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Synthesis 2004(16): 2697-2703  
DOI: 10.1055/s-2004-831243
PAPER
© Georg Thieme Verlag Stuttgart · New York

Reactions of 1,4-Benzodiazepinic N-Nitrosoamidines with Tosylmethyl Isocyanide: A Novel Synthesis of Midazolam

Carlos del Pozo*, Alberto Macías, Eduardo Alonso, Javier González*
Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, Julián Clavería 8, 33071 Oviedo, Spain
e-Mail: fjgf@uniovi.es;
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Publication History

Received 14 April 2004
Publication Date:
22 September 2004 (online)

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Abstract

Reaction of 1,4-benzodiazepinic N-nitrosoamidines, used as synthetic equivalents of imidoyl chlorides, with the mono-anion of tosylmethyl isocyanide is described. The process gives entry to 3-(4-tosyl)imidazo[1,5-a][1,4]benzodiazepines, compounds which have not been described yet in the literature. These systems can be derivatized to the corresponding trisubstituted 1,4-benzodiazepines by alkylation or acylation of the imidazole ring. These new heterocyclic derivatives are potentially useful in the field of medicinal chemistry. In addition, midazolam 3, the anesthetic properties of which are well established, can be easily prepared in one step by desulfonylation of compound 7a.

Key words

heterocycles - cyclizations - reductions - benzodiazepines - isocyanides

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40-25

For a slightly different reduction process using Zn-AcOH and leading to a similar product see earlier reference.13m