Process hazards, microreactors

The Chemical Development Drug Evaluation branch of Johnson Johnson Pharmaceutical Research Development LLC in Raritan, USA, investigated the ring-expansion reaction of N-Boc-4-piperidone with ethyl diazoacetate in a microreactor system as an example of processing hazardous substances [34],... 

W-Methyl-A/ -nitroso-p-toluenesulfonamide (MNTS) is an important precursor for the production of diazomethane. Diazomethane is then further converted to a range of useful molecules in the pharmaceutical and fine chemical industry [69]. Production of MNTS is a highly exothermic process and includes the presence of the extremely toxic materials. Stark et al. [70] have explored the application of microreactor technology for the production of this industrially valuable material, assuming that due to the efficient heat exchange and the closed system, microflow conditions provide a safer environment for these hazards. 

Hazardous perfluorination processes with high yields were carried out safely in microreactors, such as the perfluorination of tetrahydrofuran and cyclohexane derivatives [309]. 

Researchers at Johnson and Johnson have reported the use of microreactors in the drug development process. They utilized a commercially available CYTOS benchtop system, shown in Fig. 15, to examine several reactions. One such reaction was the highly exothermic reaction to form A-methoxycarbonyl-L-rert-leucine by the addition of methylchloroformate to L-tert leucine. Such highly exothermic reactions present safety hazards in large-scale systems. Utilizing the CYTOS system, they were able to perform this reaction in the laboratory and achieved 91% yield. ... 

One way of process simplification is to make molecular complex compounds out of much simpler building blocks (e.g., by multi-component one-pot syntheses like the Ugi reaction), at best directly out of the elements. Especially in the latter case, this is often quoted as a dream reaction [14]. Typically, such routes have been realized so far with hazardous elements, easily undergoing reaction, but lacking selectivity. One example is direct fluorination starting with elemental fluorine, which has been performed both with aromatics and aliphatics. Since the heat release cannot be controlled with conventional reactors, the process is deliberately slowed down. While, for this reason, direct fluorination needs hours in a laboratory bubble column it is completed within seconds or even milliseconds when using a miniature bubble column operating close to the kinetic limit. Also, conversions with the volatile and explosive diazomethane, commonly used for methylation, have been conducted safely with microreactors in a continuous mode [14]. 

In recent years, the main focus of the patents has shifted from the development of novel microstructured device to the well-defined application of the device to proper reaction process. Homogeneous liquid reactions are occupying a large part of patents. The main improvement of these patents is to achieve the faster reaction in microreactor than batch reactor or to conduct the reaction with hazardous chemicals without human exposure. Microreactors also can be applied to multiphase and gas-phase reactions. Recently, the carbonylation reaction using carbon monoxide in microreactor has been reported [15]. The polymerization process can be also controlled with microreactors. The microreactor leads to the concise synthesis of polymers with a narrow molecular weight distribution. 

In this chapter, the microstructured devices are introduced underlying their potential benefits for the process industries. The reduced scale facilitates the temperature control giving an opportunity to maintain the temperature within any window required. Enhanced (heat/mass) transfer rates allow control of highly exothermic and hazardous reactions. It also increases production rates and thus reduces the total processing volume. In addition, microreactors can be simply numbered up for large-scale production, avoiding the problem of scale-up of conventional reactors. 

When handling strong exothermic processes or hazardous substances, safety issues also became a major driver for the use of microreactors. Finally, several academic studies can be found in the literature focusing on the analysis of mass transport and flow characteristics within microfluidic charmels by using electrophilic aromatic substitutions as model reactions. 

A particular challenge in azo couplings is the hazardous potential of diazonium salts, which tend to undergo abrupt decomposition or even explosion when exposed to light, heat or mechanical impact. Therefore, a major driver for using microreactors is to ensure safe processing of potentially hazardous azo couplings. 

Perfluorination of tetrahydrofuran and cyclohexane derivatives can be achieved to give the perfluorinated product in high yield (Scheme 8.6). These hazardous perfluorination processes can be carried out safely in single-channel microreactors with high yields. 

Some of the DSM products have been produced in campaigns for many years and therefore need a limited amount of special equipment. These products are often characterized by hazardous chemistry. A few years ago, microreactors were evaluated for such a manufacturing process in the DSM fine chemical plant at Linz. 

One of the main aspects of modem chemistry is the safety of the chemical processes. It is easy to see that the volume of a batch reactor must be some orders of magnitude higher than that of the continuous-flow microreactor to reach the identical quantity of final products (using equal amounts of reactants). The small quantity of reactants in the reactor minimizes the potential of thermal explosion by dangerous reactions. Indeed, explosion or depressurization of reaction systems with hazardous substances in the continuous microreactors leads only to insignificant technical problems or to a minimum leakage of chemicals, as opposed to the scales of explosions or leaks in standard reactor volumes. Microreactors, with their narrow channel dimensions, hold such a small quantity of reaction fluid that a mechanical failure in one reactor requires merely a temporary shutdown and subsequent replacement. 

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