Preparation method of linezolid derivative

A technology of linezolid and derivatives, applied in the field of medicine, can solve problems such as being difficult to obtain, and achieve the effects of low production cost, strong operability, and easy analysis and control

Inactive Publication Date: 2015-06-24
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But in the prior art, it is difficult to obtain as the standard substance of the linezolid derivative used for analysis, and there is no report on the preparation method of the linezolid derivative at present, so it is necessary to study on the basis of the prior art Design a preparation method for linezolid derivatives that can realize large-scale industrial production

Method used

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  • Preparation method of linezolid derivative
  • Preparation method of linezolid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of Linezolid Derivatives (I)

[0031] like figure 1 Shown, the preparation of intermediate 2: Take linezolid intermediate 1 (10 g, 0.051 mol) and dissolve in dichloromethane (100 ml), add triethylamine (10.29 g, 0.101 mol) under ice-cooling, then Then add benzyl bromide (13g, 0.075 mol) to the reaction solution obtained and reflux at 45°C for 24 hours, point plate to observe that about half of the raw material remains in the reaction, add 50ml saturated sodium bicarbonate to the reaction solution, and separate the organic phase. The aqueous phase was extracted with dichloromethane again, and the combined organic phase was concentrated to obtain 15 g of oil, which was then further purified by silica gel column chromatography, and the eluent was petroleum ether:ethyl acetate=95:5 to obtain 5.4 g of yellow intermediate Body 2 is solid.

[0032] Intermediate 2 1 H NMR (300 MHz, CDCl3) data is:

[0033] 1H NMR (300 MHz, CDCl3) δ: 7.27~7.35 (m, 5H), ...

Embodiment 2

[0044] Example 2 Preparation of Linezolid Derivatives (I)

[0045] like figure 1 As shown, the preparation of intermediate 2: Dissolve linezolid intermediate 1 (10 g, 0.051 mol) in dichloromethane (100 ml), add under ice-cooling, pyridine (0.201 mol), and then add benzyl bromide (0.101 mol) of the reaction solution obtained was refluxed at 45°C for 24 hours, and the plate was observed to observe that about half of the raw materials remained in the reaction, and 50ml of saturated sodium bicarbonate was added to the reaction solution, and the organic phase was separated, and the aqueous phase was then washed with dichloromethane Methane extraction, the combined organic phases were concentrated to obtain 15 g of oil, which was further separated and purified by silica gel column chromatography, the eluent was petroleum ether:ethyl acetate=95:5, and 5.4 g of yellow intermediate 2 was obtained as a solid.

[0046] Intermediate 2 1 H NMR (300 MHz, CDCl3) data is:

[0047] 1H NMR ...

Embodiment 3

[0058] Example 3 Preparation of Linezolid Derivatives (II)

[0059] like figure 2 As shown, the preparation of intermediate 6: Take intermediate 3 (2.74g, 0.008mol) and intermediate 4 (2.88g, 0.008mol) prepared in Example 1 and react in isopropanol (55 ml) at 80°C for 16h , Spot the plate to observe that there are about 20% of the raw material remaining, and the crude product obtained by concentrating the reaction solution is purified through the column, and the developing solvent is dichloromethane:methanol=98:2~90:10, and 2.5 grams of the intermediate 6 product is obtained.

[0060] Preparation of Intermediate 7: Dissolve Intermediate 6 (2.5g, 0.003mol) in dichloromethane (30 ml), add pyridine (0.56g, 0.007mol), acid anhydride (0.36g, 0.003mol), and react at room temperature After 2 hours, the plate reaction was almost complete, water (50 ml) was added, dichloromethane was used for extraction, the combined organic phase was evaporated to dryness, and the column was purifie...

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Abstract

The invention discloses a preparation method of a linezolid derivative. Abundant screening experiments are performed to determine the optimal reactant consumption, reaction temperature, reaction time, reaction solvent and the like in the preparation technique; and the whole preparation technique has the advantages of high operability, high preparation efficiency and low production cost, and can implement industrialized mass production. The bosentan metabolite (hydroxy bosentan) prepared by the method has the advantages of higher bioavailability and lower untoward effect, and directly can have the antihypertensive effect.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to an antibacterial drug, a preparation method of a linezolid derivative, and belongs to the technical field of medicine. Background technique [0002] Linezolid, a synthetic oxazolidinone antibacterial drug, was developed by Pharmacia and Upjohn. Approved by the US FDA in 2000 for the treatment of infections caused by Gram-positive (G+) cocci, including suspected or confirmed nosocomial-acquired pneumonia (HAP), community-acquired pneumonia (CAP), complicated skin or skin caused by MRSA Soft tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) infection. [0003] However, during the production and preparation of linezolid, the API often contains linezolid derivatives or multiple structurally similar components, and the content of each linezolid derivative has strict limits. In the actual drug production process, these Linezolid derivatives are used for content ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/135C07D263/20
CPCC07D263/20C07D295/135
Inventor 郝昆明凌通徐一鸣刘春
Owner TLC NANJING PHARMA RANDD CO LTD
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