Development of new drugs enabled by efficient synthesis of indole derivatives, a significant element in many pharmaceuticals.

A research group at Nagoya University in Japan has succeeded in developing a simple, ultra-rapid synthetic method for producing indole derivatives. Their findings are expected to make drug production more efficient and expand the range of potential indole-based drugs to treat a variety of diseases. Their findings have been published in Communication chemistry.

Indole is an organic compound consisting of a benzene ring and a pyrrole ring. The heterocyclic alkylation of the carbon atom next to the indole ring is particularly useful for the creation of a wide range of novel indole derivatives and the many anti-inflammatory, anticancer and antimicrobial therapeutics they contain.

In the past, such heteroatom alkylation has proven difficult because indoles easily and quickly undergo unwanted dimerization/dimerization, processes in which two or more molecules combine during a reaction to form larger, unwanted molecules. These unwanted by-products limit the yield of the desired product.

Because indoles are common to many drugs, an efficient method of their synthesis is essential. Now, a team made up of Assistant Professor Hisashi Masui (him/her), graduate student Sena Kanda (him/her), and Professor Shinichiro Fuse (him/her) at the Graduate School of Pharmaceutical Sciences, Nagoya University, has obtained the targeted indole – High yield based product with reduced side reactions using the new micro-flow synthesis method.

Their method consists of flowing the solution through a small channel with an inner diameter of about 1 mm. Due to its small size, the channel has a high surface area to volume ratio, which allows mixing of the solution in just a few milliseconds. This allows precise control of short reaction times and limits the time during which unstable intermediates are present in the reaction process to only about 0.1 s. This is fast enough to prevent unwanted dimerization/multimerization.

“Although mixing solutions using a beaker takes several seconds, the microflow synthesis method does it in less than a few milliseconds,” Feuz said.

Therefore, short reaction times of less than a second can be generated that can be more accurately controlled and the reaction temperature can be fully controlled. We generated an activated indole complex in 20 ms to achieve a target product yield of 95%. When the same reaction occurred, it was performed in standard flask, and the target product could not be obtained at all, and side reactions occurred while mixing the solutions.”

“Because the method developed can be used to synthesize different indole derivatives, our study is useful for creating drug candidates and improving drug production efficiency,” Feuz said. “The reaction occurs at a very high speed under moderate room temperature conditions, and the reactants used are readily available and inexpensive, which makes them very practical.”

The group sees many potential industrial applications. Fuse confirmed that the flux synthesis method can be scaled up repeatedly by continuous pumping, making it an ideal choice for manufacturing facilities. “Indole is one of the most abundant compounds in pharmaceuticals,” he said. “We expect it to contribute to drug candidate creation and drug production efficiency.”