Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation
Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation
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DOI：
10.1021/acs.oprd.2c00288
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发表时间：
2022-12-14
影响因子：
3.4
通讯作者：
Davies, Huw M. L.
中科院分区：
文献类型：
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作者：
Lathrop, Stephen P.;Mlinar, Laurie B.;Davies, Huw M. L.
我们报道了一种用于安全生成、提取和干燥芳基重氮乙酸酯2的连续流动工艺的开发和演示，该工艺能够直接用于进料批次的由镝催化的对映体选择性环丙烷化反应，以提供环丙烷4。以安全为主要目标设计该工艺，我们确定了合适的芳磺酰肼起始原料和有机可溶性碱，以促进Bamford-Stevens重氮生成流动过程在30摄氏度，远低于热起始温度(起始温度=57摄氏度)，同时也最大限度地减少高能重氮中间体(AHD=-729 J/g)的积累。Bamford-Stevens反应的副产物通过使用液-液疏水膜分离器的连续水萃取有效地去除。有机层的连续分子筛干燥被证明可以保持水位
We report the development and demonstration of a continuous-flow process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction to provide cyclopropane 4. Designing this process with safety as a primary objective, we identified the appropriate arylsulfonyl hydrazone starting material and organic soluble base to facilitate a Bamford-Stevens diazo-generating flow process at 30 degrees C, well below the thermal onset temperature (Tonset = 57 degrees C), while also minimizing accumulation of the highly energetic diazo intermediate (AHD = -729 J/g). The Bamford-Stevens reaction byproducts are efficiently removed via a continuous aqueous extraction utilizing a liquid-liquid hydrophobic membrane separator. Continuous molecular sieve drying of the organic layer was demonstrated to maintain water levels