Parallel synthesis of derivatives of 1 H -1,2,4-triazole-3-carboxylic acids with heterocyclic substituents at position 5
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Parallel synthesis of derivatives of 1H-1,2,4-triazole-3-carboxylic acids with heterocyclic substituents at position 5 Lyubov E. Grebenkina1, Andrey V. Matveev1*, Mikhail V. Chudinov1 1
MIREA – Russian Technological University, Institute of Fine Chemical Technologies named after M. V. Lomonosov, 78 Vernadskogo Ave., Moscow 11945, Russia; е-mail: [email protected]
Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(9), 1173–1179
Submitted February 21, 2020 Accepted after revision July 6, 2020
A mild universal method for the synthesis of derivatives of 5-substituted 1H-1,2,4-triazole-3-carboxylic acids from a single precursor, ethyl β-N-Boc-oxalamidrazone, has been proposed. The method was applied for the parallel synthesis of a library of 1H-1,2,4-triazole3-carboxamides with heterocyclic substituents at position 5. Keywords: β-N-Boc-oxalamidrazone, 1,2,4-triazole-3-carboxamide, 1,2,4-triazole-3-carboxylic acids, cyclization, parallel synthesis.
1,2,4-Triazole is a widely known privileged fragment of the chemical structure of many classes of pharmacologically active compounds, including antiviral1 and antitumor.2,3 A number of strategies exist for the synthesis of 3,5-disubstituted 1,2,4-triazole ring4,5 leading to satisfactory results in cases where there is no electronwithdrawing group, for example, the carboxyl, at position 3(5). The main method for the synthesis of derivatives of 5-substituted 1,2,4-triazole-3-carboxylic acids 1 is thermal cyclization of β-acylamidrazones 26–11 (Scheme 1). Product yields are usually low, especially for labile β-acyl groups (R1 in Scheme 1), which is not surprising, since the cyclization temperature usually exceeds 140°C. Scheme 1
0009-3122/20/56(9)-1173©2020 Springer Science+Business Media, LLC
One of the areas of research of our laboratory is the synthesis of analogs of the antiviral nucleoside drug ribavirin, the heterocyclic base of which is 1,2,4-triazole3-carboxamide. Ribavirin analogs substituted at position 5 of the base are promising antiviral and antitumor agents.12,13 They can be obtained in two main ways: 1) chemical14,15 or chemico-enzymatic16 glycosylation of the 1,2,4-triazole base, 2) substitution or addition to the functional group previously introduced at position 5 of the base.17–24 In order to systematically study biological properties and determine the structure–activity parameters, mechanisms of action, and metabolic pathways, it is often necessary to synthesize not only the nucleoside analogs themselves, modified at a heterocyclic base or at a carbohydrate fragment, but also their heterocyclic bases. The main synthetic precursors of heterocyclic bases of ribavirin analogs are esters of 1,2,4-triazole-3-carboxylic acids. Therefore, in order to study the biological properties of nucleoside analogs containing the 1,2,4-triazole-3-carboxamide fragment with labile substituents at position 5, we needed to develop a mild universal method for the synthesis of 1H-1,2,4-triazole-3-carboxylic acid derivatives. The approach proposed by us earlier25 was
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