Preparation method of tildipirosin

A technology of tylosin and tylosin, which is applied to the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve unfavorable industrial scale-up production, incomplete silanization protection, and prone to side reactions, etc. problem, to achieve the effect of low cost, simple and easy operation, and reduced production cost

Active Publication Date: 2017-05-31
HUBEI LONGXIANG PHARMA TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The synthesis method reported in the patent CN 104497082 is that tylosin is prepared through 5 steps of hydrolysis, reduction ammoniation, sulfonate esterification, iodination and ammoniation, and there are many reaction steps, which is not conducive to industrial scale-up production
[0014] The synthesis method reported in patent CN 105254693 is that after tylosin undergoes reductive amination and hydrolysis of a sugar, the hydroxyl group on the allosyl group and the two hydroxyl groups in the mycaminosyl group are protected by silanization, and then combined with three Methyl iodosilane is subjected to iodination reaction, and finally amination reaction to prepare Tedirosin. This method has many reaction steps, and the silanization protection is not thorough and prone to side reactions

Method used

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  • Preparation method of tildipirosin
  • Preparation method of tildipirosin
  • Preparation method of tildipirosin

Examples

Experimental program
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Effect test

Embodiment 1

[0033] (1) Preparation of hydrolyzate

[0034] Dissolve 40g of tylosin tartrate in 100mL of water, add 110g of hydrochloric acid with a mass fraction of 20%, raise the temperature to 55°C and keep it warm for 3 hours. After the liquid phase monitors that the reaction is complete, cool down to room temperature and add 250mL of dichloromethane to the reaction solution , adjust the pH to 9-10 with 30% sodium hydroxide solution under ice-bath conditions, extract and separate the layers, and wash the organic layer three times with 300 mL water respectively.

[0035] (2) Preparation of sulfonated product

[0036] Take the organic layer of the previous reaction, add 8g p-toluenesulfonyl chloride and 9g triethylamine respectively, raise the temperature to reflux state and keep it warm for 3 hours, after the liquid phase monitors the reaction is complete, cool down to room temperature and add 200mL saturated sodium bicarbonate, extract and separate layers, After the organic layer was ...

Embodiment 2

[0040] (1) Preparation of hydrolyzate

[0041] Dissolve 40g of tylosin tartrate in 100mL of water, add 145g of hydrochloric acid with a mass fraction of 20%, raise the temperature to 60°C and keep it warm for 1.5 hours. After the liquid phase monitors that the reaction is complete, cool down to room temperature and add 250mL of ethyl acetate to the reaction solution , adjust the pH to 9-10 with 30% sodium hydroxide solution under ice-bath conditions, extract and separate the layers, and wash the organic layer three times with 300 mL water respectively.

[0042] (2) Preparation of sulfonated product

[0043]Take the organic layer of the reaction in the previous step, add 7.5g p-toluenesulfonyl chloride and 8.1g triethylamine respectively, raise the temperature to 50°C and keep it warm for 1.5 hours. After the organic layer was washed three times with 250 mL of water, the organic solvent was removed by rotary evaporation to obtain a total of 22.8 g of light yellow solid.

[00...

Embodiment 3

[0047] (1) Preparation of hydrolyzate

[0048] Dissolve 40g of tylosin tartrate in 100mL of water, add 130g of hydrochloric acid with a mass fraction of 20%, raise the temperature to 55°C and keep it warm for 2 hours. After the liquid phase monitors that the reaction is complete, cool down to room temperature and add 250mL of dichloromethane to the reaction solution , adjust the pH to 9-10 with 30% sodium hydroxide solution under ice-bath conditions, extract and separate the layers, and wash the organic layer three times with 300 mL water respectively.

[0049] (2) Preparation of sulfonated product

[0050] Take the organic layer of the previous step reaction, add 8.4g p-toluenesulfonyl chloride and 7.6g triethylamine respectively, raise the temperature to reflux state and keep it warm for 2.5 hours, after the liquid phase monitoring reaction is complete, cool down to room temperature and add 200mL saturated sodium bicarbonate, extract After the organic layer was washed three...

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Abstract

The invention provides a preparation method of tildipirosin. The preparation method comprises the following steps: tylosin A is hydrolyzed in an acidic solution, a hydrolysis product is extracted into an organic solvent A after hydrolysis, a sulfonate esterification reagent is added for sulfonate acidification reaction in the presence of alkali, extraction and layering are performed after the reaction, and a sulfonate esterified product is prepared; finally, the sulfonate esterified product is dissolved in an organic solvent B, piperidine and formic acid are added for a reductive amination reaction, a solvent is removed by distillation after the reaction, then an organic solvent C is added to dissolve the remaining reaction product, piperidine and alkali are added for an ammoniation reaction, acid is added after the reaction for extraction, layering and alkali regulation, and the final product of tildipirosin is prepared. The preparation method has the advantages that the reaction route is shortened, the total yield is increased, the reaction condition is mild, the operation is simple, and industrial production is facilitated.

Description

technical field [0001] The invention relates to a preparation method of tediroxin, which belongs to the field of organic synthesis of veterinary antibiotics. Background technique [0002] Tedirosin is a new type of macrolide semisynthetic antibiotic specially used for sixteen-membered ring animals. It is a derivative of tylosin and has high-efficiency and broad-spectrum antibacterial activity. Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica and Mannheimia hemolyticus have a good curative effect on respiratory diseases caused by pigs, cattle and other animals. [0003] On March 8, 2011, the brand name Zuprevo Sterile Injection developed by Intervet Animal Health Products Co., Ltd. of the Netherlands, with Tedirosin as the main ingredient, passed the approval of the Veterinary Drug Committee of the European Medicines Agency, and has been launched in the European Union. country market. At present, the product is not listed in our country. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H1/00
CPCC07H1/00C07H17/08
Inventor 陈清平许灵艳吴仲元刘甜甜
Owner HUBEI LONGXIANG PHARMA TECH CO LTD
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