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Method for synthesis of 4H-imidazo[1, 5-a][1, 4]benzodiazepine, especially midazolam

A benzodiazepine and 5-a technology, applied in the field of midazolam, to reduce the formation of isomers, improve safety, and mild reaction conditions

Inactive Publication Date: 2013-09-25
XUZHOU CARDIOVASCULAR INST +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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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

Method used

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  • Method for synthesis of 4H-imidazo[1, 5-a][1, 4]benzodiazepine, especially midazolam
  • Method for synthesis of 4H-imidazo[1, 5-a][1, 4]benzodiazepine, especially midazolam
  • Method for synthesis of 4H-imidazo[1, 5-a][1, 4]benzodiazepine, especially midazolam

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Experimental program
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Embodiment 1

[0030] 50 g of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-2-carboxylate of formula (VI) Acid and 90ml NMP, 1.52g DBU were charged into a 250mL Mitsui flask equipped with a magnetic stirrer and coolant. It was heated at T=140°C-160°C for one hour using an oil bath. 1 ml of the solution was collected for HPLC analysis. The product of the reaction was midazolam with a titer (w / w) of 87% (determined by HPLC titration, corrected for solvent) containing 1% imidazolam. By adding Na 2 CO 3 After raising the pH of the aqueous solution to 10, the product was extracted with isopropyl acetate.

Embodiment 2

[0031] The decarboxylation synthesis condition comparison of embodiment 2-midazolam

[0032] Give a table summarizing the results of the decarboxylation of the compound.

[0033]

[0034] * = ratio of midazolam / isomidazolam only (other impurities not considered).

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Abstract

The invention relates to a method for preparation of 4H-imidazo[1, 5-a][1, 4]benzodiazepine, especially midazolam through a selective decarboxylation reaction of formula (VII) with a DBU (1,8-diazabicyclo[5.4.0.]-undec-7-ene) novel catalyst in an NMP (N-methyl pyrrolidone) solvent. According to the invention, isomerization of 4H-imidazo[1, 5-a][1, 4]benzodiazepine is avoided, the midazolam synthesis yield is enhanced, and the post-treatment difficulty 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 ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/55A61P23/00A61P25/20
Inventor 朱海亮宫海滨胡杨
Owner XUZHOU CARDIOVASCULAR INST
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