Pressure-driven microreactor

The Novartis Institute for BioMedical Research in Basel, Switzerland, and the University of Hull, UK, performed the diastereoselective alkylation of metal-stabilized enolates using a pressure-driven microreactor at — 100°C, whereby increased conversions and diastereoselectivity were observed compared to the batch process [20]. 

Later, de Mello and coworkers described the two-step syntheses of three different azo dyes in a pressure-driven microreactor made of glass 39]. They integrated both reaction steps (generation of the diazonium salt and its subsequent in situ reaction to the azo dyes) into one microfluidic reactor design. The diazonium salt was synthesized by the reaction of an arylamine with sodium nitrite in aqueous DMF. After passing a residence time microchannel to allow complete conversion, the dissolved diazonium salt was mixed with a basic solution of P-naphthol to form the corresponding azo dye with yields up to 52% (Scheme 4.19). 

Another demonstration of a continuous flow operation is the psi-shaped microreactor that was used for lipase-catalyzed synthesis of isoamyl acetate in the 1-butyl-3-methylpyridinium dicyanamide/n-heptane two-phase system [144]. The chosen solvent system with dissolved Candida antarctica lipase B, which was attached to the ionic liquid/n-heptane interfacial area because of its amphiphilic properties, was shown to be highly efficient and enabled simultaneous esterification and product removal. The system allowed for simultaneous esterification and product recovery showed a threefold reaction rate increase when compared to the conventional batch. This was mainly a consequence of efficient reaction-diffusion dynamics in the microchannel system, where the developed flow pattern comprising intense emulsification provided a large interfacial area for the reaction and simultaneous product extraction. Another lipase-catalyzed isoamyl acetate synthesis in a continuously operated pressure-driven microreactor was reported by the same authors [145]. The esterification of isoamyl alcohol and acetic acid occurred at the interface between n-hexane and an aqueous phase with dissolved lipase B from Candida antarctica. Controlling flow rates of both phases reestablished a parallel laminar flow with liquid-liquid boundary in the middle of the microchannel and a separation of phases was achieved at the y-shaped exit of the microreactor (Figure 10.25). The microreactor approach demonstrated 35% conversion at residence time 36.5 s at 45 °C and at 0.5 M acetic acid and isoamyl alcohol inlet concentrations and has proven more effective and outperformed the batch operation, which could be attributed to the favorable mass and heat transfer characteristics. 

The swelling of polymeric supports in organic solvents is another major drawback of these catalysts. This may cause pressure drop along the microchannel, resulting in variations in the residence time for pressure-driven microreactors. This problem can be overcome using electroosmotic flow [39], but the latter is limited to polar solvents. 

An important advantage of the use of EOF to pump liquids in a micro-channel network is that the velocity over the microchannel cross section is constant, in contrast to pressure-driven (Poisseuille) flow, which exhibits a parabolic velocity profile. EOF-based microreactors therefore are nearly ideal plug-flow reactors, with corresponding narrow residence time distribution, which improves reaction selectivity. 

Compared with the above examples, whereby an array of pharmaceutically important molecules have been synthesized under pressure-driven flow, Garcia-Egido et al. (2002) reported the synthesis of fanetizole (207), an active compound for the treatment of rheumatoid arthritis, utilizing EOF. Employing a borosilicate glass microreactor fabricated at The University of Hull, the authors demonstrated the first example of a heated EOF-controlled reaction. As Scheme 60 illustrates, using... 

Table 3.1 A selection of the results obtained for the acylation of aliphatic amines in a metal microreactor (under pressure-driven flow).

Figure 11 Graphical illustration of a digital dual-core microreactor (DCM). The operation of the circuit was computer controlled using color-coded pressure-driven valves red, positive pressure, off/on yellow, peristaltic pumping green, vacuum.

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