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Preparing method for linezolid and intermediate thereof

A technology of linezolid and its compounds, applied in the fields of organic chemistry, organic chemistry, etc., can solve the problems of insufficient optical purity of linezolid and its intermediates, low total yield of synthetic routes, unsuitability for industrial production, etc., to avoid Inflammable, explosive and toxic reagents, easy operation, mild reaction effect

Active Publication Date: 2016-05-11
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The present invention aims at the deficiencies in the prior art that the optical purity of linezolid and its intermediates is insufficient, the starting materials are not easy to obtain, the total yield of the synthetic route is low, and a large amount of flammable, explosive and toxic chemical reagents are used, which are not suitable for industrial production, and provide A simple synthetic method for synthesizing high-purity linezolid, aimed at overcoming some shortcomings in the above synthetic method of linezolid that are not suitable for industrial production

Method used

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  • Preparing method for linezolid and intermediate thereof
  • Preparing method for linezolid and intermediate thereof
  • Preparing method for linezolid and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1, the preparation of compound B

[0047]

[0048] In a 500ml autoclave under a hydrogen atmosphere, add compound A: ethyl 4-chloroacetoacetate (50g, 0.30mol), 5ml hydrochloric acid (AR, content 36% to 38%), 300ml methanol, stir the reaction solution to dissolve, add Chiral ruthenium metal catalyst (R)-RuCl 2 (BINAP) (50mg), the reaction liquid was replaced with hydrogen twice, the pressure was raised to 8-10 atmospheres, and the temperature was kept at 95-98°C for 1-2 hours. The reaction was cooled to room temperature and analyzed directly by GC to measure the conversion (column: HP-10125m / 0.2mm) and enantiomeric excess (column: Lipodex-E25m / 0.25mm). The enantiomeric excess was 99.95% and the conversion was 100%. After the filtrate was dried and filtered, the solvent was distilled off under reduced pressure to obtain compound B, which was directly used in one-step reaction.

Embodiment 2

[0049] Embodiment two, the synthesis of compound C

[0050]

[0051] The compound B obtained in Example 1 was dissolved in 200ml of dichloromethane, sodium carbonate (37.2g, 0.35mol) was added to the reaction solution to cool down to 0-5°C, acetyl chloride (23.5g, 0.30mol) was added dropwise, and the reaction was kept for 5h , 200ml of water was added, the organic phase was washed successively with water and saturated brine, dried and filtered, and the solvent was distilled off under reduced pressure to obtain 53.5 g (0.256 mol) of the crude product of Compound C, with a molar yield of 95%.

Embodiment 3

[0052] Embodiment three, the synthesis of compound D

[0053]

[0054] Compound C (53.5 g, 0.256 mol) synthesized in Example 2 was dissolved in 200 ml of dichloromethane, 3-fluoro-4-morpholinoaniline (compound IV, 52 g, 0.265 mol) was added, stirred at room temperature to dissolve, and added Sodium carbonate (35.3g, 0.33mol), keep stirring at room temperature for 4 to 8 hours, TLC detects that the reaction is complete, add 200ml of water and stir for 1h, the organic phase is washed with water in turn, washed with saturated saline, dried and filtered, and the solvent is distilled off under reduced pressure to obtain intermediate Body D84g (0.23mol), molar yield 90%.

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Abstract

The invention relates to a preparing method for linezolid and an intermediate thereof. The preparing method includes the step that 4-chloracetyl acetate compound (I) serves as a starting raw material and is subjected to asymmetric chiral reduction, acetylation, condensation, ammonolysis, Hoffman degradation, acetylation and cyclization to obtain (S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide (linezolid). Compared with other linezolid synthesis methods, the preparing method is high in total yield and product purity, raw materials are cheap and easy to obtain, flammable, combustible and poisonous reagents are avoided, and the production technology is safe and environmentally friendly.

Description

technical field [0001] The invention relates to a synthesis method of linezolid and its intermediate. 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 for clinical use in the treatment of infections caused by Gram-positive (G+) cocci, including suspected or confirmed cases caused by MRSA Hospital-acquired pneumonia (HAP), community-acquired pneumonia (CAP), complicated skin or skin and soft tissue infection (SSTI), and vancomycin-resistant enterococcus (VER) infection. In addition, the clinical efficacy of linezolid is better than or It is equivalent to conventional antibacterial drugs, and the toxicity is very small, and it is safe and easy to use. Linezolid has a unique drug structure and mechanism of action. It is an inhibitor of bacterial protein synthesis. It does not affect the activity of peptidyl transferase, but sele...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20C07D295/135
CPCC07B2200/07C07D263/20C07D295/135
Inventor 杨勇乔智涛陈安丰周炳城刘丙贤周君安葛旭
Owner JIANGSU HANSOH PHARMA CO LTD
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