Chemists from Tolyatti State University (TSU), together with colleagues from the Ufa Institute of Organic Chemistry, UFIC RAS, and the A.N. Nesmeyanov Institute of Organoelement Compounds, RAS, have developed a new method for the synthesis of pyrazoles and pyrazolines. These compounds are key components of many modern medicines used, for example, in the fight against cancer or AIDS. A special feature of the proposed approach is the ability to control the synthesis process by changing the proportions of reagents, which makes it possible to obtain various types of compounds with high selectivity.
Researchers at TSU's S. P. Korshunov Laboratory of Organic Synthesis and Analysis worked with complex organic molecules with several active centers for chemical transformations. The second key component was hydrazine, a highly active reagent containing nitrogen. Scientists have found that by simply changing the proportions of the starting materials, it is possible to precisely control which useful chemical compounds will be obtained.
"If we take the components in a 1:1 ratio, the reaction proceeds along the same path, and as a result, pyrazolines are formed — cyclic molecules that are in great demand in pharmacology, and the yield of a useful product reaches 92%. If you add significantly more hydrazine, the reaction switches to the second pathway, and other valuable compounds are obtained — pyrazoles with a yield of 79-84%," said one of the authors of the study, TSU Professor Alexander Golovanov.
According to scientists, pyrazoles were previously obtained using the classical method, mixing organic compounds with hydrazine. However, this approach was not ideal: often, instead of one desired substance, a mixture of similar products was formed, which were very difficult to separate. Many reactions had to be carried out at high temperatures, for a long time, or using aggressive chemicals. But the main problem was the lack of flexibility of the method. In particular, it was poorly suited for creating complex molecules with specified properties, since it did not allow for the easy addition of specific fragments important for biological activity to the right places of the molecule.
"The most valuable thing is that we were able to obtain pure pyrazolines in their original form. Previously, their synthesis was practically impossible. These molecules are very "moody": they have a particularly active place — a nitrogen atom, which reacts easily even with air and can spoil the substance. Therefore, in order to study them, chemists had to temporarily "protect" them. Under the right conditions, this active site of pyrazoline remains accessible for attaching other parts to it, which is extremely important for the creation of new compounds, and, consequently, for the development of new, more effective drugs," said the first author of the article, a graduate student at TSU. Evgeny Zatynatsky.
The new approach developed at TSU helped overcome the existing limitations. The authors not only observed the result, but also thoroughly studied the mechanism of the process using modern analysis methods, including nuclear magnetic resonance spectroscopy and X-ray diffraction analysis, and also experimentally proved that pyrazoles and pyrazolines are formed in parallel rather than transformed into each other, which makes the method particularly clean and effective.
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