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Preparation of Benzodiazepine-Containing Drugs
Drugs such as sedatives, hypnotics, and anticonvulsants often contain a benzodiazepine moiety. They are useful in the treatment of, for example, anxiety, insomnia, agitation, and seizures. The 1,5-benzodiazepin-2-one skeleton in particular is considered a “privileged” scaffold in medicinal chemistry and drug development. The pharmacological importance of benzodiazepine derivatives therefore justifies new efforts for their synthesis. As recently reported in the European Journal of Organic Chemistry, a Columbian/French team led by Yoann Coquerel and Jean Rodriguez have now introduced a general domino sequence to provide new synthetic entry to 1,3-dihydro-2H-1,5-benzodiazepin-2-ones.
An important focus of modern organic synthesis is economy, and many transformations have been developed to allow the creation of molecular complexity and functional diversity in a single chemical operation. These transformations are best performed with polyfunctionalized substrates in which the distinct reactive groups react selectively in a well-defined order to give a single product. α-Oxo ketenes exhibiting two carbonyl groups and one double bond distributed over three carbon atoms are highly reactive molecules that fall into this class of compounds. α-Oxo ketenes have already been used to prepare a number of heterocycles, and the scientists have already shown that these compounds can be obtained through the rearrangement of 2-diazo-1,3-dicarbonyl compounds. The team was further interested in the reactions of 2-diazoalkane-1,3-diones with bis(N-nucleophiles) in a domino sequence to prepare the desired benzodiazepine derivatives.
Although synthetic routes to benzodiazepines exist, they are often sensitive to the type of substrate and the reaction conditions; moreover, these methods usually require long reaction times and are often complicated by side reactions. Importantly, using their domino methodology and without any additives, the researchers found that microwave irradiation of a 1:1 mixture of a set of diazo compounds with o-phenylenediamine furnished a series of bi- and tricyclic 1,3-dihydro-2H-1,5-benzodiazepin-2-ones, which are among the most promising compounds containing the benzodiazepine structure. The authors postulate that the reaction follows this sequence: rearrangement, nucleophilic addition, and intramolecular imination. This reaction represents a new and advantageously complementary synthetic approach to a valuable class of drug-like compounds.
Original publication
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Topic world Synthesis
Chemical synthesis is at the heart of modern chemistry and enables the targeted production of molecules with specific properties. By combining starting materials in defined reaction conditions, chemists can create a wide range of compounds, from simple molecules to complex active ingredients.
Topic world Synthesis
Chemical synthesis is at the heart of modern chemistry and enables the targeted production of molecules with specific properties. By combining starting materials in defined reaction conditions, chemists can create a wide range of compounds, from simple molecules to complex active ingredients.
