Preparation method of acid hydrolytic impurity in linezolid

A technology of linezolid and acidic hydrolysis, applied in the field of medicine, can solve problems such as potential safety hazards, achieve the effects of convenient operation, simple preparation conditions, and avoid side reactions

Inactive Publication Date: 2018-01-12
GUILIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the commonly used dosage form of linezolid is injection, which contains acid excipients such as citric acid, and linezolid injection is prone to degradation reaction to produce acidic hydrolysis impurities
The impurities produced by it have a great hidden danger to the safety of medication, so it is necessary to study the preparation method of its acidic hydrolyzed impurities

Method used

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  • Preparation method of acid hydrolytic impurity in linezolid
  • Preparation method of acid hydrolytic impurity in linezolid
  • Preparation method of acid hydrolytic impurity in linezolid

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Embodiment 1

[0039] The preparation method of the acidic hydrolysis impurity of linezolid in this embodiment comprises the following steps:

[0040] (1) Hydrolysis: In a 250ml round-bottomed flask, take 10g of linezolid shown in formula II, add 20ml of 6mol / L hydrochloric acid dropwise under 40g of absolute ethanol, acid hydrolyze at 70°C for 20h, remove the acetyl group, and cool down to 20 DEG C, obtain the hydrochloride of formula I;

[0041] (2) Distillation: steaming dehydrated alcohol described in step (1);

[0042] (3) Alkalization and extraction and purification: the pH of the solution is adjusted to 7 with a mass percent concentration of 5% sodium hydroxide solution, filtered to obtain a red filtrate and filter cake; the filtrate is extracted with n-butanol 30ml × 2 to obtain n-butanol Alcohol extract 1; the filter cake was stirred with dichloromethane for 30 minutes, filtered, washed with dichloromethane, dissolved in 20ml of water, and added with a mass percent concentration of...

Embodiment 2

[0047] The preparation method of the acidic hydrolysis impurity of linezolid in this embodiment comprises the following steps:

[0048] (1) Hydrolysis: In a 250ml round-bottomed flask, take 10g of linezolid shown in formula II, add 20ml of 4mol / L hydrochloric acid dropwise under 50g of anhydrous methanol, and heat under reflux at 80°C for 16 hours to remove the acetyl group. Cool down to 22°C to obtain the hydrochloride of formula I;

[0049] (2) Distillation: steam the anhydrous methanol described in step (1);

[0050] (3) Alkalization and extraction and purification: the pH of the solution is adjusted to 8 with a mass percent concentration of 5% sodium hydroxide solution, filtered to obtain a red filtrate and filter cake; the filtrate is extracted with n-butanol 30ml × 2 to obtain n-butanol Alcohol extract 1; the filter cake was stirred with chloroform for 30 minutes, filtered, washed with chloroform, the insoluble matter was dissolved in 20ml of water, and the pH of the so...

Embodiment 3

[0055] The preparation method of the acidic hydrolysis impurity of linezolid in this embodiment comprises the following steps:

[0056] (1) Hydrolysis: In a 250ml round-bottomed flask, take 10g of linezolid, add 20ml of 7.5mol / L hydrochloric acid dropwise under 80g of anhydrous methanol, perform acidic hydrolysis at 90°C for 10h, remove acetyl groups, cool down to 20°C, Obtain the hydrochloride of formula I;

[0057] (2) Distillation: steam the anhydrous methanol described in step (1);

[0058] (3) Alkalization and extraction and purification: it is 10 to adjust the pH of the solution with a mass percent concentration of 5% potassium hydroxide solution, and filter to obtain a red filtrate and filter cake; the filtrate is extracted with n-butanol 30ml×2 to obtain n-butanol Alcohol extract 1; the filter cake was stirred with dichloromethane for 30 minutes, filtered, washed with dichloromethane, dissolved in 20ml of water, and 5% potassium hydroxide solution was added to adjust ...

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Abstract

The invention discloses a preparation method of an acid hydrolytic impurity in linezolid and belongs to the technical field of medicines. The preparation method comprises the following steps: (1) hydrolysis; (2) distillation: steaming an alcohol organic solvent in the step (1); (3) alkalization and extraction purification; (4) crystallization purification. With the adoption of the method disclosedby the invention, the prepared acid hydrolytic impurity in the linezolid is stable in fine quality and high in purity, is up to 99.942 percent and can be taken as a reference substance of linezolid acid hydrolytic impurity (S)-5-(amino methyl)-3-(3-fluorine-4-morpholine phenyl)-2-oxazolidone, and the reference substance is used for detecting the content of the acid hydrolytic impurity in the linezolid and is of great significance in the quality control of the linezolid.

Description

technical field [0001] The invention relates to a method for preparing linezolid acidic hydrolysis impurities, which belongs to the technical field of medicine. Background technique [0002] Linezolid, chemical name (S)-5-(acetamidomethyl)-3-[(3-fluoro-4-morpholinyl)phenyl]-1,3-oxazolidine-2 -Ketone, an oxazolidinone antibiotic, was first launched in the United States in 2000 for the treatment of pneumonia and generalized skin infections caused by methicillin-resistant P. aureus (MRSA) and by vancomycin-resistant enterococci (VREF ) or bacteremia caused by penicillin-resistant Streptococcus pneumoniae (PRSP). Its structure is shown in formula II: [0003] [0004] Linezolid is prone to degradation reactions and produces impurities, which will affect its safety and effectiveness in clinical use, and the impurities produced by linezolid degradation in acidic and alkaline hydrolysis are different. The current reports are all preparation methods of alkaline hydrolyzed impu...

Claims

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Application Information

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IPC IPC(8): C07D263/20
Inventor 刘玮黎昌贵张浩潘梅
Owner GUILIN PHARMA
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