Abstract
The information related to the methods of the synthesis of 4- and 6-trifluoromethyl-3,4-dihydropyrimidine- 2-ones and their condensed analogs as potent molecular platforms for the synthesis of bioactive compounds has been analyzed and systematized. The role of inter- and intramolecular cyclocondensations of CF3-containing substrates, as well as nucleophilic addition to C=N bond as key steps for construction of 4-trifluorinated derivatives has been emphasized. The major part of this article is devoted to the construction of trifluoromethyldihydropirimidones of a high optical purity and their thioanalogs based on the condensation of the chiral ureas and thioureas. A special attention is paid to asymmetric reactions, which are used for the synthesis of chiral analogs of the anti-HIV drug Efavirenz. It has been noted that Biginelly reaction of the corresponding fluorinated ketoesters is the common way for obtaining 6-trifluoromethylpyrimidones. The method allows obtaining the target products in one stage although it has limitations due to the need to isolate intermediate cyclic products, which in the future should be subjected to dehydration. The effect of the catalyst nature on the course of Biginelly reaction of trifluoromethylated substrates has been analyzed. It has been shown that nucleophilic 3,6-addition to 4-CF3- dihydropyrimidones is effective method for the synthesis of dihydroorotic acid derivatives.
Highlights
Vovk Trifluoromethyl-containing 3,4-dihydropyrimidine-2-ones and their condensed analogs The information related to the methods of the synthesis of 4- and 6-trifluoromethyl-3,4-dihydropyrimidine2-ones and their condensed analogs as potent molecular platforms for the synthesis of bioactive compounds has been analyzed and systematized
The major part of this article is devoted to the construction of trifluoromethyldihydropirimidones of a high optical purity and their thioanalogs based on the condensation of the chiral ureas and thioureas
A special attention is paid to asymmetric reactions, which are used for the synthesis of chiral analogs of the anti-HIV drug Efavirenz
Summary
Що етоксикарбонілімін гексафтороацетону екзотермічно реагує з N,N-диметил-6-аміноурацилом з утворенням продукту приєднання по активованому С=N зв’язку 26, який при дії основи в подальшому циклізується до цільової сполуки 27 (схема 6). При детальному дослідженні реакції сполук з ацетоном в умовах асиметричного органокаталізу із використанням каталізатора (S)-PMP спочатку в реакційній суміші утворюється кінетичний продукт 3,6-приєднання 36, який з часом перетворюється на більш термодинамічно стабільний енантіомерно збагачений продукт 3,4-приєднання 37 [12] (схема 9). Відновлення нітрогрупи дало можливість отримати амінопохідні 40, які при нагріванні впродовж 2 год у присутності лугу циклізуються з утворенням відповідних піролопіримідиндіонів 41 (схема 10). При цьому продукти приєднання 81 були отримані з виходами 90–99 % та енантіомерним надлишком 55-99 %.
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