Optimization continuous microreactor

Application of On-line Raman Spectroscopy to Characterize and Optimize a Continuous Microreactor... 

As approaches to high-throughput experimentation, process intensification and process optimization continue to develop and show value to the researcher, then the engineer or the analytical chemist will be under increased pressure to use microanalysis tools. This will be to evaluate the operations of the microreactors (such as diagnostics of the microchaimels and composition of the reactor). The results of these applications will be seen in distributed manufacturing approaches and number-up versus scale-up of processes. These successes in engineering will also increase the demand for the effective use of microanalytical instrumentation. 

Struempel M, Ondruschka B, Stark A (2009) Continuous production of the diazomethane precursor N-methyl-N-nitroso-p-toluenesulfonamide batch optimization and transfer into a microreactor setup. Org Process Res Dev 13(5) 1014—1021... 

In order to increase the efficiency of biocatalytic transformations conducted under continuous flow conditions, Honda et al. (2006, 2007) reported an integrated microfluidic system, consisting of an immobilized enzymatic microreactor and an in-line liquid-liquid extraction device, capable of achieving the optical resolution of racemic amino acids under continuous flow whilst enabling efficient recycle of the enzyme. As Scheme 42 illustrates, the first step of the optical resolution was an enzyme-catalyzed enantioselective hydrolysis of a racemic mixture of acetyl-D,L-phenylalanine to afford L-phenylalanine 157 (99.2-99.9% ee) and unreacted acetyl-D-phenylalanine 158. Acidification of the reaction products, prior to the addition of EtOAc, enabled efficient continuous extraction of L-phenylalanine 157 into the aqueous stream, whilst acetyl-D-phenylalanine 158 remained in the organic fraction (84—92% efficiency). Employing the optimal reaction conditions of 0.5 gl min 1 for the enzymatic reaction and 2.0 gl min-1 for the liquid-liquid extraction, the authors were able to resolve 240 nmol h-1 of the racemate. 

The optimal contact between two immiscible solvents (MTBE/H2O) in the microreactor set-up resulted in a high initial reaction rate and enantio-selectivity, comparable to the batch process in which optimized conditions were only obtained under vigorous stirring (2008CEJS89). In-line work-up of the cyanohydrin 6 was achieved via a membrane-based phase separation, allowing the continuation of the two-step reaction approach toward the protected mandelonitrile 7, while both steps have incompatible reaction conditions (2015OBC1634). 

The group of Ley employed a sequence of flow-based microreactors with integrated sohd-supported reagents and an in-line ReactIR flow cell to design, optimize, and develop a continuous flow synthesis of a heterocy-chc benzamide 74 (Scheme 19). N,N-Diethyl-4-(3-fluorophenylpiperdin-4-yhdenemethyl)benzamide 74 was hence synthesized from the ester 72 and l-Boc-4-piperidone 73. The in-line IR device was used to detect the desired signal and hence to synchronize pumping of a late input stream to match with the reactive components (2010SL505). 

Most of these substitution reactions have already been investigated in microstruc-tured reactors, some of them more intensively than others. Researchers were in particular interested in finding routes to process optimization and process intensification compared with macroscopic processes by making use of the improved heat and mass transfer characteristic of microstmctured reactors. In this context, microreactors turned out to be efficient tools for systematic and fast parameter screenings under conditions of continuous processing, consuming only small amounts of chemicals. 

To test the viability of the method for such applications, 12 hydrolytic enzymes were investigated with two automated multiple enzyme analysis systems [46]. Hydrolases in continuous-flow systems were successfully appHed to determine glycogen without interference from free glucose [47] and for the determination of total serum cholesterol [48]. Microreactor technology combined with a hydrolase-based enzymatic method was applied for high-throughput optimization of the HCN addition to aldehydes by enantioselective Lewis acid/Lewis base catalysis [49]. 

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