Application of Continuous Flow-Flash Chemistry to Scale-up Synthesis of 5-Cyano-2-formylbenzoic Acid

被引：6
|
作者：
Seto, Masaki [1 ]
Masada, Shinichi [1 ]
Usutani, Hirotsugu [2 ,4 ]
Cork, David G. [2 ,5 ]
Fukuda, Koichiro [1 ,3 ]
Kawamoto, Tetsuji [1 ,3 ]
机构：
[1] Takeda Pharmaceut Co Ltd, Neurosci Drug Discovery Unit, Res, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan
[2] Takeda Pharmaceut Co Ltd, Proc Chem, Pharmaceut Sci, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan
[3] Axcelead Drug Discovery Partners Inc, Chem Res Div, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2510012, Japan
[4] Kyoto Univ, Kyoto Univ Original Co Ltd, Sakyo Ku, Kyoto 6068501, Japan
[5] 2-4-56 Ueno Higashi, Toyonaka, Osaka 5600013, Japan
来源：
ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2019年 / 23卷 / 07期
关键词：
flow synthesis; flash chemistry; flow microreactor; 5-cyano-2-formylbenzoic acid; alkoxycarbonyl group; cyano group; ISOINDOLINONES; RESOLUTION; THIQS;
D O I：
10.1021/acs.oprd.9b00180
中图分类号：
O69 [应用化学];
学科分类号：
081704 ;
摘要：
Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer 6-cyano-3-hydroxy-2-benzofuran1(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 degrees 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.
引用
收藏
页码：1420 / 1428
页数：9
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