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Credit: Anton Sehtnev
Scientists from RUDN University jointly with their colleagues from Yaroslavl have developed a new way to synthesize 1,2,4-oxadiazole derivatives present in many drugs. 1,2,4-oxadiazoles include ataluren, the active ingredient of the drug used in genetic disorders treatment. The results of the work are published in the Tetrahedron Letters journal.
"Many candidate medications are not developed further and the reasons often are high costs and technological complexity of their production. Moreover, any rise in cost of a chemical process in drug production ultimately affects the consumer. Our latest development simplifies and reduces the cost of one of the stages in active ingredients production," says Anton Shetnev, one of the authors of the study from the Research Institute of Chemistry of RUDN.
Many organic compounds are thermosensitive, that is why classical 1,2,4-oxadiazole production methods which involve heating often lead to resinification of the reaction mass and undesirable side processes. With the new method 1,2,4-oxadiazoles with carboxylic acid - a functional group which enables further modification of the compound - can be produced rapidly, with high yield and without expensive reagents.
The usual method of production of 1,2,4-oxadiazoles is carried out in two stages. Intermediate products of the reaction in the first stage are subsequently converted into the desired 1,2,4-oxadiazoles under relatively high temperature (about 100-140 °C).
The authors of the study offered a method of 1,2,4-oxadiazole production in a single step at room temperature. Chemists came up with a soft and workable synthetic procedure for 1,2,4-oxadiazoles (in the amount of several grams): the reaction of the precursors (amidoximes and dicarboxylic acid anhydrides) was carried out in the presence of sodium hydroxide (NaOH) with dimethylsulfoxide as a solvent. The new synthesis method created by RUDN scientists is based on the superbase catalysis principles. The point is that sodium hydroxide turns into a superbase under the reaction conditions becoming much stronger than usual alkali (NaOH dissolved in water). Due to the addition of a superbase the process of 1,2,4-oxadiazole production can be carried out even at room temperature and without toxic and expensive reagents.
"We have published a series of articles devoted to the application of this methodology, and we are planning to continue the research. All these data are available online, and some scientific groups have already used our work in their studies. If an oxadiazole derivative-based drug appears in the future, I believe that our method will be able to make its production very effective," the scientist concludes.
The research was carried out in collaboration with colleagues from the Yaroslavl State Pedagogical University named after K.D.Ushinsky.
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Journal
Tetrahedron Letters