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Application of Continuous Flow-Flash Chemistry to Scale-up Synthesis of 5-Cyano-2-formylbenzoic Acid
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2019-05-30 00:00:00 , DOI: 10.1021/acs.oprd.9b00180 Masaki Seto 1 , Shinichi Masada 1 , Hirotsugu Usutani 2 , David G. Cork 2 , Koichiro Fukuda 1 , Tetsuji Kawamoto 1
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2019-05-30 00:00:00 , DOI: 10.1021/acs.oprd.9b00180 Masaki Seto 1 , Shinichi Masada 1 , Hirotsugu Usutani 2 , David G. Cork 2 , Koichiro Fukuda 1 , Tetsuji Kawamoto 1
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Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer 6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1) as a key intermediate for various biologically important compounds has been achieved from isopropyl 2-bromo-5-cyanobenzoate (8c) by means of continuous flow-flash chemistry using flow microreactors. It was found that Br/Li exchange reaction of 8c, bearing both a carboisopropoxy group and a cyano group, with BuLi took place within 0.1 s at −50 °C, and the resulting highly reactive aryllithium intermediate underwent formylation with DMF to afford 1, which is extremely difficult to achieve by a conventional batch process. Optimization of the continuous flow-flash reaction conditions and modification of the reaction system brought about the production of 237 g of 1 from 897 g of 8c in 270 min, without purification by column chromatography. The results suggest that phthalaldehydic acid derivatives bearing electrophilic group(s) can be synthesized conveniently from the corresponding 2-bromobenzoic acid esters by means of flow-flash chemistry using flow microreactors.
中文翻译：
连续流闪化学在放大合成5-氰基-2-甲酰基苯甲酸中的应用
有效地按比例放大合成5-氰基-2-甲酰基苯甲酸或其环状异构体6-氰基-3-羟基-2-苯并呋喃-1（3 H）-一（1）作为各种生物学上重要的化合物的关键中间体通过使用流动微反应器的连续流动闪蒸化学方法，从2-溴-5-氰基苯甲酸异丙酯（8c）中获得了上述化合物。结果发现，在-50℃下，带有碳异丙氧基和氰基的8c与BuLi的Br / Li交换反应在0.1 s内发生，所得高反应性芳基锂中间体与DMF甲酰化，得到1，这是通过常规批处理过程很难实现的。连续流动闪蒸反应条件的优化和反应体系的改进导致在270分钟内从897 g 8c生成237 g 1。结果表明，通过使用流动微反应器的流动闪蒸化学，可以从相应的2-溴苯甲酸酯方便地合成带有亲电基团的邻苯二酸衍生物。
更新日期：2019-05-30
中文翻译：
连续流闪化学在放大合成5-氰基-2-甲酰基苯甲酸中的应用
有效地按比例放大合成5-氰基-2-甲酰基苯甲酸或其环状异构体6-氰基-3-羟基-2-苯并呋喃-1（3 H）-一（1）作为各种生物学上重要的化合物的关键中间体通过使用流动微反应器的连续流动闪蒸化学方法，从2-溴-5-氰基苯甲酸异丙酯（8c）中获得了上述化合物。结果发现，在-50℃下，带有碳异丙氧基和氰基的8c与BuLi的Br / Li交换反应在0.1 s内发生，所得高反应性芳基锂中间体与DMF甲酰化，得到1，这是通过常规批处理过程很难实现的。连续流动闪蒸反应条件的优化和反应体系的改进导致在270分钟内从897 g 8c生成237 g 1。结果表明，通过使用流动微反应器的流动闪蒸化学，可以从相应的2-溴苯甲酸酯方便地合成带有亲电基团的邻苯二酸衍生物。
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