Authors:Antimo Gioiello, Valentina Mancino, Paolo Filipponi, Serena Mostarda and Bruno Cerra
The integration of flow systems with statistical design of experiments is emerging as a valuable strategy to develop new synthetic routes towards relevant building blocks, chemical probes, and drug compounds. Optimization by experimental design incorporates statistical algorithms, mathematical models and equations, predicting tools, feedback control, and validation to generate new optimal conditions. Continuous-flow chemistry is ideally suited for this scope, as the integration of in-line analysis is simple; experimental parameters such as temperature, pressure, and flow rate can be easily controlled and fine-regulated; and automation of reaction screening can be accomplished with software assistance. This review article aims to illustrate how the combination of flow synthesizers and design of experiments can be profitable to speed up the development and optimization of more efficient, safer, and reproducible protocols for modern synthetic methods and manufacturing processes.
In this work, the synthesis of N,N’-dialkyl-6,6’-dibromoisoindigo derivatives by continuous-flow chemistry is explored as a means to enhance material availability and structural diversity, in particular toward the application of isoindigo-based semiconductors in high-performance organic photovoltaic devices. The individual steps in the conventional batch synthesis protocol are evaluated and, when needed, adapted to flow reactors. To overcome the low solubility of non-alkylated 6,6’-dibromoisoindigo in common organic solvents, the flow condensation reaction between the 6-bromo-isatin and 6-bromo-oxindole precursors is evaluated in polar aprotic solvents. Dialkylation of 6,6’-dibromoisoindigo is readily performed in flow using a solid-phase reactor packed with potassium carbonate. In an alternative strategy, solubility is ensured by first introducing the N-alkyl side chains on 6-bromo-isatin and 6-bromo-oxindole (accessible via a high-yielding flow reduction of alkylated 6-bromo-isatin), followed by condensation using the conventional method in acetic—hydrochloric acid medium. The N,N’-dialkylated 6,6’-dibromoisoindigo derivatives indeed show enhanced solubility in the hot reaction mixture compared to the non-alkylated material but eventually precipitate when the reaction mixture is cooled down. Nevertheless, the condensation between both alkylated starting materials is achieved in flow without any blockages by keeping the outlet from the reactor heated and as short as possible. The latter strategy allows the preparation of both symmetrically and asymmetrically N-substituted isoindigo compounds.
. V. Ley , D. E. Fitzpatrick , R. M. Myers , C. Battilocchio , R. Ingham Angewandte Chemie International Edition 2015 , 54 , 10122 – 10136
“ The synthesis of active pharmaceutical ingredients (APIs) using continuousflow
Authors:Dong-Hyeon Ko, Ki-Won Gyak and Dong-Pyo Kim
system integration and process diversification have greatly enhanced the system performance for continuous-flowchemistry [ 3 ].
Among the microfluidic components, microreaction modules and microseparation units are the major components that can
of continuous-flowchemistry in nearly all aspects of chemical synthesis [ 10 – 12 ]. Adaptation of syntheses of many active pharmaceutical ingredients (APIs) and drugs to continuous flow have also been reviewed extensively and will not be covered in
Authors:Gregory A. Price, Debasis Mallik and Michael G. Organ
continuous-flowchemistry from a cutting-edge research science to an alternative production platform for industrial applications. The objectives can be summarized in 5 steps:
Development of on-line, in-line, and at-line measurement tools to improve
continuous-flowchemistry, inline analytics, and automation technology has shown great potential to gather accurate reaction data [ 36 ]. Such integrated systems allow to reduce the total optimization time and the required amount of material. Recently, Jensen
Authors:Gellért Sipos, Tamás Bihari, Dorottya Milánkovich and Ferenc Darvas
[ 24 ]. If we accept (as we frequently do during the daily work in the laboratory) that extractions are chemical processes, then we can consider the ISSpresso as an archetypal continuous-flowchemistry instrument [ 25 ]. In this, the water is fed into