Benzodiazepine compounds

A technology for benzodiazepines and compounds is applied in the field of benzodiazepine compounds and their preparation, and can solve the problems such as separation of degraded impurities, structure confirmation, unstable compounds, and low content that have not yet been seen.

Inactive Publication Date: 2018-05-18
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the compound shown in formula (II) is extremely unstable. In the test of the influencing factors of forced degradation, it is easy to produce degraded impurities. The content of these degraded impurities is very small, which requires long-term separation and enrichment for structural identification. So far , there is no relevant report on the separation, structure confirmation and application research of these degraded impurities

Method used

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Experimental program
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Effect test

Embodiment 1

[0064] The preparation of compound (R is methyl) shown in embodiment 1 formula (I)

[0065] Dissolve 5 g of the compound represented by formula (II) (R is methyl) in 50 ml of dichloromethane, add 7 g of DBN, stir at 40°C until the reaction is complete, wash with acetic acid aqueous solution to pH 8-9, and dry overnight with anhydrous magnesium sulfate , concentrated, and passed through the column (eluent is ethyl acetate:petroleum ether=1:30), the eluent was concentrated under reduced pressure, the residue was heated to 60°C with a small amount of ethanol, 1g of oxalic acid was added, stirred for 30min, and cooled to 0~ Stir and crystallize at 5°C, filter, and neutralize the filter cake with sodium bicarbonate, and form a salt with benzenesulfonic acid to obtain 0.5 g of the compound represented by formula (I). The content is 98.5% as measured by HPLC area normalization method.

[0066] Mp: 195.3℃~197.4℃

[0067] MS: 439.1[M+H] + , 461.1[M+Na] +

[0068] 1 H-NMR (500MHz, ...

Embodiment 2

[0070] The preparation of compound (R is hydrogen) shown in embodiment 2 formula (I)

[0071] Dissolve 5 g of the compound represented by formula (II) (R is hydrogen) in 35 ml of acetonitrile, add 10 g of DBU, stir at 70°C until the reaction is complete, add 100 ml of dichloromethane, wash with acetic acid aqueous solution to pH 8-9, anhydrous sulfuric acid Dry the magnesium overnight, concentrate, pass through the column (eluent is ethyl acetate:petroleum ether=1:30), concentrate the eluent under reduced pressure, heat the residue to 45°C with a small amount of acetone, add 1g of oxalic acid, stir for 30min, cool down Stir and crystallize at 0-5°C, filter, neutralize the filter cake with sodium bicarbonate, and form a salt with benzenesulfonic acid to obtain 0.35 g of the compound represented by formula (I).

[0072] Mp: 183.9℃~185.3℃

[0073] MS: 425.1[M+H] +

Embodiment 3

[0074] The preparation of compound (R is ethyl) shown in embodiment 3 formula (I)

[0075] Dissolve 5 g of the compound represented by formula (II) (R is ethyl) in 60 ml of tetrahydrofuran, add 12 g of TBD, stir at 60°C until the reaction is complete, add 100 ml of dichloromethane, wash with acetic acid aqueous solution to pH 8-9, anhydrous Magnesium sulfate was dried overnight, concentrated, and passed through the column (eluent: ethyl acetate: petroleum ether = 1:30), the eluent was concentrated under reduced pressure, and the residue was separated with a preparative liquid phase. The mobile phase was methanol: acetonitrile: Water: triethylamine = 45: 25: 30: 0.01, the fractions were received and concentrated, and salted with benzenesulfonic acid to obtain 0.65 g of the compound represented by formula (I).

[0076] Mp: 202.3℃~204.1℃

[0077] MS: 453.3 [M+H] +

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Abstract

The invention relates to benzodiazepine compounds shown in a formula (I) as well as a preparation method and an application thereof. The compounds can be used for preparing a sterilizing agent.

Description

technical field [0001] The present invention relates to a kind of benzodiazepine Compounds and preparation methods thereof, and the application of compounds represented by formula (I) as antibacterial infection drugs. Background technique [0002] Benzodiazepines are widely used clinically for anxiolytic, sedative and hypnotic effects. As the first water-soluble benzodiazepine derivative, midazolam has been widely used in clinical sedation, hypnosis, analgesia, antiepileptic, anxiolytic and general anesthesia. When midazolam is injected into the human body as an anesthetic, it can be oxidized to α-hydroxy midazolam by cytochrome P450 isoenzyme. The oxide still has pharmacological activity, so the anesthesia takes a long time and the recovery is slow. Therefore, the development of new water-soluble derivatives of benzodiazepines with fast anesthesia induction time and short maintenance time has always been paid attention to by medicinal chemists. [0003] The chemical na...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/5517A61P31/04
CPCC07D487/04Y02A50/30
Inventor 郭建锋符义刚周志文吕金良田峦鸢曲龙妹李莉娥李仕群李杰杜文涛廖宗权张敏
Owner YICHANG HUMANWELL PHARMA
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