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Benzodiazepines

A technology of benzodiazepines and compounds, which is applied in the application field of cardiovascular and cerebrovascular drug composition preparations, can solve the problems of compound instability, low content, separation of degraded impurities, and structural confirmation, etc.

Inactive Publication Date: 2018-05-08
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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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: the preparation of compound (R is methyl) shown in formula (I)

[0051] Dissolve 5 g of the compound represented by formula (II) (R is methyl) in 50 ml of methanol, cool down to -40°C, add dropwise 10% aqueous sodium hydroxide solution to adjust the pH to 9-10, and keep the reaction solution at this level all the time. pH value, keep the reaction temperature at -40~-30°C and stir until the reaction is complete, wash with dilute hydrochloric acid aqueous solution to pH 6~7, extract with 200ml dichloromethane, dry the dichloromethane layer with anhydrous magnesium sulfate overnight, concentrate, and Column (eluent is ethyl acetate:petroleum ether=1:15), the eluent is concentrated under reduced pressure, the residue is heated to 60°C with a small amount of ethanol, 1g of oxalic acid is added, stirred for 30min, cooled to 0-5°C and analyzed crystallized, filtered, and the filter cake was neutralized with sodium bicarbonate, and dried to obtain 0.96 g of the co...

Embodiment 2

[0056] Embodiment 2: the preparation of compound (R is hydrogen) shown in formula (I)

[0057] Dissolve 5g of the compound represented by formula (II) (R is hydrogen) in 35ml of ethanol, cool down to -30~-20°C, add dropwise 5% potassium hydroxide aqueous solution to adjust the pH to 10~12, and keep the pH during the reaction. pH value, keep warm at -20~-10°C for reaction, add 200ml of dichloromethane after the reaction is completed, wash with acetic acid aqueous solution to pH 6~7, dry over anhydrous magnesium sulfate, concentrate, pass through the column (eluent is ethyl acetate: n-Hexane=1:20), the eluent was concentrated under reduced pressure, the residue was heated to 45°C with a small amount of acetone, 1.6g maleic acid was added, stirred for 30min, cooled to 0-5°C, stirred and crystallized, filtered, and used for filter cake Sodium bicarbonate neutralized and dried to obtain 1.57 g of the compound represented by formula (I).

[0058] Mp: 203.4℃~205.1℃

[0059] MS: 411...

Embodiment 3

[0060] Embodiment 3: the preparation of compound (R is ethyl) shown in formula (I)

[0061] Dissolve 5g of the compound represented by formula (II) (R is ethyl) in 60ml of isopropanol, cool down to -10~-5°C, add 0.5g of lithium hydroxide monohydrate in batches, stir at room temperature until the reaction is complete, add 200ml of dichloromethane, washed with dilute hydrochloric acid solution to pH 6-7, dried over anhydrous magnesium sulfate, concentrated, passed through the column (eluent: ethyl acetate: petroleum ether = 1:10), the eluent was concentrated under reduced pressure , 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 to obtain 1.15 g of the compound represented by formula (I).

[0062] Mp: 213.4℃~215.1℃

[0063] MS: 437.1 [M-H] +

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Abstract

The invention relates to a compound shown in a formula (I), a preparation method thereof, and application in preparing antithrombotic drugs or cardiovascular drugs. The formula is shown in the description.

Description

technical field [0001] The present invention relates to a short 3-benzodiazepine Compounds and preparation methods thereof, and the application of compounds represented by formula (I) as antithrombotic drugs in cardiovascular and cerebrovascular pharmaceutical composition preparations. 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. However, 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 ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/5517A61P7/02A61P9/10
CPCC07D487/04
Inventor 吕金良符义刚郭建锋周志文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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