乙酰苯胺在双温区碳化硅微通道反应器中的氯磺化反应及柳氮磺胺吡啶的合成

Chlorosulfonation of Acetanilide in a Dual-Temperature-Zone Silicon Carbide Microchannel Reactor and Synthesis of Sulfasalazine

采用具有高传热系数和强耐腐蚀性的双温区碳化硅微通道反应器,在10 min内实现了乙酰苯胺的氯磺化反应,对乙酰氨基苯磺酰氯的产率高达96%,中试生产的产率为92%.该反应的第一阶段采用较低温度(40℃),有利于生成对位磺化产物对乙酰氨基苯磺酸;第二阶段采用较高温度(100℃),加速了对乙酰氨基苯磺酰氯的生成.为了考察这一反应体系的实用性,将其应用于抗菌消炎药柳氮磺胺吡啶的合成,通过氯磺化、氨化、碱性水解、重氮化和偶联等五步反应,以75%的总产率获得目标产物.两步连续反应不仅解决了对乙酰氨基苯磺酰氯合成过程中釜式反应器存在的反应温度低导致的反应慢、温度高又难以控制反应并伴有副产物生成的问题,也避免了反应过程中因大量放热而产生的安全隐患,还减少了间歇生产过程中使用大过量的氯磺酸引发的环境污染.以上研究为对乙酰氨基苯磺酰氯及其磺胺类药物的工业化大规模生产提供了技术支持.

Chlorosulfonation of acetanilide was accomplished within 10 min in up to 96%yield via a highly thermoconductive and corrosion-resistant dual-temperature-zone silicon carbide microchannel reactor.The yield of pilot production was up to 92%.In the first stage,low reaction temperature(40℃)was employed to effect a high sulfonation selectivity at the para position of acetanilide.In the second stage,a higher reaction temperature(100℃)led to a faster formation of chlorosulfonation product.To illustrate the application of this reaction,sulfasalazine with antimicrobial and anti-inflammatory activities was synthesized in total yield of 75%via chlorosulfonation,sulfamide formation,hydrolysis under base conditions,diazotization and coupling with salicylic acid.The two-step continuous reaction helped to solve the problems in batch reactor,such as low temperature leading to slow reaction and high temperature resulting byproducts and/or temperature runaway,the safety concern aroused by heat accumulation,and the polution caused by the use of large excess of chlorosulfonic acid in batch production.The above research provides technical support for the large-scale industrial production of p-acetylaminobenzenesulfonyl chloride and its sulfonamides.