymmetric hydrogenation of (hetero)aromatic enamides has been realized using a Rh-Quinaphos catalyst immobilized in a supported ionic liquid phase (SILP) and employing supercritical CO₂ modified with toluene (modCO₂) as the mobile phase. This approach allows expansion of the scope of the original SILP/scCO₂ system to nonvolatile substrates with poor solubility in pure CO₂. The potential of a SILP catalyst in combination with modCO₂ was demonstrated for an industrial case study using the continuous flow hydrogenation for the synthesis of a key intermediate of an active pharmaceutical ingredient (API) from AstraZeneca’s portfolio. Toluene was selected as the most promising modifier, and the influence of the ratio of modifier to CO₂ was evaluated in detail. The catalyst support was found to play a major role for maintaining constant performance and the use of hydrophobic fluorous reverse-phase silica (FRP-SiO₂) instead of dehydroxylated silica strongly enhanced the long-term stability under continuous flow operation. Virtually a single enantiopure product was obtained over a prolonged time-on-stream of 90 h (quantitative single-pass conversion, ee > 99%) reaching a total turnover number of 10 300 at a space–time yield (STY) of 24 g L^–1 h^–1. No metal contamination was detected in the product solutions, indicating effective catalyst retention.

中文翻译：

使用改性的CO ₂作为流动相的负载型离子液体催化剂的连续流不对称加氢：从模型底物到活性药物成分

使用固定在负载离子液体相（SILP）中的Rh-Quinaphos催化剂，并使用甲苯（mod CO ₂）改性的超临界CO ₂作为流动相，已经实现了（杂）芳香族酰胺的连续流动不对称氢化。这种方法允许将原始SILP / sc CO ₂系统的范围扩展到在纯CO _2中具有较差溶解度的非易失性底物。SILP催化剂与mod CO ₂结合的潜力在工业案例研究中证明了这一点，该研究使用连续流氢化从阿斯利康的产品组合中合成了活性药物成分（API）的关键中间体。选择甲苯作为最有前途的改性剂，并详细评估了改性剂与CO ₂的比例的影响。发现催化剂载体在保持恒定性能中起主要作用，并且使用疏水性氟反相二氧化硅（FRP-SiO ₂）代替脱羟基二氧化硅大大增强了连续流动操作下的长期稳定性。几乎在90个小时的长时间运行时间内获得了一种对映纯产品（定量单程转化，ee> 99％），以24 g L ^–1 h ^–1的时空产量（STY）达到10300的总周转量。在产物溶液中未检测到金属污染，表明有效的催化剂保留。

更新日期：2018-03-16

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