Packed-Bed Reactors for Continuous-Flow C-N Cross-Coupling
Packed-Bed Reactors for Continuous-Flow C-N Cross-Coupling
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DOI：
10.1002/anie.201004425
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Buchwald, Stephen L.
中科院分区：
文献类型：
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作者：
Naber, John R.;Buchwald, Stephen L.
连续流技术已经在石化行业中大规模牢固地建立起来，随着精益制造的不断推进，它正成为制药行业许多公司的关注点。[1, 2] 分离中间体数量的减少、资本设备占地面积的减少以及对生产线更好的控制是这些方法的一些主要优势。使用具有小通道的微流体系统可以为均相反应提供快速混合和有效的传质。然而，与间歇反应的情况一样，混合和传质是涉及多相（液/液或液/气）的流动反应中的主要问题。由于这些问题，对药物制备至关重要的大量反应需要进行重大修改才能在流程中运行，并且需要实用的方法来克服这些障碍。 [3]微流体在这一研究领域具有相当大的应用，因为无需大量试剂和溶剂即可进行大量反应的能力对于实验室规模的研究来说是理想的。进行大量反应的能力可以彻底优化反应条件，还可以研究反应动力学，以帮助从实验室规模向生产规模的过渡。 [4]芳基卤化物的钯催化胺化反应是制药工业中广泛使用的转化，[5]因此在流程中进行该反应的通用方法[6]将极大地有助于活性药物成分（API）的流程合成的发展。然而，虽然大量研究致力于开发高活性催化剂系统，以促进各种芳基亲电子试剂与许多胺亲核试剂的偶联，但这些方法中的绝大多数涉及不溶性无机碱和/或形成不溶性盐副产物。 [7]此外，在这些反应中使用可溶性有机碱的尝试取得了有限的成功。[8]我们假设具有有机溶剂和水的双相系统可以溶解这些反应的有机和无机组分，并且可能是流动中形成固体的通用解决方案。[9, 10]使用氢氧化物碱的双相胺化反应，
Continuous-flow technology, already firmly establishd on very large scale in the petrochemical industry, is becoming a point of emphasis for many companies in the pharmaceutical industry as the push for lean manufacturing intensifies.[1, 2] The decrease in the number of isolated intermediates, the reduction of the capital equipment footprint, and better control over the production line are some of the key benefits of these methods. The use of microfluidic systems with small channels can provide fast mixing and efficient mass transfer for homogeneous reactions. However, as is the case in batch reactions, mixing and mass transfer are major issues in flow reactions involving multiple phases (liquid/liquid or liquid/gas). As a result of these issues, a large number of reactions that are vital to the preparation of pharmaceuticals require significant modification to be run in flow, and practical methods are required to overcome these obstacles.[3] Microfluidics have found considerable application in this area of research, as the ability to perform a large number of reactions without the need for a large amount of reagents and solvents is desirable for research on a laboratory scale. The ability to perform a large number of reactions allows for thorough optimization of the reaction conditions and can also allow for studies of the reaction kinetics to aid in the transition from laboratory scale to production scale.[4] The palladium-catalyzed amination reaction of aryl halides is a widely utilized transformation in the pharmaceutical industry,[5] and thus a general method for performing this reaction in flow [6] would greatly aid in the development of flow syntheses of active pharmaceutical ingredients (APIs). However, while a great deal of research has been devoted to the development of highly active catalyst systems that can facilitate the coupling of a wide range of aryl electrophiles with a host of amine nucleophiles, the vast majority of these methods involve insoluble inorganic bases and/or form insoluble salt by-products.[7] Moreover, attempts to use soluble organic bases in these reactions have seen limited success.[8]We postulated that a biphasic system with an organic solvent and water could solubilize both the organic and inorganic components of these reactions and could be a general solution to the formation of solids in flow.[9, 10] Biphasic amination reactions that employ hydroxide bases,