The National Institute of Advanced Industrial Science and Technology (AIST, President: Hiroyuki Yoshikawa) and Osaka Organic Chemical Industry Ltd. (CEO: Yasumasa Shizume) have jointly developed a multistage-collision type microreactor which can effectively produce intermediates of curative medicines.

This microreactor has many micro-channels of 200 µm in width and depth, in which reaction solutions can undergo multistage collisions with one another. Thus, the microreactor enables the reaction solutions to be sufficiently mixed and to complete chemical reactions. Moreover, the microreactor enables reactions which had only been below –70°C to be at -30°C, thereby reducing the cooling cost and the environmental load.

In fact, using isobutyl aluminum hydride, we have succeeded in the rapid, highly selective, low environmental load production of various kinds of aldehydes as intermediate materials for curative medicines from various kinds of esters.

This technique uses a flow-system for chemical reactions, instead of reaction vessels (flasks), and this new tool is expected to greatly cut the lead-time from research and development to production in the synthesis of curative intermediates and materials for electronics, which need a fine control of chemical reactions.

Details of this work were presented at "The Fourth International Workshop on Micro Chemical Plants" held at Kyoto from January 26 to 27, 2006.

Generally, batch reactors are used in various fields to synthesize chemical products, where solution reactions are executed in vessels (flasks) with mechanical mixing. However, the reactors take a long lead time from research development to production, because in order to scale up, reaction vessels must be decided according to volumes necessary, and then the investigation for optimizing reaction conditions must be done for each vessel.

On the other hand, compared to the batch production systems, the microreactor technique, which drives chemical reactions in a flow system consisting of microchannels of several hundreds µm in width made by a micro fabrication technique, has the following advantages.

1. Thermal control, such as heating and cooling, for reactions is easy, because the reaction device is small.
2. By controlling solution flow in the microchannels, the solution mixing effect can be more highly enhanced than that of batch reactors.
3. The production amount can be arbitrarily controlled by varying the flow velocity of solutions in the microchannels.

The microreactor techniques have been expected to be a new tool to shorten the lead-time in medical intermediate production industries which need precise control of chemical reactions, and in the electronic material industries where highly functional materials are always required to supply in short lifecycles.

At present, environmental consciousness is increasing globally, and low waste production processes have been desired in the chemical industries. However, in the medical intermediate and electronic material industries, where conventional production processes based on mass-production and mass-consumption are used, it is very difficult to precisely control chemical reactions, and to manage both rapid research-development-production and environmental load reduction.

 

To realize a sustainable developed society, AIST has carried out research and development aiming at the minimization of discharge of harmful substances, the enhancement of energy efficiency, and the transformation of raw materials into recycling resources.

For this purpose, AIST and Osaka Organic Chemical Industry have jointly carried out the development of a microreactor which is most suitable for synthesizing medical intermediates, and worked on the synthesis of aldehydes, which are useful as medical intermediates, using the microreactor.

In synthetic chemistry, aldehydes are very useful intermediates which can be derived into various kinds of chemicals, and are one of the intermediate materials usable for medical and agricultural chemicals and electronic materials. As the synthesis method of aldehydes, the reduction  of esters with isobutyl aluminum hydride (DIBAL-H) is considered preferable from the standpoint of material cost and atom economy which is utilization efficiency for small amount of wastes. However, for the DIBAL-H reduction reaction, if the reaction temperature is high, the produced aldehydes will over react with DIBAL-H to produce alcohol. Thus, the reaction process must be carried out at low temperatures below -70°C, but hardly executed industrially, because a low temperature reaction in large reaction vessels (butch reactors) means high cooling costs. So, the development of reagents which are alternatives to DIBAL-H has been advanced, and as a result, methods which enable the reduction reaction near room temperature have been developed. However, problems occur regarding atom utilization efficiency and waste water treatment.

The microreactor we have developed has such a special structure consisting of many micro channels 200 µm in width and depth made by grooving an aluminum substrate, such that the injected fluids therein can undergo multistage collisions. Fluids (DIBAL-H and ester) injected separately from two different inlets can react with high selectivity by multistage collisions, and resultantly, the aimed for aldehyde flows out from the outlet. Furthermore, the microreactor enables DIBAL-H reduction reaction of esters with high selectivity and high reproducibility even at -30°C, which until now had had to be below -70°C. Thus, our microreactor can be considered to be a next-generation chemical process technique which may contribute to energy saving followed by a reduction in cooling cost and environmental load.

A part  of this study was carried out for the grant program "Development of a Flow Micromixer for Coordination Polymerization" (fiscal years of 2002-2004) in the "Microchemical Technology for Production, Analysis and Measurement Systems" project of the New Energy and Industrial Technology Development Organization (NEDO).