One-Flow Operation via 4-Bromopyridine Enables Flash Synthesis of AChE Inhibitor

Hiroki Soutome; Yusuke Kimuro; Tomoko Kawaguchi; Dong-eun Yoo; Yiyue Yao; Shuto Oshida; Hiroki Nakayama; Masatomo Iwata; Ruka Ebisawa; Ryuhei Kikuchi; Kyosuke Tomite; Shuto Wada; Yosuke Ashikari; Aiichiro Nagaki

doi:10.1055/a-2218-9048

Synthesis, Inhaltsverzeichnis

Synthesis 2024; 56(05): 821-827
DOI: 10.1055/a-2218-9048

paper

Special Issue Flow Chemistry

One-Flow Operation via 4-Bromopyridine Enables Flash Synthesis of AChE Inhibitor

Authors

Hiroki Soutome

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

^bYokohama Technical Center, AGC Inc., Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
Yusuke Kimuro

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

^cResearch and Development Center, Juzen Chemical Corp., 1-10 Kiba-cho, Toyama 930-0806, Japan
Tomoko Kawaguchi

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Dong-eun Yoo

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Yiyue Yao

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Shuto Oshida

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Hiroki Nakayama

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Masatomo Iwata

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Ruka Ebisawa

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Ryuhei Kikuchi

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Kyosuke Tomite

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Shuto Wada

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Yosuke Ashikari

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Aiichiro Nagaki ∗

^aDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

Abstract

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Abstract

4-Bromopyridine is a building block that can be converted into valuable compounds, but due to its low stability, it is commercially available in the form of hydrochloride salt. Therefore, the hydrochloride salt is usually desalted with a basic aqueous solution and dried before organic reaction. In this study, to simplify the preparation and reaction procedure of 4-bromopyridine, multiple operations, desalting with a base, separation of the aqueous layer, and subsequent halogen–lithium exchange reaction were integrated into a single flow reaction. The reaction sequence was completed within 20 seconds and the yields were higher than the conventional methods. This is because the subsequent reaction can be performed immediately after the generation of 4-bromopyridine, which is unstable under ambient conditions.

Key words

one flow operation - flow microreactors - flash chemistry - integrated flow reactions - bromopyridine hydrochloride - liquid-liquid separate membrane - AChE inhibitors

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Referenzen

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