1. A preparation method of binary one-pot tiamulin is characterized by comprising the following steps: firstly, adding pleuromutilin, 2-diethylaminoethanol and a reaction solvent into a reaction bottle, then adding a certain amount of a chlorinating agent, controlling the reaction temperature and the reaction time, evaporating to remove the solvent after the reaction is finished to obtain a product A, adding a solvent and thiourea into the product A, carrying out reflux reaction to obtain a solution B, cooling to room temperature, adding alkali and purified water, continuing the reaction to obtain a solution C, extracting, drying, and evaporating to remove the solvent of the reaction to obtain tiamulin.

2. The method for preparing tiamulin of a binary system in one pot as claimed in claim 1, wherein the reaction solvent is any one of chloroform, dichloromethane, methyl acetate, ethyl acetate and butyl acetate, preferably ethyl acetate.

3. The method for preparing tiamulin in one-pot binary system according to claim 1, wherein the chlorinating agent is one of hydrogen chloride, thionyl chloride, phosphorus pentachloride and phosphorus trichloride, preferably thionyl chloride.

4. The method for preparing tiamulin of a binary system in one pot according to claim 1, wherein the solvent is any one of absolute ethyl alcohol, methyl alcohol, 95% ethyl alcohol and 95% methyl alcohol, preferably absolute ethyl alcohol.

5. The method for preparing tiamulin of a two-system one-pot method according to claim 1, wherein the base is any one of triethylamine, triethanolamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate, preferably triethylamine.

6. The method for preparing the binary system tiamulin according to claim 1, which comprises the following steps: firstly, adding pleuromutilin, 2-diethylaminoethanol and ethyl acetate into a reaction bottle, then adding a certain amount of thionyl chloride, controlling the reaction temperature and the reaction time, evaporating to remove the solvent after the reaction is finished to obtain a product A, adding absolute ethanol and thiourea into the product A, carrying out reflux reaction to obtain a solution B, cooling to room temperature, adding triethylamine and purified water, continuing the reaction to obtain a solution C, extracting, drying, and evaporating to remove the solvent for the reaction to obtain tiamulin, wherein the operation method is simpler, the yield is more than 95%, and the method is more suitable for industrial production.

Background

The tiamulin is a special antibiotic for livestock and poultry, and has high safety, basically no drug resistance and low residue. Has good curative effect on mycoplasma infection of pigs and poultry, swine dense spiral dysentery and chicken staphylococcus synovitis, has growth promoting effect, and is widely used as veterinary drug and feed additive.

The production process adopted by the enterprises at present is to synthesize tiamulin by reacting pleuromutilin with 2-diethylaminoethanethiol in a solvent. The biggest problem of the process is that the 2-diethylaminoethanethiol with foul smell is used and is leaked carelessly, which has great environmental impact on production sites. In addition, 2-diethylaminoethanethiol belongs to the banning chemical industry control and is greatly limited in raw material use. In recent years, with the proposal of firmly striking the selling of antibiotics used by both human and animals by the ministry of agriculture, tiamulin has a wide prospect as a special antibiotic for livestock, so that how to develop a green and efficient synthetic route and a synthetic method for preparing tiamulin is particularly important.

Patent CN201310068656.2 discloses a preparation method of tiamulin base, which comprises chlorinating the hydroxy group in pleuromutilin structure with a suitable chlorinating agent, reacting with thiourea to obtain a salt solution, reacting the salt solution with 2-diethylaminoethanol chloride to obtain a solution containing tiamulin base, and treating to obtain tiamulin base with yield of more than 80%. The mechanism of the invention is that firstly, hydroxyl in a pleuromutilin structure is chlorinated to obtain chlorinated pleuromutilin, then the chlorinated pleuromutilin reacts with thiourea to obtain thiourea salt of the pleuromutilin, then 2-diethylaminoethanol is singly chlorinated to obtain chloride of the 2-diethylaminoethanol, and then the chloride and the 2-diethylaminoethanol are mixed to react and obtain tiamulin alkali after treatment.

Patent CN201310068687.8 discloses a new preparation method of tiamulin, comprising chlorinating hydroxyl group in the structure of the tiamulin with a proper chlorinating agent to obtain chlorinated pleuromutilin, then chlorinating 2-diethylaminoethanol to obtain chloride of 2-diethylaminoethanol, reacting the chloride of 2-diethylaminoethanol with thiourea to obtain a salt solution, reacting the salt solution with chlorinated pleuromutilin to obtain a solution containing tiamulin, and treating to obtain tiamulin with yield of more than 80%. The mechanism of the invention is that firstly, hydroxyl in a pleuromutilin structure is chlorinated to obtain chlorinated pleuromutilin, then 2-diethylaminoethanol is chlorinated to obtain 2-diethylaminoethanol chloride, the 2-diethylaminoethanol chloride reacts with thiourea to obtain thiourea salt, and then the two are mixed for reaction and treated to obtain tiamulin.

Although the two reaction routes eliminate 2-diethylaminoethanethiol, the phenomena of complex operation process, low yield and incomplete reaction still exist, and in order to solve the problems, the invention adopts a binary system and a one-pot mode to prepare tiamulin.

Firstly, pleuromutilin and 2-diethylaminoethanol are subjected to chlorination reaction in a solvent at the same time, two chlorination products are subjected to salt forming reaction with thiourea at the same time, and alkali is added to synthesize tiamulin directly.

Disclosure of Invention

The invention aims to provide a preparation method of tiamulin by a binary system one-pot method, which is simpler and realizes that tiamulin is prepared by the binary system one-pot method with the yield of more than 95 percent.

In order to achieve the purpose, the invention adopts the following technical scheme:

firstly, adding pleuromutilin, 2-diethylaminoethanol and a reaction solvent into a reaction bottle, then adding a certain amount of a chlorinating agent, controlling the reaction temperature and the reaction time, evaporating to remove the solvent after the reaction is finished to obtain a product A, adding a solvent and thiourea into the product A, carrying out reflux reaction to obtain a solution B, cooling to room temperature, adding alkali and purified water, continuing the reaction to obtain a solution C, extracting, drying, and evaporating to remove the solvent of the reaction to obtain tiamulin.

The reaction solvent is any one of chloroform, dichloromethane, methyl acetate, ethyl acetate and butyl acetate, and ethyl acetate is preferred.

The chlorinating agent is one of hydrogen chloride, thionyl chloride, phosphorus pentachloride and phosphorus trichloride, and the preferable is thionyl chloride.

The solvent is any one of absolute ethyl alcohol, methanol, 90% ethyl alcohol and 90% methanol, and the preferred solvent is absolute ethyl alcohol.

The alkali is any one of triethylamine, triethanolamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate, and triethylamine is preferred.

The invention relates to a preparation method of binary system tiamulin by one-pot method, which comprises the following steps: firstly, adding pleuromutilin, 2-diethylaminoethanol and ethyl acetate into a reaction bottle, then adding a certain amount of thionyl chloride, controlling the reaction temperature and the reaction time, evaporating to remove the solvent after the reaction is finished to obtain a product A, adding absolute ethanol and thiourea into the product A, carrying out reflux reaction to obtain a solution B, cooling to room temperature, adding triethylamine and purified water, continuing the reaction to obtain a solution C, extracting, drying, and evaporating to remove the solvent for the reaction to obtain tiamulin, wherein the operation method is simpler, the yield is more than 95%, and the method is more suitable for industrial production.

Detailed Description

The following are examples of the present invention which are intended to be illustrative only and should not be construed as limiting the invention.

Examples

Firstly, 6g of pleuromutilin (the content of 90 percent), 4ml of 2-diethylaminoethanol and 30ml of ethyl acetate are added into a reaction bottle, then 6ml of thionyl chloride is added, the reaction temperature is kept at 40 ℃ for reaction for 4 hours, after the reaction is finished, the ethyl acetate is evaporated to obtain a product A, after 30ml of absolute ethanol and 9g of thiourea are added into the product A, reflux reaction is carried out to obtain a solution B, the solution B is cooled to room temperature, 5ml of triethylamine and 10g of purified water are added, the reaction is continued to obtain a solution C, after extraction and drying, the solvent of the reaction is evaporated to obtain tiamulin, and the yield is 98.3 percent.

The above detailed description of the preparation method of binary system tiamulin according to the present invention is provided, and the principle and the embodiment of the present invention are explained by using specific examples, and the description of the above examples is only used to help understanding the method and the core idea of the present invention, and meanwhile, for a person skilled in the art, according to the idea of the present invention, there are changes in the specific embodiment and the application scope, and in conclusion, the content of the present description should not be understood as a limitation to the present invention.