Process for the synthesis of 4h-imidazo[1,5-a][1,4]benzodiazepines, especially midazolam

Abstract

The present invention relates to the preparation of 4H-imidazo[1,5-a][1,4]benzodiazepines, especially midazolam, by selective decarboxylation of formula (VII) using DBU novel catalysts under NMP solvent Methods. The isomerization of 4H-imidazo[1,5-a][1,4]benzodiazepine is avoided, the yield of midazolam synthesis is improved and the difficulty of post-treatment is reduced.

Description

technical field [0001] The object of the present invention is a process for the preparation of 4H-imidazo[1,5-a][1,4]benzodiazepines, especially midazolam. Background technique [0002] 4H-imidazo[1,5-a][1,4]benzodiazepines are a class of benzodiazepines with general formula (I). [0003] [0004] Among them, 1,4-diazepine ring is fused with 1,3-imidazole ring. Such compounds are widely used in anesthesia and sedation, among which midazolam (II) is the most important. [0005] [0006] Other important compounds Clomazolam of formula (III): [0007] [0008] and desmethyl midazolam (IV) and I-hydroxy midazolam (V) [0009] [0010] All of these are biologically active substances with neuropharmacological and sedative effects. [0011] The synthesis of midazolam as described in US 4280957 to Hoffman-La Roche provides 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazole according to the following scheme And [1,5-a][1,4]benzodiazepine-2-carboxylic acid carries out ...

AI Technical Summary

Problems solved by technology

However, this reaction carried out at high temperature and pressure results in a considerable percentage of isomidazolam, still requiring a basic isomerization step

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