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Preparation method of linezolid and intermediate thereof

一种利奈唑胺、时间的技术，应用在利奈唑胺的制备方法及其中间体领域，能够解决设备要求高、繁琐、操作条件苛刻等问题，达到后处理简单、工艺简单、易得价格的效果

Active Publication Date: 2010-07-14
LIANHE CHEM TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] The technical problem to be solved by the present invention is to overcome the harsh operating conditions in the existing preparation method of linezolid, which is not conducive to industrial production, has high requirements for equipment, has certain potential safety hazards, low yield, and difficult separation of by-products. , high cost, difficult access to chiral raw materials and cumbersome processes and other defects, a preparation method of linezolid and its intermediates are provided

Method used

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  • Preparation method of linezolid and intermediate thereof
  • Preparation method of linezolid and intermediate thereof

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Experimental program
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Effect test

Embodiment 13

[0058] Preparation of embodiment 13-fluoro-4-morpholinyl nitrobenzene

[0059] Morpholine (60g, 0.69mol) was added in 300mL ethyl acetate, triethylamine (70g, 0.69mol) was added, 3,4-difluoronitrobenzene (100g, 0.63mol) was added dropwise, and the temperature of the feed liquid was controlled to be lower than 50°C, drop it within 1 hour. Maintain the temperature at 45-50°C for 10 hours until the reaction is complete. Extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and dried to obtain 138 g of a yellow solid with a yield of 97%.

[0060] 1 H NMR (300MHz, CDCl 3 )δ: 3.28 (m, 4H, CH 2 CH 2 N), 3.88 (m, 4H, CH 2 CH 2 O), 6.92(t, 1H, Ar H ), 7.91 (dd, 1H, Ar H ), 7.99 (dd, 1H, Ar H ) HPLC: 99.1%.

Embodiment 23

[0061] Preparation of embodiment 23-fluoro-4-morpholinylaniline

[0062] Add 3-fluoro-4-morpholinylnitrobenzene (40g, 177mmol), ammonium formate (50g, 793mmol), 10% Pd / C 4.0g into 200mL ethyl acetate, heat to 45-50°C for 8h, until The response is complete. Filter, add water to separate layers, wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate, filter, and distill off the solvent to obtain 33 g of solids, with a yield of 95%.

[0063] 1 H NMR (300MHz, CDCl 3 )δ: 3.01 (m, 4H, CH 2 CH 2 N), 3.56 (br, 2H, Ar NH 2 3.86 (m, 4H, CH 2 CH 2 O), 6.41 (m, 2H, Ar H ), 6.79 (m, 1H, Ar H ) HPLC: 99.0%.

Embodiment 3

[0064] The preparation of embodiment 3N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline (compound 3)

[0065] 3-Fluoro-4-morpholinoaniline (26g, 133mmol) was added to 200mL of acetone, sodium bicarbonate (17g, 202mmol) and 150mL of water were added. The feed solution was cooled to -10~0°C, benzyl chloroformate (26 g, 152 mmol) was added dropwise, and the dropwise was completed in 1 hour. The feed solution naturally rose to room temperature (25° C.), and the reaction was maintained for 2 hours. The feed solution was poured into 500 mL of ice water, filtered, and dried to obtain 39 g of off-white solid with a yield of 90%.

[0066] 1 H NMR (300MHz, CDCl 3 )δ: 3.01 (m, 4H, CH 2 CH 2 N), Ar NH 2 3.85 (m, 4H, CH 2 CH 2 O), 5.14(s, 2H, Ar CH 2 )6.93 (m, 3H, Ar H ), 7.35 (m, 6H, Ar H 、CN H c)

[0067] HPLC: 98.2%, recrystallized from ethyl acetate to obtain 37.6 g of white solid, HPLC: 99.4%.

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Abstract

The invention discloses a preparation method of linezolid (a compound 1), which comprises the following steps: (1) carrying out debenzylation reaction on a compound 4 in a solvent for preparing a compound 5; and (2) carrying out amino-group acetylation reaction on the compound 5 prepared in the first step for preparing and obtaining the compound 1. The invention also discloses an intermediate for preparing the compound 1. The preparation method of the invention has the advantages that chiral raw materials can be easily obtained and have low price, the process is simple, the post treatment is simple, both the intermediate product and the final product can be purified easily, the total yield is high, the purity is high, and the industrial production can be easily realized.

Description

technical field [0001] The invention relates to a preparation method of a medicine and an intermediate thereof, in particular to a preparation method of linezolid and an intermediate thereof. Background technique [0002] Linezolid, the English name is linezolid, the chemical name is (S)-N-{[3-(3-fluoro-4-(4-morpholinophenyl)-2-oxo-5-oxazolinyl] Methyl}-acetamide, its structural formula is as follows. [0003] [0004] Linezolid is the first synthetic oxazolidinone antibiotic, which was researched and developed by Pharmacia & Upjhon in the United States, and was approved for marketing by the FDA on April 18, 2000. The drug can treat nosocomial pneumonia, skin and soft tissue infection, community infectious pneumonia and other diseases, and its efficacy has been confirmed by clinical research. In addition, the clinical efficacy of linezolid is better than or equal to that of conventional antibacterial drugs, and it is effective against infections caused by methicillin-re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20C07C215/08
CPCC07D263/20
Inventor 王萍潘强彪李杨州郑道亮
Owner LIANHE CHEM TECH
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