Preparation method for Linezolid

The technology of linezolid and compound is applied in the field of preparation of oxazolidinone antibiotics, can solve the problems of easy moisture absorption, difficult to store, uneconomical atom/process, etc., and achieves mild reaction conditions, high yield and purity, The effect of easy availability of reagents

Active Publication Date: 2016-02-24
ANHUI YOUCARE KAIYUE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, lithium alkoxides (such as lithium tert-butoxide, lithium tert-amyloxide, etc.) are easy to absorb moisture and are not easy to store. It is difficult for commercially available lithium alkoxides to meet the purity requirements for the preparation of linezolid, whether they are reagent grade or industrial grade. The reaction is promoted with freshly prepared lithium alkoxide
Taking the preparation of lithium tert-butoxide as an example, the document OrganicSyntheses, 1988, 6, 259 reported that lithium tert-butoxide was prepared by reacting tert-butanol and n-butyllithium, and directly participated in the esterification reaction after the solvent was evaporated; this method is feasible but the atom / process Uneconomical, demanding purification operations and anhydrous

Method used

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  • Preparation method for Linezolid
  • Preparation method for Linezolid
  • Preparation method for Linezolid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Under the protection of nitrogen, add 0.33g (1.0mmol) compound I, 0.05g (1.2mmol) lithium chloride, 0.14g (1.5mmol) sodium tert-butoxide, 0.13g (1.2mmol) trimethylchlorosilane (1.2mmol) to 20mL dry tetrahydrofuran ), stirred at room temperature for 40 minutes, cooled to 0°C, added dropwise 0.28g (2.5mmol) of compound II dissolved in 10mL of tetrahydrofuran, stirred at 0°C for 30 minutes, then raised the temperature to 28°C for 12 hours, HPLC showed that 85% of the raw compound I had reacted completely. Add acetic acid to neutralize to a pH value of 6-7, then add 50mL dichloromethane and 30mL water solution, extract the water phase with 3×30mL dichloromethane, combine the organic phases with anhydrous sodium sulfate, filter and concentrate, and the oily product is washed with acetic acid Ethyl ester was recrystallized, cooled to room temperature and then crystallized at -15°C, filtered, washed with glacial ethyl acetate, and vacuum dried to obtain 0.18 g of white powdery...

Embodiment 2

[0028] Under nitrogen protection, add 0.33g (1.0mmol) of compound I, 0.07g (0.8mmol) of lithium bromide, 0.16g (1.3mmol) of potassium tert-amylate, and 0.11g of trimethylformamide to 15mL of dry N,N-dimethylformamide Chlorosilane (1.1mmol), stirred at room temperature for 40min, cooled to 0°C, 0.21g (1.8mmol) of compound II dissolved in 5mL N,N-dimethylformamide was added dropwise, stirred at 0°C for 30min, then heated to 30 React at ℃ for 10 hours, add saturated ammonium chloride aqueous solution to neutralize to pH 6-7, then add 50mL chloroform and 30mL water solution, extract the water phase with 3×30mL chloroform, combine the organic phases and dry them with anhydrous sodium sulfate, filter and concentrate. The oil was recrystallized with acetone, cooled to room temperature and then crystallized at -15°C, filtered, washed with ice acetone, and vacuum dried to obtain 0.15 g of a white powdery solid with a purity of >96% and a yield of 47%.

Embodiment 3

[0030] Under the protection of argon, add 0.33g (1.0mmol) compound I, 0.04g (1.0mmol) lithium chloride, 0.28g (2.5mmol) potassium n-butoxide, 0.15g trimethylchlorosilane (1.4 mmol), stirred at room temperature for 40 minutes, cooled to 0°C, added dropwise 0.32 g (3.0 mmol) of compound II dissolved in 5 mL of acetonitrile, and stirred at 0°C for 40 minutes, then raised the temperature to 30°C for 22 hours, added saturated ammonium chloride aqueous solution to neutralize To pH 6-7, add 50mL chloroform and 30mL water solution, extract the water phase with 3×30mL chloroform, combine the organic phase and dry it with anhydrous sodium sulfate, filter, concentrate, recrystallize the oil with butyl acetate, and cool to room temperature Then crystallize at -15°C, filter, wash the filter cake with glacial butyl acetate, and vacuum dry to obtain 0.20 g of white powdery solid with a purity of >96% and a yield of 61%.

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Abstract

The invention relates to the oxazolidinone antibiotic medicine preparation field, and concretely relates to a preparation method for Linezolid. A compound I and a compound II are employed as raw materials, halogenated lithium, alkyl alcohol sodium or alkyl alcohol potassium and trimethylchlorosilane are added to promote construction of an oxazolone ring, and furthermore a Linezolid bulk drug is prepared. The reaction chemical equation is shown in the specification. The preparation method has advantages of atom economy, easily available reagents, mild reaction conditions, environmental protection, high yield and purity and the like compared with the prior art.

Description

technical field [0001] The present invention relates to the field of preparation of oxazolidinone antibiotic drugs, in particular to a method of promoting the construction of oxazolone ring by taking lithium halide, sodium or potassium alkoxide and trimethylchlorosilane to prepare linezolid bulk drug Methods. Background technique [0002] Linezolid (Linezolid, trade name Zyvox) is an oxazolidinone antibiotic approved by the US FDA in 2000 for the treatment of bacteremia caused by vancomycin-resistant Enterococcus (VER) and methicillin-resistant Staphylococcus aureus Treatment of pneumonia and complex skin infections caused by (MRSA) and bacteremia caused by penicillin-resistant Streptococcus pneumoniae (PRSP). [0003] One of the difficulties in the preparation of linezolid is the construction of the five-membered ring of oxazolone in its structure. From the perspective of synthetic strategy, the ring closure of oxazolone can be carried out by using one molecule of amideox...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/20
CPCC07D263/20
Inventor 周如国刘维坦邢怀阳
Owner ANHUI YOUCARE KAIYUE PHARMA
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