A general outlook of the changing face of chemical synthesis is provided in this article through recent applications of continuous flow processing in both industry and academia.
SummaryIn this paper, a micro-fluidic optimized process for the continuous flow synthesis of azo compounds is presented. The continuous flow synthesis of Sudan II azo dye was used as a model reaction for the study. At found optimal azo coupling reaction temperature and pH an investigation of the optimum flow rates of the reactants for the diazotization and azo coupling reactions in Little Things Factory-MS microreactors was performed. A conversion of 98% was achieved in approximately 2.4 minutes and a small library of azo compounds was thus generated under these reaction conditions from couplers with aminated or hydroxylated aromatic systems. The scaled up synthesis of these compounds in PTFE tubing (i.d. 1.5 mm) was also investigated, where good reaction conversions ranging between 66–91% were attained.
Herein, we illustrate how microreactor technology can be used as a tool for reaction screening and optimization, in addition to improving the reaction chemistry. We report the in-situ generation of azo compounds by reactive quenching of diazonium intermediates in microreactors. This involves an electrophilic aromatic substitution reaction, namely, an azo-coupling reaction performed in continuous-flow systems in the presence of a phase transfer catalyst with great emphasis on compounds that do not easily couple. Capitalizing on the benefits of a large surface area and the short molecular diffusion distances observed in microreactors, in-situ phase transfer catalyzed azo-coupling reaction of diphenylamine to p-nitroaniline was investigated. A rapid and easy optimization protocol was established which yielded a 99%, 22%, and 33% conversion of diphenylamine, carbazole, and triphenylamine, respectively, in approximately 2.4 min.
Herein, we demonstrate an elegant multistep continuous flow synthesis for stavudine (d4T), a potent nucleoside chemotherapeutic agent for human immunodeficiency virus, acquired immunodeficiency syndrome (AIDS) and AIDS-related conditions. This was accomplished via six chemical transformations in five sequential continuous flow reactors from an affordable starting material, 5-methyluridine. In the first instance, single step continuous flow synthesis was demonstrated with an average of 97% yield, 21.4 g/h throughput per step, and a total of 15.5 min residence time. Finally, multistep continuous flow synthesis of d4T in 87% total yield with a total residence time of 19.9 min and 117 mg/h throughput without intermediate purification was demonstrated.
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