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Preparation method of linezolid in type B crystal form

A technology of linezolid and crystal form, applied in the field of preparation of linezolid crystal form B, can solve the problems of low yield, easy moisture absorption and deterioration, unstable linezolid hydrochloride and the like, and achieves good reproducibility , the effect of high yield and high purity

Active Publication Date: 2016-04-27
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Linezolid hydrochloride is the key raw material for the preparation of crystalline form B of linezolid, but linezolid hydrochloride is unstable, especially in an environment with water, it is easy to absorb moisture and deteriorate, and it is inconvenient to store and transport
The preparation of linezolid hydrochloride reported in existing documents US2009062534 and WO2008000418 is carried out in organic solvents such as acetone, acetonitrile, ethyl acetate or tetrahydrofuran. This method not only has a low yield, but also easily leads to the formation of crystal form B of linezolid in the finished product. Residual solvents exceed the standard, affecting the safety of drug use

Method used

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  • Preparation method of linezolid in type B crystal form
  • Preparation method of linezolid in type B crystal form
  • Preparation method of linezolid in type B crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Put 10.0g of linezolid crude product, with a chemical purity of 96.5%, and 500ml of toluene in a reaction bottle, stir and heat to 70°C~80°C, the solid dissolves, and hydrogen chloride gas is introduced, and the reaction liquid immediately turns into white turbidity. When the pH of the reaction liquid = 2.0~2.5, stop feeding the hydrogen chloride gas, cool the reaction solution to room temperature naturally, continue to stir for 2 hours, filter and wash. The filter cake was vacuum-dried at 40°C to 50°C to obtain amorphous linezolid hydrochloride.

[0041] Transfer the amorphous linezolid hydrochloride to the reaction bottle, add 40 times the volume of water, stir and heat to 40°C, add 10% potassium carbonate solution dropwise, adjust the pH of the reaction solution to 9~10, stir and crystallize, Naturally cool to room temperature, filter and wash with water. The resulting filter cake was vacuum-dried at 40°C to 50°C for 4 to 6 hours to obtain 9.1 g of linezolid crystal...

Embodiment 2

[0043] Put 50g of linezolid crude product, with a chemical purity of 96.5%, and 2.5L of ethanol in a reaction flask, stir and heat to 60°C~70°C, the solid dissolves, and hydrogen chloride gas is introduced, and the reaction liquid immediately becomes white turbid. When the pH of the reaction liquid =1.5~2.0, stop feeding the hydrogen chloride gas, cool the reaction solution to room temperature naturally, continue to stir for 2 hours, filter and wash. The filter cake was vacuum-dried at 40°C to 50°C to obtain amorphous linezolid hydrochloride.

[0044]Transfer the amorphous linezolid hydrochloride to the reaction bottle, add 45 times the volume of water, stir and heat to 40°C, add 10% potassium carbonate solution dropwise, adjust the pH of the reaction solution to 9~10, stir and crystallize, Naturally cool to room temperature, filter and wash with water. The resulting filter cake was vacuum-dried at 40°C~50°C for 4~6 hours to obtain 45.6g of Linezolid Form B, with a chemical p...

Embodiment 3

[0045] Embodiment 3 process parameter investigation

[0046] Operation is basically the same as in Example 1, and the results are shown in Table 1, Table 2 and Table 3.

[0047] Table 1. The influence of different solvents and their dosages on the yield, purity and residual solvent of Linezolid Form B.

[0048] NA: not detected

[0049] Table 2. Using toluene as a solvent, investigate the influence of the pH value of the reaction solution on the yield of Linezolid Form B after hydrogen chloride gas is introduced.

[0050]

[0051] Table 3. The influence of the amount of water on the yield, purity and residual solvent of linezolid crystal form B was investigated.

[0052]

[0053] NA: not detected

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Abstract

The present invention provides a preparation method of linezolid in the type B crystal form. The linezolid is used as a raw material and forms a salt with hydrochloric acid in an organic solvent, which solves the problems that the linezolid hydrochloride is low in yield and inconvenient in storage and transportation. At the same time, during the crystallization process, water is used as a solvent, which effectively solves the problem of excessive residual solvent in the finished product of the linezolid. The obtained product by the method is high in yield and high in purity; the operation is good; the reproducibility is good; and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of crystal forms, and in particular relates to a preparation method of linezolid crystal form B. Background technique [0002] Linezolid, chemical name: (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] Methyl]acetamide, is the first synthetic oxazolidinone antibacterial drug used in clinical practice, used to treat infections caused by Gram-positive (G+) cocci, including suspected or confirmed nosocomial infections caused by MRSA Acquired pneumonia (HAP), community-acquired pneumonia (CAP) complicated skin or skin and soft tissue infection (SSTI), and vancomycin-resistant enterococcus (VER) infection, its molecular formula is C 16 h 20 FN 3 o 4 , has the structure of the following formula (I): [0003] [0004] (I) [0005] A variety of crystal forms of linezolid have been reported, and the literature (J.Med.Chem.39 (3) 673-679, 1996) discloses the crystal form I of linezolid, whic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20
CPCC07B2200/13C07D263/20
Inventor 杨勇陈安丰周君安葛旭周炳城乔智涛刘丙贤
Owner JIANGSU HANSOH PHARMA CO LTD
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