连续流反应器中的可扩展巴尔茨-席曼反应方案
Summary
提出了一个详细的可扩展连续流动方案，用于通过Balz-Schiemann反应从芳基胺合成芳基氟化物。
Abstract
制药和精细化工行业对芳烃氟化物的需求正在稳步增长。Balz-Schiemann反应是通过制备和转化重氮四氟硼酸盐中间体 ，从 芳基胺制备芳基氟化物的直接策略。然而，在扩大规模时处理芳基重氮盐存在重大安全风险。为了尽量减少危害，我们提出了一种连续流动方案，该方案已在千克尺度上成功执行，该协议消除了芳基重氮盐的分离，同时促进了有效的氟化。重氮化过程在10 °C下进行，停留时间为10 min，然后在60 °C下进行氟化过程，停留时间为5.4 s，收率约为70%。通过引入这种多步连续流动系统，反应时间已大大缩短。
Introduction
Balz−Schiemann反应是一种经典的方法，通过在不使用溶剂1，2的情况下加热ArN2 + BF4−来用氟取代重氮基团。该反应可应用于多种芳基胺底物，使其成为合成芳基胺的普遍适用方法，芳基胺经常用于制药或精细化工行业的高级中间体2，3。不幸的是，巴尔茨-席曼反应中经常采用苛刻的反应条件，并且反应生成具有潜在爆炸性的芳基重氮盐4，5，6，7，8。与Balz-Schiemann反应相关的其他挑战是在热分解过程中形成副产物及其适度的产率。为了尽量减少副产物的形成，可以在非极性溶剂中或使用纯重氮盐9，10进行热脱氮，这意味着芳基二氮盐应被分离。然而，芳香胺的重氮化通常是放热和快速的，这是与分离爆炸性重氮盐相关的风险，特别是在大规模生产中。
近年来，连续流动合成技术有助于克服与Balz-Schiemann反应相关的安全问题11，12。尽管有一些使用连续微反应器在对芳基氯、5-偶氮和氯磺酰化的位置进行脱氨的芳胺重氮化的例子，但这些贡献仅在实验室规模上报告13，14，15，16，17。Yu及其同事开发了一种连续的千克级工艺，用于合成芳基氟化物18。他们已经表明，改善流动系统的传热和传质将有利于重氮化过程和氟化过程。然而，他们使用了两个独立的连续流反应器;因此，分别研究了重氮化和热分解过程。Buchwald及其同事19发表了进一步的贡献，他们提出了一个假设，即如果产物形成通过SN2Ar或SN1机制进行，那么可以通过增加氟化物源的浓度来提高产量。他们开发了一种流动到连续搅拌釜式反应器（CSTR）混合工艺，其中重氮盐以连续和受控的方式产生和消耗。然而，作为管流反应器，连续搅拌罐式反应器的传热和传质效率还不够好，不能指望大型连续搅拌罐式连续搅拌罐与爆炸性重氮盐一起大规模生产。随后，Naber及其同事开发了一种完全连续的流动工艺，从2，6-二氨基嘌呤20合成2-氟腺嘌呤。他们发现放热Balz-Schiemann反应在连续流动方式下更容易控制，并且流动反应器的管道尺寸会影响传热和温度控制方面 – 大尺寸的管式反应器显示出积极的改进。然而，管式反应器的放大效应会显著，极性芳基重氮盐在有机溶剂中的溶解度差，给面临堵塞风险的静态管式反应器带来麻烦。尽管已经取得了显著进展，但大规模巴尔茨-席曼反应仍然存在一些问题。因此，开发一种改进的方案，以提供对芳基氟的快速和可扩展的获取仍然具有重要意义。
与大规模Balz-Schiemann反应处理相关的挑战包括：（i）在短时间内积累的重氮中间体的热不稳定性21;（ii） 处理时间长;（iii）重氮氟硼酸盐中加热不均匀或存在水，导致无法控制的热分解和副产物形成增加22，23。此外（iv）在某些流动处理模式下，由于其低溶解度14，仍然需要分离重氮中间体，然后将其送入不受控制的速率分解反应中。处理大量在线重氮盐的风险是无法避免的。因此，开发连续流动策略以解决上述问题并避免不稳定重氮物种的积累和分离具有显着的好处。
为了在药品中建立本质上更安全的化学品生产，我们集团专注于多步连续流动技术。在这项工作中，我们将这项技术应用于千克级的Balz-Schiemann合成，以消除芳基重氮盐的分离，同时促进有效的氟化。
Protocol
Representative Results
Discussion
Balz-Schiemann反应的连续流动方案已经通过微通道流动反应器和动态混合流动反应器的组合成功执行。与间歇工艺相比，该策略具有以下几个优点：（i）受控重氮盐形成更安全;（ii）它更适合更高的反应温度，10°C与-20°C;（iii）无需隔离重氮中间体即可提高效率，在一个连续过程中分为两步。具体来说，连续流动设备设置过程对于该协议至关重要，因为除了化学转化之外，流动过程的可靠性主要取?…
Offenlegungen
The authors have nothing to disclose.
Acknowledgements
感谢深圳市科技计划（批准号：KQTD20190929172447117）的支持。
Materials
| 2-Methylpyridin-3-amine | Raffles Pharmatech Co. Ltd | C2021236-SM5-H221538-008 | HPLC: >98%, Water by KF ≤0.5% |
| 316L piston constant flow pump | Oushisheng (Beijing) Technology Co.,Ltd | DP-S200 | |
| BF3.Et2O | Whmall.com | B802217 | |
| Citric acid | Titan Technology Co., Ltd | G83162G | |
| con.HCl | Foshang Xilong Huagong | 1270110101601M | |
| Dynamically mixed flow reactor | Autichem Ltd | DM500 | 316L reator with 500 mL of internal volume |
| Heptane | Shenzhen Huachang | HCH606 | Water by KF ≤0.5% |
| Micro flow reactor | Corning Reactor Technology Co.,Ltd | G1 Galss AFR | Glass module with 9 mL of internal volume |
| PTFE piston constant flow pump | Sanotac China | MPF1002C | |
| Sodium hydroxide | Foshang Xilong Huagong | 1010310101700 | |
| tert-Butyl methyl ether | Titan Technology Co., Ltd | 01153694 | |
| tert-Butyl nitrite | Whmall.com | XS22030900060 | |
| Tetrahydrofuran | Titan Technology Co., Ltd | 1152930 | Water by KF ≤0.5% |
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