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Synthesis method of linezolid intermediate

A compound and water volume technology, applied in the field of synthesis of linezolid intermediates, can solve problems such as low yield, and achieve the effects of high reaction yield, cheap and readily available raw materials, and mild reaction

Active Publication Date: 2013-05-15
ANGELYEAST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to provide a method for synthesizing oxazolidinone as shown in formula II for the shortcoming of low yield in the synthesis method of linezolid intermediate oxazolidinone in the prior art

Method used

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  • Synthesis method of linezolid intermediate
  • Synthesis method of linezolid intermediate
  • Synthesis method of linezolid intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: the fermentation preparation of dehalogenase

[0043] (1) Seed tank fermentation:

[0044] Medium components: peptone 10-15g / L, yeast extract 5-20g / L, glucose 8-20g / L (or glycerol 5-10g / L), KH 2 PO 4 10-15g / L, (NH 4 ) 2 HPO 4 4.0-5.0g / L, (NH 4 ) 2 SO 4 1-2g / L, MgSO 4 ·7H 2 O 1-1.5g / L, citric acid 1.5-2.0g / L, CoCl 2 ·6H 2 O 2-3mg / L, MnCl 2 4H 2 O 12-15.0mg / L, CuCl 2 4H 2 O 1-2mg / L, biotin 4-5mg / L, vitamin B1 4-5mg / L.

[0045] Base medium preparation: peptone, yeast extract, KH 2 PO 4 , (NH 4 ) 2 HPO 4 , (NH 4 ) 2 SO 4 , citric acid, CoCl 2 ·6H 2 O, MnCl 2 4H 2 O, CuCl 2 4H 2 O was stirred and dissolved, and the pH of the solution was adjusted to 6-7 with NaOH, kept at 121°C for 30 min, and cooled for later use. Glucose (or glycerol), MgSO 4 ·7H 2 O is sterilized separately and kept at 121°C for 20min. Biotin and vitamin B1 were sterilized by sterile membrane filtration. Then sterile glucose (or glycerol), MgSO 4 ·7H 2 O...

Embodiment 2

[0056] Embodiment 2: Preparation of 5-chloromethyl-2-oxazolidinone

[0057] synthetic route:

[0058]

[0059] Add 500ml of water into a 1000ml four-necked flask equipped with mechanical stirring, dissolve 32g of sodium cyanate, adjust the pH to 8 with 20% dilute sulfuric acid, add 25g of S-epichlorohydrin, slowly heat to 50°C, and add Halogenase 12.5 million units, control the pH at 8 during the reaction process, add 3g of activated carbon and stir for 30 minutes after the reaction for 8 hours, filter with suction, evaporate the filtrate to dryness under reduced pressure, dissolve and evaporate the dry matter with 1000ml methanol, and remove the insoluble substance by suction filtration. The filtrate was distilled under reduced pressure to obtain 40 g of the product, and the content of the target product was detected to be 84%, and the yield was 90%.

[0060] The hydrogen NMR spectrum of the reaction product ( 1 HNMR) detection and identification are correct.

Embodiment 3

[0065] Embodiment 3: the comparison of the yield of 5-chloromethyl-2-oxazolidinone prepared under different conditions

[0066] Synthetic route: with embodiment 2

[0067] According to the synthesis method of Example 2, different experimental conditions were changed, such as reaction temperature, reaction time, reaction pH value, concentration of added substrate and enzyme consumption, to compare the yield of the product obtained under each reaction condition. The results are shown in Table 1.

[0068] Comparison of product yields under different conditions in table 1

[0069]

[0070] The experimental results show that the concentration and temperature of the reaction substrate have a great influence on the reaction. From reactions 4 and 5, it can be seen that under the same conditions, the yield of low-concentration substrate is higher, this is because the substrate has a great influence on the activity of the enzyme, and the reason that the concentration is too high wi...

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Abstract

The invention discloses a preparation method of a linezolid intermediate. According to the method, the linezolid intermediate is obtained by reaction of an epoxide and a cyanate in water under the catalysis of dehalogenase. The reaction temperature is 40-60 DEG C, the reaction pH is 7.0-9.0, the content in percentage by mass-water volume of the epoxide is 1%-15%, and the amount of the dehalogenase is 50000U of the epoxide per gram-2 million U of the epoxide per gram. According to the preparation method disclosed by the invention, the dehalogenase is used for a catalytic reaction, the yield can achieve 90%, and in comparison with the yield without the use of the dehalogenase, the yield is obviously greatly improved; and furthermore, chiral separation is not required, high-temperature and high-pressure conditions are not required, the reaction is mild, the safety is high, the preparation method is environment-friendly, the raw materials are low in cost and easy to obtain, the reaction yield is high, and the preparation method is further suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing a linezolid intermediate. Background technique [0002] Oxazolidinone antibacterial drugs are another class of fully synthetic antibacterial drugs that have been marketed after sulfonamides and fluoroquinolones. They have a very broad antibacterial spectrum against Gram-positive bacteria. Staphylococcus vancomycin-resistant enterococcus, penicillin-resistant pneumococcus and anaerobic bacteria all have antibacterial activity. [0003] Linezolid is widely used as a typical oxazole antibiotic. This type of drug has shown good prospects in the treatment of multi-drug-resistant Gram-positive bacteria and Mycobacterium tuberculosis infection. The new mechanism of action makes it non-cross-resistant with other antibacterial drugs and has attracted the attention of domestic and foreign medical circles. It is expected to become another large class of new syn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/14C07D263/20
Inventor 付坤林俞学锋李知洪余明华余华顺邹林汉
Owner ANGELYEAST CO LTD
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