Chemists developed a simplified method for pharmaceutical compounds synthesizing

February 09, 2021

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% of the initial homophthalic anhydride turned into THIQ lactam, and 78% 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, D.Sc. in Chemistry, Research Professor at the Institute of Living Systems (BFU), and the Head of the Department of the Chemistry of Natural Products (SPbSU).
-end-


Immanuel Kant Baltic Federal University

Related Pharmaceutical Industry Articles from Brightsurf:

TalTech chemists' new method is a significant step towards greener pharmaceutical industry
The rapid changes in the chemical industry are connected one hand with the depletion of natural resources and deepening of environmental concerns, on the other hand with the growth of environmental awareness.

GARDP partners with Japanese pharmaceutical in pursuit of new antibiotics
The Global Antibiotic Research and Development Partnership (GARDP) has today announced an agreement with Daiichi Sankyo for GARDP to access and screen the Daiichi Sankyo chemical library.

The integrated catalysts can simplify pharmaceutical manufacturing
Prof. In Su Lee and his research team from POSTECH developed catalytic platforms based on metal organic frameworks.

Study: Pharmaceutical companies marketing stimulants to physicians
Results of a new study show that a large number of physicians in the US may have received marketing payments from pharmaceutical companies that produce stimulant medications.

3D printing with applications in the pharmaceutical industry
This achievement will have applications in the pharmaceutical industry, such as in the preparation of biocompatible biosensors based in gold, which have already been shown to be effective in the detection of carcinogenic cells and tumour biomarkers.

Turning wood into pharmaceutical ingredients 
Production of hazardous waste during drug manufacturing is a serious concern for the pharmaceutical industry.

New pharmaceutical target reverses osteoporosis in mice
Biomedical engineers at Duke University have discovered that an adenosine receptor called A2B can be pharmaceutically activated to reverse bone degradation caused by osteoporosis in mouse models of the disease.

Active pharmaceutical ingredients can persist in the environment
A study finds trace levels of medicines in drinking water from private wells.

BU conducts first experimental evaluation of pharmaceutical industry-led access program
A new study led by Boston University School of Public Health (BUSPH) researchers is the first to use a randomized trial design to generate rigorous evidence on the impact of a pharmaceutical industry-led medicines access program.

A step ahead in pharmaceutical research
Researchers of the University of W├╝rzburg have developed a method that makes it possible to measure the activation of receptors in a very short time.

Read More: Pharmaceutical Industry News and Pharmaceutical Industry Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.