Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α-Chloroketones,Organic Process Research & Development

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Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α-Chloroketones
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2019-06-21 00:00:00 , DOI: 10.1021/acs.oprd.9b00115
Michaela Wernik _{1,

2} , Peter Poechlauer ₃ , Christoph Schmoelzer ₃ , Doris Dallinger _{1,

2} , C. Oliver Kappe _{1,

2}

Affiliation

The development of a continuous diazomethane generator comprising a continuous stirred tank reactor (CSTR) cascade and membrane separation technology is reported. This reactor concept was applied for the telescoped three-step synthesis of a chiral α-chloroketone, a key building block for many HIV protease inhibitors, via a modified Arndt–Eistert reaction starting from N-protected l-phenylalanine. The initial mixed anhydride was generated in a coil reactor and directly introduced into the CSTR diazomethane cascade. The use of a semipermeable Teflon membrane (AF-2400) allowed the generation of anhydrous diazomethane, which diffuses through the membrane into the CSTR where it is immediately consumed by the anhydride to furnish the corresponding diazoketone. The subsequent halogenation with concentrated HCl was performed downstream in batch and allowed production of the α-chloroketone on a multigram scale, with a productivity of 1.54 g/h (5.2 mmol/h).

中文翻译：

用于膜基重氮甲烷生产的连续搅拌釜反应器级联的设计和优化：α-氯酮的合成

据报道，包括连续搅拌釜反应器（CSTR）级联和膜分离技术的连续重氮甲烷发生器的开发。该反应器概念通过修饰的Arndt-Eistert反应（从受N保护的l开始），用于三步手性α-氯酮的伸缩式三步合成，α-氯酮是许多HIV蛋白酶抑制剂的关键组成部分。-苯丙氨酸。最初的混合酸酐在盘管反应器中生成，并直接引入CSTR重氮甲烷级联反应中。使用半渗透性的Teflon膜（AF-2400）可以产生无水重氮甲烷，该重氮甲烷通过该膜扩散到CSTR中，在CSTR中，酸酐立即将其消耗掉，以提供相应的重氮酮。随后用浓HCl进行的卤化在下游分批进行，并允许以克数生产α-氯酮，生产率为1.54 g / h（5.2 mmol / h）。

更新日期：2019-06-21

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