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A kind of preparation method of linezolid intermediate

A technology for linezolid and intermediates, applied in the field of preparation of linezolid intermediates, to achieve the effects of reduced production costs, low prices, and high product yields

Active Publication Date: 2022-06-24
泰州申合泰尔生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The object of the present invention is to provide a kind of preparation method of linezolid intermediate, to solve the problem raised in the above-mentioned background technology

Method used

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  • A kind of preparation method of linezolid intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The preparation step of the intermediate N-(3-phthalimido-2-(S)-hydroxypropyl)-3-fluoro-4-(morpholinyl)aniline (I) of linezolid is as follows:

[0035] Preparation of raw materials: N,N-dimethylacetamide is the amide dipolar solvent, and sodium bromide is selected as the reaction accelerator;

[0036] The (II):(III) molar ratio was 2:1.

[0037] (1) In a 250 ml reaction flask, dissolve 4.0 g (II) in 30 ml of N,N-dimethylacetamide solvent, add 2.4 g (III) and 1.0 g sodium bromide, stir for 20 min, and heat up to Under the condition of 100℃, react for 20h to obtain a reaction solution;

[0038] (2) The reaction solution obtained in step (1) was cooled to room temperature; 50ml of dichloromethane and 50ml of water were added, and the liquid was stirred and separated, 50ml of water was added to the organic phase, washed 3 times, and the organic phase was dried with anhydrous magnesium sulfate, The crude product was obtained by concentration, and the crude product was sepa...

Embodiment 2

[0040] The preparation step of the intermediate N-(3-phthalimido-2-(S)-hydroxypropyl)-3-fluoro-4-(morpholinyl)aniline (I) of linezolid is as follows:

[0041]Preparation of raw materials: N,N-dimethylacetamide is the amide dipolar solvent, and sodium bromide is selected as the reaction accelerator;

[0042] The (II):(III) molar ratio was 1.77:1.

[0043] (1) In a 250 ml reaction flask, dissolve 3.5 g of (II) in 30 ml of N,N-dimethylacetamide solvent, add 2.4 g of (III) and 1.5 g of sodium bromide, stir for 20 min, and heat up to Under the condition of 100℃, react for 20h to obtain a reaction solution;

[0044] (2) The reaction solution obtained in step (1) was cooled to room temperature; 50ml of dichloromethane and 50ml of water were added, and the liquid was stirred and separated, 50ml of water was added to the organic phase, washed 3 times, and the organic phase was dried with anhydrous magnesium sulfate, The crude product was obtained by concentration, and the crude produ...

Embodiment 3

[0046] The preparation step of the intermediate N-(3-phthalimido-2-(S)-hydroxypropyl)-3-fluoro-4-(morpholinyl)aniline (I) of linezolid is as follows:

[0047] Preparation of raw materials: N,N-dimethylacetamide is the amide dipolar solvent, and tetrabutylammonium bromide is selected as the reaction accelerator;

[0048] The (II):(III) molar ratio was 1.83:1.

[0049] (1) In a 250ml reaction flask, dissolve 3.6g (II) in 30ml of N,N-dimethylacetamide solvent, add 2.4g (III) and 1.5g tetrabutylammonium bromide, stir for 25min , the temperature was raised to 120 °C, and the reaction was carried out for 21 h to obtain a reaction solution;

[0050] (2) The reaction solution obtained in step (1) was cooled to room temperature; 50ml of dichloromethane and 50ml of water were added, and the liquid was stirred and separated, 50ml of water was added to the organic phase, washed 3 times, and the organic phase was dried with anhydrous magnesium sulfate, The crude product was obtained by c...

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Abstract

The invention discloses a preparation method of a linezolid intermediate. Using 3-fluoro-4-(4-morpholino)-aniline and 2-((S)-3-chloro-2-hydroxypropyl) isoindoline-1,3-dione as main raw materials, In an amide dipolar solvent, at a temperature of 90-150°C, a substitution reaction occurs to obtain an important intermediate N-(3-phthalimido-2-(S)-hydroxypropyl base)-3-fluoro-4-(morpholinyl)aniline. The preparation steps of the intermediate are simple, and the preparation process does not use dangerous reagents such as butyllithium, sodium azide, chloroformate, methanesulfonyl chloride, etc. in the conventional process, which are flammable, explosive, and highly toxic, and have high safety. ; The main raw materials 3‑fluoro‑4‑(4‑morpholinyl)‑aniline and 2‑((S)‑3‑chloro‑2‑hydroxypropyl) isoindoline‑1,3‑dione are stable sources , low cost, and the used amide dipole solvent is easy to recycle, which can reduce environmental pollution.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a preparation method of a linezolid intermediate. Background technique [0002] Linezolid is the first new type of oxazolidinone antibacterial drug to be used in clinic, and it shows high antibacterial activity against all kinds of gram-positive cocci in vitro and in vivo. Linezolid is a bacterial protein synthesis inhibitor that acts on the bacterial 50S ribosomal subunit to terminate bacterial protein synthesis. Linezolid has a unique action site and mode, and it is not easy to cross-resistance with other antibacterial drugs that inhibit protein synthesis, and it is not easy to induce drug resistance in vitro. It is mainly used to treat bacteremia caused by vancomycin-resistant enterococci (VRE), pneumonia and combined skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA), and bacteremia caused by penicillin-resistant Streptococcus pneum...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/48C07D413/06
CPCC07D209/48C07D413/06C07B2200/07
Inventor 孙炳峰孙炳峻孔德剑
Owner 泰州申合泰尔生物医药有限公司
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