The Continuous-Flow Synthesis of Ibuprofen
The Continuous-Flow Synthesis of Ibuprofen
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DOI：
10.1002/anie.200903055
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
McQuade, D. Tyler
中科院分区：
文献类型：
--
作者：
Bogdan, Andrew R.;Poe, Sarah L.;McQuade, D. Tyler
有机合成是一个强大的企业，不断开发更具选择性和高效的化学方法和合成路线。为了合成复杂的分子，无论是在学术实验室还是工业生产中，反应通常在间歇反应器中迭代进行。虽然这些逐步的方法是有效的，但它们也是非常浪费的。例如，制药工业每合成一公斤复杂分子就会产生25-100公斤废物。[1]尽管化学家们一直在努力设计更有效的合成方法，但最近对资源有限的世界的提醒强调了对更可持续的方法和技术的需求，以合成重要分子。[2]微反应器等新技术在有机合成中的应用可以实现这一目标。[3-13]微反应器是一种发展中的技术，用于在微通道或窄孔管道中进行更安全，更有效，更有选择性的化学转化。[3-19]与在流动中进行反应相关的许多优点归因于大的表面积与体积比[5]，其允许通过快速传热和混合进行精确的反应控制。[20-23]合成可以通过运行单个反应器延长时间[24]或通过并联添加更多相同的流动反应器来扩大规模，该过程称为编号。[25-27]尽管微型反应器在有机合成中的大多数应用都集中在单步反应上，[3-19]但最近的例子已经展示了流动中的多步反应序列。[20我们的团队长期以来一直对开发能够快速有效合成重要小分子的新方法感兴趣。[33-36]具体来说，我们的目标是在一锅（即在间歇反应器中）[35，36]或串联（即在微反应器中）中运行多步反应序列。[33本文报道了一种三步连续流合成布洛芬的方法，布洛芬是一种高容量的非甾体抗炎药（NSAID），使用简化的微-
Organic synthesis is a powerful enterprise that continues to develop more selective and efficient chemical methods and synthetic routes. To synthesize complex molecules, whether in academic laboratories or industrial manufacturing, reactions are often performed iteratively in batch reactors. Although these stepwise methods are effective, they are also very wasteful. The pharmaceutical industry, for example, produces 25–100 kg of waste for every kilogram of a complex molecule synthesized.[1] Though chemists are constantly striving to devise more efficient syntheses, recent reminders of a resource-limited world underscore the need for more sustainable methods and technologies to synthesize molecules of importance.[2] The application of new technologies, such as microreactors, to organic synthesis can be used to achieve this goal.[3–13]Microreactors are a developing technology used to perform safer, more efficient, and more selective chemical transformations in microchannels or narrow-bore tubing.[3–19] The many advantages associated with conducting reactions in flow are attributed to large surface-area-to-volume ratios [5] that allow precise reaction control through rapid heat transfer and mixing.[20–23] The syntheses can be scaled up by running a single reactor for extended periods of time [24] or by the addition of more identical flow reactors in parallel, a process known as numbering up.[25–27] Although most applications of microreactors in organic synthesis have focused on single-step reactions,[3–19] recent examples have demonstrated multistep reaction sequences in flow.[20, 28–32] Our group has a long-standing interest in the development of new methodologies that enable the rapid and efficient synthesis of important small molecules.[33–36] Specifically, we have aimed to run multistep reaction sequences in one pot (ie in batch reactors)[35, 36] or in series (ie in microreactors).[33, 34] We report herein a three-step, continuous-flow synthesis of ibuprofen, a high-volume, nonsteroidal anti-inflammatory drug (NSAID), using a simplified micro-