A research group at the University of Tokyo has succeeded in continuously synthesizing the anti-Alzheimer's drug memantine using a continuous flow reaction.

 Small molecule drugs remain in high demand due to their relatively low manufacturing costs and ease of mass production. However, in Japan, where many of the main ingredients of small molecule drugs are produced overseas, it is not easy to achieve a stable supply through domestic production.

 In this context, in order to maximize production efficiency, it is useful to use a continuous production method called "continuous flow molecular transformation," in which raw materials and additives are fed into one side of a reactor while simultaneously removing the product from the other side of the reactor. In this study, we focused on the synthesis of the basic structure of the anti-Alzheimer's drug "memantine hydrochloride," which has a unique diamond structure called "adamantane," and achieved continuous synthesis, which had been extremely difficult to achieve until now.

 In this study, it was found that the adamantane skeleton, which was previously considered to be a difficult carbon molecule to synthesize, can be obtained continuously by a two-step continuous flow reaction using the polycyclic aromatic compound acenaphthene as a raw material. In order to convert acenaphthene to the desired adamantane, it is necessary to completely hydrogenate the stable aromatic structure of acenaphthene and then to transfer the skeleton of the resulting polycyclic saturated hydrocarbon skeleton using a strong acid. These were achieved by using a continuous flow aromatic hydrogenation reaction using a high-performance catalyst that can hydrogenate aromatic compounds under mild conditions, and a flow skeleton transfer reaction using an ionic liquid complexed with a strong acid. Furthermore, by adding the subsequent radical nitration and hydrogenation of the nitro compound, a four-step synthesis reaction was performed, and memantine was successfully synthesized from acenaphthene. All four steps consist of a continuous flow method in which raw materials and reagents are fed into a column-type reactor and the desired product is discharged.

 This method can significantly reduce carbon dioxide emissions compared to conventional methods, and is expected to be a clean method suitable for small-scale, multi-variety production of small molecule drugs domestically.

Paper information:[Chemistry, A European Journal] Development of Continuous-Flow Reactions for the Synthesis of Anti-Alzheimer Drug Memantine

Tokyo University

Established in the 10th year of the Meiji era.A university with the longest history in Japan and at the forefront of Japanese knowledge

The University of Tokyo was established in 1877 (Meiji 10) by integrating the Tokyo Kaisei School and the Tokyo Medical School.Since its establishment, it has developed education and research in a unique way in the world as a leading university in Japan and an academic center for the fusion of East and West cultures.As a result, many human resources have been produced in a wide range of fields, and many research achievements […]

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