Reaction Scale-up

The conversion of 2 to 3 was optimized at full scale in the VRT reactor. In addition to confirming the productivity, safety, product quality, and economic benefit of the process, the robustness of the process was also demonstrated. Finally, this pilot study provided the basis for a full-scale commercial manufacturing design specification. Having fixed the optimum residence time, the process was then transferred into a plant Fixed Residence Time (FRT) cyanation reactor which employed a fixed length of jacketed static mixer for commercial manufacture. This FRT was capable of producing 300 metric tonnes per year of 3, with the same purified step yield of 80% that was achieved in the laboratory capillary reactor. 

3) Micro-mixer Tees from Swagelock were used to connect the various feeds to a coil of 254gm stainless steel HPLC capillary tubing immersed in a Huber oil bath. 

4) VRT technology is a patented Phoenix technology (WO 2004103551) that is being 

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Only a little effort is necessary to reduce solvent 1 demand used during reaction scale-up. The quantity used in the laboratory stage was reduced to 59% in the operation stage (Table 5.1). However, related to substrate 2, 96% of solvent 1 is still used. Thus, 87% of the original quantity of solvent will be fed to the incinerator for disposal, while the recycle rate is only 9.1% (from 96% to 87%, Table 5.1). Considering that there is a factor of five difference in solvent 1 demand between the operation scale and the literature procedure (see the segments Solvent of the mass index, in Figure 5.10), the potential for optimiz-... 

Reaction scale-up using the Voyager system in genuine continuous-flow format is achieved by the use of special coiled flow-through cells. The reaction coils are made of glass or Teflon (Fig. 3.24) with a maximum flow rate of 20 mL min-1 and operational limits of 250 °C or 17 bar. The continuous-flow format should only be used for homogeneous solution-phase chemistry, as slurried mixtures may cause prob-... 

In the case of exothermic or endothermic reactions, scale-up may impair conditions for heat input or removal because the ratio of the heat transfer surface area to the reactor volume is reduced. Identical conditions for heat transfer in both the model and full-scale plants may be achieved in exothermal reactions if both have the same thermal stability coefficient. This requirement is obtained by introducing external heat exchangers. Alternatively, a reactor with a strong exothermic reaction can be divided into several small size reactors. In this manner, the ratio of the external heat transfer surface area to the reactor volume is increased, thereby avoiding an excessive temperature rise in the reactor. 

Another description of large scale analysis come from AstraZeneca in a study directed towards the synthesis of a neurokinin inhibitor of the central nervous system [100]. The synthesis inherited from the research stage already contained a Newman-Kwart rearrangement for the introduction of the sulfur atom (Scheme 40). This step was maintained in the reaction scale-up [101,102]. 

Finally, if a solid is generated during a reaction, scale-up is far from easy. One... 

Sasaki K, Wang JX, Naohara H, Marinkovic N, More K, Inada H, Adzic RR (2010) Recent advances in platinum monolayer electrocatalysts for the oxygen reduction reaction scale-up synthesis, structure and activity of Pt shells on Pd cores. Electrochim Acta 55 2645-2652... 

Synthetic highlights The initial step in the synthetic pathway to efavirenz involves the asymmetric addition of an alkyne anion to the ketone C=0 bond. The generation of chiral Li" aggregates elegantly determines the stereoselectivity of the reaction. Scale-up of aUcynylation is promoted by the use of EtaZn as a weak Lewis acid. 

Liquid-liquid complex reactions have been classified as one of the most difficult—if not the most difficult—reaction scale-up mixing problem (Leng, 1997). The complexities of drop formation and coalescence both change with scale. They both depend on the location in a vessel and on very subtle changes in the composition of the fluids. These variations can cause problems like Bill s when a complex reaction occurs between reagents in separate liquid phases. 

A year later, Sergio Bacchi et al. reported a safe and reliable synthesis of aryl 1,2,3-triazoles 35 from the corresponding anilines 34 via intermediate aryl azides 2, using a continuous-flow process (Scheme 4.11) [14]. The method was applied to a variety of substrates with good to excellent yields, without the need to isolate the reactive and possibly unstable intermediates, which were constantly kept at low concentration in the matrix environment. The tight control of the reaction variables combined with the advantages offered by the continuous-flow application for the reaction scale-up made this process an undoubtedly synthetic utility. 

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