Yukako Asano

Development of a Microreactor for Synthesis of 18F-Labeled Positron Emission Tomography Probe

Background: The application of microreactors to positron emission tomography (PET) probe radiosynthesis has attracted a great deal of interest because of its potential to increase specific activity and yields of probes and to reduce reaction time, expensive regent consumption, and the footprint of the device/instrument. To develop a microreactor platform that enables the synthesis of various 18F-labeled PET probes, a prototype microreactor with a novel “split-flow and interflow mixing” (split mixing) was fabricated and applied to 18F-labeling reactions.

Optimization of Chemical Reaction Processes in Microreactors Using Reaction Rate Analyses

We applied microreactors to the three following reactions: a consecutive bromination reaction, the two-step Sandmeyer reaction, and an acetylation reaction including solvent effects. We obtained the reaction rate constants from few experimental data or quantum chemical calculations and optimized the reaction conditions such as the reaction times and temperature. We then experimentally validated them by microreactors. A consecutive bromination reaction, where the objective reaction was followed by the side reaction, was one of the processes. The reaction temperature played an important role in the effects of a microreactor. The yield of the objective product was improved by about 40% using a microreactor. The two-step Sandmeyer reaction was also applied, where the 1st-step reaction was followed by the 2nd-step reaction to produce the objective product. The 1st-step reaction had the diffusion-controlled process, while the 2nd-step reaction had the reaction-controlled one. The yield of the objective product was improved when microreactors were used and the reaction time for the 2nd-step reaction was set appropriately. Moreover, an acetylation reaction including solvent effects on reaction rates was considered and the solvent effects could be predicted from quantum chemical calculations. The calculation suggested that acetic acid with the larger electron-accepting property gave more stability to the species formed in the transition state. The reaction time was shortened using a microreactor, when the reaction process was changed from reaction-controlled to diffusion-controlled by changing the solvent used.Copyright

Prediction of Chemical Reaction Yield in a Microreactor and Development of a Pilot Plant Using the Numbering-Up of Microreactors

The chemical reaction yield was predicted by using Monte Carlo simulation. The targeted chemical reaction of a performance evaluation using the microreactor is the consecutive reaction. The main product P1 is formed in the first stage with the reaction rate constant k1. Moreover, the byproduct P2 is formed in the second stage with the reaction rate constant k2. It was found that the yield of main product P1 was improved by using a microreactor when the ratio of the reaction rate constants became k1/k2 >1. To evaluate the Monte Carlo simulation result, the yields of the main products obtained in three consecutive reactions. It was found that the yield of the main product in cased of k1/k2 >1 increased when the microreactor was uesd. Next, a pilot plant involving the numbering-up of 20 microreactors was developed. The 20 microreactor units were stacked in four sets, each containing five microreactor units arranged. The maximum flow rate when 20 microreactors were used was 1 × 104 mm3 /s, which corresponds to 72 t/year. Evaluation of the chemical performance of the pilot plant was conducted using a nitration reaction. The pilot plant was found to capable of increasing the production scale without decreasing the yield of the products.Copyright