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Method for preparing tiamulin from isothiourea salt and p-toluenesulfonic acid pleuromutilin ester

A technology of p-toluenesulfonic acid and pleuromutilin ester is applied in the field of chemical synthesis of veterinary raw materials, and can solve the problems such as low yield of tiamulin

Pending Publication Date: 2020-08-25
新疆上昵生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the above three methods have successfully avoided diethylaminoethanethiol, the yield of tiamulin is much lower than the traditional method using diethylaminoethanethiol; new control chemicals have also been introduced, For example, diethylaminoethanol, diethylaminoethane derivatives, and mercaptoethanol; the chlorination process strictly controlled by the national safety supervision department is adopted; so the above three methods have no meaning in industrial production

Method used

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Examples

Experimental program
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Effect test

preparation example Construction

[0019] a, the preparation of aminochloroethane: add bromochloroethane in the reactor, heat up, and then gradually add diethylamine. The feeding time of diethylamine is less than 1 hour, the feeding molar ratio of bromochloroethane and diethylamine is 1:1.0-1.3, the reaction temperature is 80-120°C, the reaction time is maintained for 1-3 hours, and the reaction solution is lowered to room temperature. Adjust the pH value to ≧12.0 for washing, then control the pH value to 6.0-7.5 for washing, and separate the aqueous phase to obtain aminochloroethane.

[0020] b, the preparation of diethylaminoethyl isothiourea hydrochloride: thiourea and water are added in the aminochloroethane of step a, the molar ratio of the addition of thiourea and the addition of bromochloroethane in step a is 1:1.0-1.1, the reaction temperature is 60-80°C, and the reaction time is maintained for 1.5-2.5 hours to generate a 60-65% diethylaminoethylisothiourea hydrochloride solution.

[0021] c, preparati...

Embodiment 1

[0025] Add 143g of bromochloroethane to a 500ml reactor with a stirring and condensing reflux device, heat up to 80°C, gradually add 73g of diethylamine within 1 hour, then maintain the reaction at 120°C for 1 hour, and drop the reaction solution to to room temperature. Use 250ml30%K 2 CO 3 Washing, and then controlling the pH value of 50ml of water to wash at 6.0-7.5, and separating the water phase to obtain aminochloroethane.

[0026]Add 80ml of water and 69.2g of thiourea to aminochloroethane, the reaction temperature is 60-75°C, and maintain the reaction for 2 hours to generate diethylaminoethylisothiourea hydrochloride solution. The content of isothiourea salt is 61.21 %,stand-by.

[0027] Add 200ml of solvent methyl isobutyl ketone to the 500ml reactor with stirring, then add 30g of pleuromutilin, 16g of p-toluenesulfonyl chloride and 15g of 32% ionic membrane caustic soda, the pH value of the reaction system is maintained at ≧12, and the reaction The temperature was...

Embodiment 2

[0031] Add 143g of bromochloroethane to the 500ml reactor with stirring and condensing reflux device, heat up to 80°C, gradually add 93g of diethylamine within 1 hour, then maintain the reaction at 100°C for 3 hours, and the reaction solution drops to room temperature. Use 250ml 30%K 2 CO 3 Wash, and then use 50 ml of water to control the pH value of 6.0-7.5 to wash, and separate the water phase to obtain aminochloroethane.

[0032] Add 80ml of water and 75g of thiourea to aminochloroethane, the reaction temperature is 65-80°C, and maintain the reaction for 1.5 hours to generate diethylaminoethyl isothiourea hydrochloride solution. The content of isothiourea salt is 62.03% ,stand-by.

[0033] Add 200ml of solvent methyl isobutyl ketone to the 500ml reactor with stirring, then add 30g of pleuromutilin, 15.5g of p-toluenesulfonyl chloride and 15g of 32% ionic membrane caustic soda, the pH value of the reaction system is maintained at ≧12, The reaction temperature was 60°C, t...

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Abstract

The invention relates to a chemical synthesis method of a veterinary bulk drug tiamulin, in particular to a method for preparing tiamulin from isothiourea salt and p-toluenesulfonic acid pleuromutilinester. The method comprises the following steps: reacting aminochloroethane prepared from bromochloroethane and diethylamine with thiourea to prepare isothiourea salt; reacting pleuromutilin with p-toluenesulfonyl chloride to prepare p-toluenesulfonic acid pleuromutilin ester, adding isothiourea salt into the p-toluenesulfonic acid pleuromutilin ester, and carrying out alkaline washing, neutral washing, phase inversion and other extraction steps on the reaction solution to obtain the high-purity tiamulin. According to the invention, the supervised dangerous intermediate diethylaminoethanethiol is completely avoided, the tiamulin is prepared by adopting a mild route, the product management and control cost is greatly reduced, and the raw materials are easy to obtain, so that the method isvery suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to a chemical synthesis method of a veterinary raw material drug, in particular to a method for preparing tiamulin by using isothiourea salt and pleuromutilin p-toluenesulfonate. Background technique [0002] Tiamulin fumarate is a special antibiotic for Pleurotus truncated animals. Its antibacterial spectrum is similar to that of macrolide antibiotics. It is mainly used to prevent and treat poultry respiratory diseases. Tiamulin fumarate has the advantages of rapid absorption, high blood concentration, wide distribution in the body, low residue, less resistance to drugs, and no pollution to the environment. Therefore, the drug has been promoted and used globally, ranking among the top ten animal With the ranks of antibiotics, the market demand is huge. [0003] Tiamulin is a semi-synthetic compound. At present, diethylaminoethanethiol is mainly used as a raw material in industry, and tiamulin is synthesized through the following...

Claims

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Application Information

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IPC IPC(8): C07C319/14C07C323/52C07C319/28
CPCC07C319/14C07C319/28C07C303/28C07C335/32C07C209/08C07C2603/82C07C323/52C07C309/73C07C211/15
Inventor 陈剑慧沈敏祥
Owner 新疆上昵生物科技有限公司
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