Simplified method to synthesize compounds for pharma industry

5:49 AM, 21st January 2021
An electron microscope images shows copper nanocubes used by Rice University engineers to catalyze the transformation of carbon monoxide into acetic acid.

A team of chemists from Immanuel Kant Baltic Federal University and Saint Petersburg State University developed a simple and efficient method to synthesize tetrahydroisoquinolines—important organic molecules for drug discovery. The method consists of just three steps. The new reaction was published in the Tetrahedron Letters journal.

The structure of organic substances tetrahydroisoquinolines (THIQ) includes a benzene ring fused with a nitrogen-containing cycle. These compounds are in high demand in the pharmaceutical industry. They are used in the synthesis of myorelaxants, antidepressants, and drugs against hypertension, cough, and insomnia. Although different variations of THIQ structures can be found in natural sources (for example, as parts of phytotoxins), modern-day pharmaceutical manufacturers are also interested in their rare types, such as spirocyclic THIQs. In their molecules, two adjacent cycles share one common atom, thus creating an unusual and very stable 3D structure. This feature is extremely important for drug design: the more stable a molecule’s spatial structure is, the more accurately it can be aimed at a protein target in a body.

The majority of existing approaches to the synthesis of spirocyclic THIQs are quite time-consuming. They involve complex cycle-forming reactions arranged in a linear sequence. A team of chemists from Immanuel Kant Baltic Federal University and Saint Petersburg State University found a way to reduce this process to just three steps and to combine the first two into one chemical operation.

The first step is the so-called Castagnoli-Cushman reaction. Earlier this year the BFU-SPbSU team had reported a new version of this reaction in which the product (various carboxylic acids) is formed from three components: homophthalic anhydride (an organic substance with a benzene ring fused to an oxygen cycle with two carbonyl groups), cyclic ketones, and ammonium acetate that works as a source of nitrogen. The team tested the new THIQ synthesis method using cyclohexanone as a ketone. After 16 hours of reaction, a carboxylic acid was formed from the reagents. The acid contained three rings, two of which already shared a common atom.

The next steps were focused on removing the waste products of the reaction while preserving the spirocyclic compound intact. First of all, the team heated the compound in dimethyl sulfoxide to remove the -COOH carboxylic group. This step did not require any purification of the first reaction products. As a result, the acid turned into THIQ lactam, a substance that only differs from the target reaction product by one extra oxygen atom. A reduction reaction of the lactam with lithium aluminum hydride completed the process.

All stages of the process proceeded in high yield: 79 percent of the initial homophthalic anhydride turned into THIQ lactam, and 78 percent of lactam produced spirocyclic THIQ. Having confirmed the efficiency of the new method, the team carried out the same series of reactions using other cyclic ketones. Of the 14 tested options, the majority also showed a high THIQ yield. Therefore, the new method can be used to obtain substances with various structures.

“We have developed an effective approach to the synthesis of spirocyclic tetrahydroisoquinolines that is also much easier compared to existing procedures. It can increase our opportunities for the development of THIQ-based compounds for the pharmaceutical industry. Moreover, the same approach can be applied to other compounds that might serve as prototypes for new drugs,” said Mikhail Krasavin, DSc in chemistry, research professor at the Institute of Living Systems (BFU), and the Head of the Department of the Chemistry of Natural Products (SPbSU).

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