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Preparation method for cyclized intermediate of florfenicol

A florfenicol and intermediate technology, which is applied in the field of preparation of florfenicol cyclic compound intermediates, can solve the problems of difficult recovery of glycerol, low product yield, long reaction time and the like, and achieves strong reduction activity and selectivity. The effect of high sex and fast reaction rate

Active Publication Date: 2019-09-10
京山瑞生制药有限公司
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AI Technical Summary

Problems solved by technology

Especially in the preparation of D-threo-2-(dichloromethyl)-4,5- Glycerol is used as a solvent in the process of dihydro-5-[p-(thymphenyl)phenyl]-4-oxazole methanol, and glycerol is not easy to recover in this process, and a large amount of water is needed for washing, and the amount of sewage is large and the cost is high. Disadvantages of reaction time of more than 20 hours
And obviously there are two directions of competitive ring-forming reactions in the cyclization reaction, resulting in many side reactions and low product yields.

Method used

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  • Preparation method for cyclized intermediate of florfenicol
  • Preparation method for cyclized intermediate of florfenicol
  • Preparation method for cyclized intermediate of florfenicol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Cyclization reaction: 287.3 g of D-threo-p-thymphenyl phenylserine ethyl ester was added to 2000 ml of ethanol, and then 132 g of dichloroacetonitrile was added. At a reaction temperature of 80 degrees, the reaction time was 2 hours. Obtain the cyclization product intermediate;

[0032] (2) Reduction reaction: the cyclization product obtained in step (1) does not need to be separated. After cooling down, 37.9 g of reducing agent sodium borohydride is added, and the reaction is carried out at 20 degrees for 4 hours. After the reaction is over, add water to lower the temperature and precipitate the product. After filtration, the key intermediate compound D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) is obtained after filtration. ) phenyl]-4-oxazolemethanol.

[0033] The product quality after drying is 320g, the yield is 94.6%, and the content is greater than 99%.

Embodiment 2

[0035] (1) Cyclization reaction: 287.3 g of D-threo-p-thymphenyl phenylserine ethyl ester was added to 2000 ml of methanol, and then 220 g of dichloroacetonitrile was added. At a reaction temperature of 40 degrees, the reaction time was 5 hours. Obtain the cyclization product intermediate;

[0036] (2) Reduction reaction: the cyclization product obtained in step (1) does not need to be separated. After cooling down, 107.9 g of reducing reagent potassium borohydride is added, and the reaction is carried out at 60 degrees for 2 hours. After the reaction is over, add water to lower the temperature and precipitate the product. After filtration, the key intermediate compound D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) is obtained after filtration. ) phenyl]-4-oxazolemethanol.

[0037] The product quality after drying is 330g, the yield is 97.6%, and the content is greater than 99%.

Embodiment 3

[0039] (1) Cyclization reaction: 287.3 g of D-threo-p-thymphenyl phenylserine ethyl ester was added to 2000 ml of methanol, and then 165 g of dichloroacetonitrile was added. At a reaction temperature of 60 degrees, the reaction time was 4 hours. Obtain the cyclization product intermediate;

[0040] (2) Reduction reaction: the cyclization product obtained in step (1) does not need to be separated, after cooling down, add 45 g of reducing agent lithium aluminum hydride, and react at 40 degrees for 3 hours. After the reaction is over, add water to lower the temperature and precipitate the product. After filtration, the key intermediate compound D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) is obtained after filtration. ) phenyl]-4-oxazolemethanol.

[0041] The product quality after drying is 333g, the yield is 98.5%, and the content is greater than 99%.

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Abstract

The invention discloses a preparation method for a key intermediate of florfenicol. The preparation method comprises the following steps: with D-threo-p-methylsulfonylphenylserine ethyl ester as a starting material, directly allowing the D-threo-p-methylsulfonylphenylserine ethyl ester to undergo a cyclization reaction with dichloroacetonitrile, and directly allowing an obtained cyclization product to undergo a reduction reaction without the need of isolation so as to prepare a key intermediate compound of the florfenicol, i.e., D-threo-2-(dichloromethyl)-4,5-dihydro-5-[para-(methylsulfonyl)phenyl]-4-oxazole methanol. The preparation method provided by the invention avoids side reactions and the use of a glycerin solvent, greatly improves economy, simplifies subsequent treatment steps, andfurther improves the yield of a product.

Description

technical field [0001] The invention belongs to the technical field of veterinary drug synthesis, and in particular relates to a preparation method of a florfenicol ring compound intermediate. Background technique [0002] Florfenicol (Florfenicol) Chinese name: fluprofen; Florfenicol is a commonly used veterinary antibiotic at present. It has a broad antibacterial spectrum, strong antibacterial effect, low minimum inhibitory concentration (MIC), and its antibacterial effect is 15-20 times that of chloramphenicol and thiamphenicol. At present, China is the main producer and exporter of veterinary antimicrobial Florfenicol. According to statistics, in 2015, the export of florfenicol in my country reached 2199 tons, and with the rectification of food safety in recent years, the amount used in the international animal protection market has continued to expand. [0003] D-threo-2-(dichloromethyl)-4,5-dihydro-5-[p-(thymphenyl)phenyl]-4-oxazolemethanol is the key intermediate fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/14
CPCC07D263/14
Inventor 张治国钟旭辉周国朝徐相雨
Owner 京山瑞生制药有限公司
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