A Continuous Process for Buchwald-Hartwig Amination at Micro-, Lab-, and Mesoscale Using a Novel Reactor Concept
A Continuous Process for Buchwald-Hartwig Amination at Micro-, Lab-, and Mesoscale Using a Novel Reactor Concept
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DOI：
10.1021/acs.oprd.5b00350
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发表时间：
2016-02-01
影响因子：
3.4
通讯作者：
Meadows, Rebecca E.
中科院分区：
文献类型：
--
作者：
Falss, Sebastian;Tomaiuolo, Giovanna;Meadows, Rebecca E.
以N-杂环卡宾[Pd（IPr*）（cin）Cl] 4为催化剂，通过连续Buchwald Hartwig反应合成了一种重要的药物中间体2。利用微反技术，可以在稀相条件下，以低的物料负荷和动力学参数的调查，优化反应。对于较大的实验室规模操作（克规模），可采用工艺相关浓度，并有效证明了连续后处理的条件（同时发布的批方法）。NHC催化剂的稳定性允许产物的连续酸萃取和催化剂在有机相中的在线再循环。在该规模下，采用超声处理以防止反应器单元中的堵塞。最后，一个定制的连续流动反应器已被开发用于进行超过实验室规模的反应。这种用于在流动中运行多相反应的新型反应器概念将连续搅拌釜式反应器（CSTR）的灵活性与常规流动反应器的平稳操作、低停留时间分布和优异的传热能力相结合。LCA（生命周期分析）的研究已经进行了比较，与现有的批处理协议，显示它是有利的，在大多数环境因素的考虑。
A continuous Buchwald Hartwig reaction using the bulky N-heterocyclic carbene (NHC) precatalyst [Pd(IPr*)(cin)Cl] 4 has been developed for the synthesis of a key pharmaceutical intermediate 2. Using microreactor technology, the reaction could be optimized under dilute conditions with low material burden and the kinetic parameters investigated. For larger lab-scale operation (gram scale), process-relevant concentrations could be employed and the conditions developed for continuous workup effectively demonstrated (batch methodology published concurrently). The stability of the NHC catalyst allowed for a continuous acidic extraction of the product and on-stream recycling of the catalyst in the organic phase. At this scale, sonication is employed to prevent clogging in the reactor unit. Finally, a bespoke continuous flow reactor has been developed for carrying out the reaction beyond lab scale. This novel reactor concept for running heterogeneous reactions in flow combines the flexibility of continuously stirred tank reactors (CSTRs) with the smooth operation, low residence time distribution and excellent heat transfer capability of a conventional flow reactor. A LCA (life cycle analysis) study has been carried out on the resulting process in comparison with the existing batch protocol, revealing it to be favorable under the majority of environmental factors considered.