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

Abstract

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.

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

“…[8] In addition, Kawamoto reported the application of the flowflash chemistry principle in the synthesis and scale-up of 5cyano-2-formylbenzoic acid, ak ey intermediate in the pharma industry.Alithiation/formylation sequence on 5-cyano-2-bromobenzoic esters was developed using af low reactorc apable to provide ar esidencet ime of 0.030 s. The process was run at large scale, and the productivity of almost 1gmin À1 represents one of the highest achievementf or using "flash-chemistry" at industriall evel. [9] Remarkably,t he use of microflow technology allowed for generating such functionalized aryllithiums at relatively highert emperature, by high-resolution residence time control.T he use of suitable micromixers allowed for spanning the residence times from seconds to submilliseconds. [10] This residence time transition, has been realized using integrated microflow devices judiciously designed and fabricated for specific tasks.…”

Towards an approach to small-scale aryllithium flash flow chemistry using low-cost, low internal volume reactors.

“…A synthesis in flash flow utilises residence times on the order of seconds, meaning that slower side reactions can often be out-competed by a faster dominant and desired process, provided sufficient in-reactor mixing has been achieved. The flash flow approach has been most successfully applied to the generation of aryllithiums from aryl halides, followed by trapping with an electrophile (Scheme 1) and has facilitated the clean lithiation and trapping of aryl halides that are: liable to aryne formation, [3] which bear esters, [2] nitriles, [4] and even ketones; [5] feats which are difficult if not impossible to achieve using 'in flask' (batch) chemistry.…”

4-Amino-TEMPO-Immobilized Polymer Monolith: Preparations, and Recycling Performance of Catalyst for Alcohol Oxidation

“…In recent years, there has been a great interest in continuous flow technology. Practical and efficient flow reactors have been developed in diverse fields, such as drug discovery, biofunctional substances, petrochemicals, and nanomaterials [ 1 , 2 , 3 , 4 ]. Continuous flow reactions are attracting attention as next-generation chemical processes and are being applied industrially.…”