Novel Linezolid intermediate, its preparation method and novel preparation method of Linezolid

A technology of linezolid and intermediates, applied in the direction of organic chemistry, can solve the problems of high cost, low yield, harsh reaction conditions, etc., and achieve the effects of low cost, reduction of hydrolyzed products, and easy purification

Inactive Publication Date: 2012-08-01
SHANDONG SALUBRIS PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The purpose of the present invention is to overcome the problems of low yield, harsh reaction conditions and high cost of existing linezolid intermediates in the process of preparing linezolid, and provide a new linezolid intermediate

Method used

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  • Novel Linezolid intermediate, its preparation method and novel preparation method of Linezolid
  • Novel Linezolid intermediate, its preparation method and novel preparation method of Linezolid
  • Novel Linezolid intermediate, its preparation method and novel preparation method of Linezolid

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Experimental program
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Embodiment 13

[0036] Preparation of embodiment 13-fluoro-4-morpholinyl nitrobenzene

[0037] Add morpholine (3.50 g, 40.1 mmol), triethylamine (4.05 g, 40.1 mmol) and ethyl acetate (30 mL) into the three-neck flask and stir. Add 3,4-difluoronitrobenzene (5.80 g, 36.5 mmol) dropwise, and react at room temperature for 17 hours. TLC monitoring showed that the reaction was completed, filtered, and the filter cake was washed with water to obtain 7.39 g of the product 3-fluoro-4-morpholinylnitrobenzene in the form of yellow crystals, with a yield of 89.7%. 1 H NMR (CDCl 3 ): δ3.27 (4H, m), 3.87 (4H, m), 6.92 (1H, t, 7.0), 7.90 (1H, m), 7.98 (1H, m).

Embodiment 23

[0038] Preparation of embodiment 23-fluoro-4-morpholinylaniline

[0039] Add 3-fluoro-4-morpholinylnitrobenzene (5.14g, 22.7mmol), NH 4 Cl (6.22g, 116.0mmol) aqueous solution, ethanol and reduced iron powder (4.46g, 79.5mmol), stirred, heated to reflux reaction, TLC monitoring, the reaction was completed, filtered, the filtrate was concentrated, the residue was cooled and filtered, filtered The cake was washed with water and dried to obtain 4.12 g of brown powdery solid product 3-fluoro-4-morpholinoaniline, yield: 92.6%. 1 H NMR (CDCl 3 ): δ3.05 (4H, m), 3.61 (4H, m), 3.89 (4H, m), 6.43 (2H, m), 6.83 (1H, m).

Embodiment 3

[0040] The preparation of embodiment 3N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline

[0041] Add 3-fluoro-4-morpholinylaniline (4.42g, 22.4mmol), NaHCO 3 (3.53g, 42.0mmol), acetone and water, stirred, and added benzyl chloroformate (CBZ-Cl) (4.42g, 25.8mmol) dropwise in an ice-salt bath, and the dropwise addition was completed. The system was heated to room temperature and reacted. TLC monitoring, the reaction is complete. The reaction solution was poured into water and stirred, filtered, the filter cake was washed with water, and dried to obtain a crude product, which was recrystallized to obtain 6.69 g of light orange product N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline, yield: 89.9%, Chemical purity: 99.8%.

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Abstract

The invention discloses a novel Linezolid intermediate, its preparation method and a novel preparation method of Linezolid, a structure of the Linezolid key intermediate is shown as a formula (I), in the formula (I), X is fluorine, chlorine, bromine or iodine. According to the invention, the Linezolid intermediate solves the problems of poor solubility of the Linezolid intermediate, and low yield and purity of the synthesized Linezolid in the prior art. The preparation methods of the invention have the advantages of easy preparation process, easy raw material acquisition, low cost, easy purification of intermediate product and final product, high yield and purity, and are suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to a new linezolid key intermediate (structure shown in formula I), its preparation method and a new preparation method of linezolid. [0002] Background technique [0003] Linezolid, chemical name (S)-N-[(3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl) Methyl]acetamide. It is the first new type of oxazolidinone antibacterial drug used clinically, and it was first listed in the United States in 2000. Its chemical structural formula (II) is as follows: [0004] [0005] Linezolid has high antibacterial activity against various Gram-positive cocci, and its antibacterial effect has nothing to do with bacterial drug resistance. A series of phase III clinical trial data on the treatment of community-acquired pneumonia, hospital-acquired pneumonia, skin and soft tissue infections and other diseases with linezolid showed that the clinical efficacy of linezolid was better than or equal to that of conventional a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20
Inventor 郑加林陈义朗韩硕张昌中许文杰谭颂德杨睿李孝仁叶宇翔叶澄海
Owner SHANDONG SALUBRIS PHARMA
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