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Preparation method for antibacterial drug linezolid

A technology of linezolid and acetamide, applied in the field of organic compound preparation, can solve the problems of high cost of industrialized production, difficult to obtain raw materials, complicated process and the like, and achieve the effects of safe industrialized production, convenient industrialized production and short reaction time

Inactive Publication Date: 2011-10-05
湖北省医药工业研究院有限公司
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Problems solved by technology

[0008] Synthetic method 2 was reported by Xu Guangyu et al. This route is based on method 1. Although n-butyllithium conditions are avoided, intermediate 11 in the route is not easy to obtain, and sodium azide is used at the same time, which is not suitable for industrialization Production; In addition, Huang Qiang, Moran-Ramallal R, etc. have also reported similar synthetic methods based on method 1, which are also not suitable for industrial production due to the difficulty in obtaining intermediates and the use of sodium azide.
[0009] Synthetic method 3 was reported by Lohray BB et al. The raw materials of this method are not easy to obtain. The whole route includes multiple hand-type conversions, and flammable and explosive reagents such as sodium azide are still used. Column chromatography purification is required, and the cost of industrial production is relatively high. Not suitable for industrial production;
[0010] Synthetic method 4 is reported by Immrodino RJ etc., the raw material of this method cannot be purchased, and industrial production cannot be completed
[0011] Synthetic method 5 was reported by Yu Desheng et al. The raw materials of this method are not easy to obtain and sodium azide is used, which is not suitable for industrial production
[0012] Synthetic method 6 is reported by Madhusudhan G etc., this method process is complicated, has used raw materials such as sodium azide, ethanethiol, is not suitable for industrialized production

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  • Preparation method for antibacterial drug linezolid

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Effect test

Embodiment 1

[0021] The preparation method of linezolid comprises the following steps: Linezolid is purified after condensation reaction in a solvent, the condensing agent is lithium tert-butoxide, the solvent is a mixed solvent of dimethylformamide, methanol and dichloromethane, dimethylformamide, methanol and dichloromethane The volume ratio of methyl chloride is: 7-9:0.8-1.2:75-85.

[0022] The condensation reaction is: add N-benzyloxyhydroxy-3-fluoro-4-morpholinoaniline, dimethylformamide, methanol, dichloromethane and lithium tert-butoxide into a container, stir, and add (S) -N-[2-acetoxy-3-chloropropyl]acetamide, heat preservation reaction at 35-45°C for 8-14 hours.

[0023] The purification is as follows: adding saturated NH4Cl, water, and saturated saline in sequence, standing for stratification, separating the organic layer, and distilling off the solvent to obtain an oily substance, which is refined with ethyl acetate and dried to obtain a white linezolid solid ; mp178-182°C, y...

Embodiment 2

[0025] 1. Synthesis of 3-fluoro-4-morpholinonitrobenzene

[0026] In a 500 ml three-necked flask, add 18 g of morpholine, 150 ml of ethyl acetate, and 20.4 g of triethylamine. While stirring at room temperature, slowly add 32.15 g of 3,4-difluoronitrobenzene dropwise at room temperature (25°C) Stir overnight, add 250 ml of ethyl acetate for extraction, wash with 250 ml of saturated brine, let stand to separate the layers, separate the organic layer, evaporate the solvent, and dry at 50°C to obtain 44.3 g of yellow solid, yield 95.3%, mp 108 °C-109 °C.

[0027] 2. Synthesis of N-benzyloxyhydroxy-3-fluoro-4-morpholinoaniline

[0028] In a 500 ml three-necked flask, add 27.2 g of 3-fluoro-4-morpholino nitrobenzene, 2.6 g of 10% Pd / C, 28.7 g of ammonium formate, and 360 ml of acetone, stir, and at an internal temperature of 47°C React for 3 h, cool to room temperature, filter with suction, transfer the filtrate to a 1000 ml three-necked flask, add 360 ml acetone and 22.4 g NaH...

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Abstract

The invention relates to a preparation method for linezolid, which comprises the following steps of: carrying out condensation reaction on N-benzyloxyl hydroxyl-3-fluoro-4-morpholinyl aniline and (S)-N-[2-acetoxyl-3-chloropropyl] acetamide in a solvent and purifying to obtain linezolid, wherein a condensating agent is lithium tert-butoxide, the solvent is a mixed solvent of dimethyl formamide, methanol and dichlormethane in volume ratio of (7-9):(0.8-1.2):(75-85). The preparation method has the advantages of simple operation, shorter reaction time and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of organic compounds, more specifically to a preparation method of linezolid, an antibacterial drug. Background technique [0002] Linezolid (Linezolid, Zyvox, U-100766, PNU-100766, Linezolidone, Morinoxone) is a new type of oxazolidinone antibacterial drug, researched and developed by Pharmacia & Upjohn Company of the United States, and was approved by the United States on April 18, 2000. FDA approval for marketing. [0003] In recent years, the widespread use or even abuse of antibiotics has made the resistance of bacteria increasingly serious, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and antibiotic-resistant Streptococcus pneumoniae (PRSP) , the emergence of multidrug-resistant Mycobacterium tuberculosis, especially vancomycin-resistant enterococci (VRE), has caused difficulties in clinical treatment. In order to solve th...

Claims

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Application Information

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IPC IPC(8): C07D263/20
Inventor 沈华凌飒刘红杨萍刘洁代利萍刘建军吴明波
Owner 湖北省医药工业研究院有限公司
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