CN111574416B - Method for preparing tiamulin from isothiourea salt and pleuromutilin p-toluenesulfonate - Google Patents

Method for preparing tiamulin from isothiourea salt and pleuromutilin p-toluenesulfonate Download PDF

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CN111574416B
CN111574416B CN202010475715.8A CN202010475715A CN111574416B CN 111574416 B CN111574416 B CN 111574416B CN 202010475715 A CN202010475715 A CN 202010475715A CN 111574416 B CN111574416 B CN 111574416B
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pleuromutilin
tiamulin
isothiourea
toluenesulfonate
reaction
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CN111574416A (en
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陈剑慧
沈敏祥
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Xinjiang Shangni Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
    • C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
    • C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline

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Abstract

The invention relates to a chemical synthesis method of tiamulin serving as a veterinary raw material, in particular to a method for preparing tiamulin by using isothiourea salt and pleuromutilin p-toluenesulfonate. The method comprises the steps of preparing isothiourea salt by reacting bromochloroethane with amino chloroethane prepared by diethylamine and thiourea, preparing pleuromutilin ester of p-toluenesulfonic acid by reacting pleuromutilin with p-toluenesulfonyl chloride, adding the isothiourea salt into the pleuromutilin ester of p-toluenesulfonic acid, and carrying out alkaline washing, neutral washing, phase inversion and other extraction steps on the reaction solution to obtain the high-purity tiamulin. The invention completely avoids the regulatory dangerous intermediate diethylaminoethanethiol, adopts a milder route to prepare tiamulin, greatly reduces the product management and control cost, has easily available raw materials, and is very suitable for the application of industrialized mass production.

Description

Method for preparing tiamulin from isothiourea salt and pleuromutilin p-toluenesulfonate
Technical Field
The invention relates to a chemical synthesis method of a veterinary bulk drug, in particular to a method for preparing tiamulin by using isothiourea salt and pleuromutilin p-toluenesulfonate.
Background
Tiamulin fumarate is a special antibiotic for pleurotus ostreatus animals, has an antibacterial spectrum similar to that of macrolide antibiotics, and is mainly used for preventing and treating respiratory diseases of poultry. The tiamulin fumarate has the advantages of rapid absorption, high blood concentration, wide in-vivo distribution, lower residue, difficult generation of drug resistance, no pollution to the environment and the like, so the tiamulin fumarate has been popularized and used in the global scope, and the veterinary antibiotic line is ascend ten times, so that the market demand is extremely large.
Tiamulin is a semisynthetic compound, and is synthesized mainly by taking diethylaminoethanethiol as a raw material in the industry at present through the following steps. Step one: 200510122952.1 "preparation method of pleuromutilin-containing raw material in production of tiamulin", published in 8/9 2006 ", discloses fermentation extraction of pleuromutilin by higher fungus Pleurotus basidiomycetes. Step two: 201210169854.3 'a method for synthesizing pleuromutilin ester of p-toluenesulfonic acid', which is disclosed in 12/18 2013, discloses that pleuromutilin ester of p-toluenesulfonic acid is prepared by the synthesis reaction of pleuromutilin and p-toluenesulfonyl chloride under the catalysis of inorganic base. Step three: 201210169855.8 'a method for synthesizing tiamulin' disclosed in 12.18.2013 discloses nucleophilic substitution reaction of pleuromutilin ester of toluenesulfonic acid and diethylamino ethanethiol under the catalysis of inorganic base to obtain tiamulin. The main problem of this scheme is that the intermediate diethylaminoethanethiol has greater toxicity and strong pungent odor, and is the main raw material for synthesizing nitrogen mustard gas as a chemical weapon, so that the second class of monitoring chemicals which are strictly controlled by the 'forbidden chemical weapon convention' are strictly monitored in purchase and use.
In order to get rid of the restriction of purchase and use of diethylaminoethanethiol, a series of methods for preparing tiamulin which diethylaminoethanethiol is avoided as a raw material are developed. For example, 201410842597.4 ' one pot method for synthesizing tiamulin ' disclosed in 3/25/2015 ' is a ' one pot method ' in which three raw materials for producing tiamulin, pleuromutilin ester of toluenesulfonic acid, diethylamine and ethylene oxide are directly mixed together for reaction. The method avoids directly using diethylaminoethanethiol, but has the advantages of more impurities, incapability of separation, extremely low tiamulin yield, and no significance in industrial production, and the method stays in the laboratory research stage all the time.
For example, 201310068656.2, 22 days of 2013 discloses a preparation method of tiamulin alkali, which is to chlorinate hydroxyl in pleuromutilin, react with thiourea to prepare pleuromutilin thiourea salt, and then add diethylaminoethanol to obtain tiamulin alkali. A201510231192.1 'method for synthesizing tiamulin' disclosed in 9.2015, 9.9 is characterized in that p-toluenesulfonic acid pleuromutilin ester, thiourea and sodium metabisulfite are used for preparing thio-pleuromutilin, and diethylaminoethane derivative and salt thereof are added for preparing tiamulin. The 201710943351.X disclosed in 14 3.2018 is a preparation method of tiamulin, which takes compound pleuromutilin as raw material, and the compound pleuromutilin is subjected to p-toluenesulfonylation, nucleophilic substitution reaction with beta-mercaptoethanol, activation by a halogenating reagent or a sulfonylating reagent, and finally reaction with diethylamine to obtain the tiamulin. Although the three methods successfully avoid diethylaminoethanethiol, the yield of tiamulin is far lower than that of the traditional method using diethylaminoethanethiol; new management chemicals such as diethylaminoethanol, diethylaminoethane derivatives, mercaptoethanol have also been introduced; the chlorination process of the strict pipe of the national security supervision department is adopted; the above three methods are not significant in industrial production.
Disclosure of Invention
The invention aims to solve the problem of avoiding the use of monitoring chemicals and provides a safe and environment-friendly synthesis method of tiamulin suitable for industrial production.
In order to solve the problems, diethylamine and bromochloroethane are reacted, and thiourea is added to react to generate isothiourea salt; reacting pleuromutilin with p-toluenesulfonyl chloride to generate p-toluenesulfonic acid pleuromutilin ester; adding isothiourea salt into pleuromutilin p-toluenesulfonate to react to generate tiamulin, and the specific technical scheme is as follows: a, preparing the amino chloroethane, adding bromochloroethane into a reactor, heating, then gradually adding diethylamine, wherein the diethylamine feeding time is less than 1 hour, the reaction temperature is 80-120 ℃, the reaction time is maintained for 1-3 hours, cooling the reaction liquid to room temperature, adjusting the pH value to be not less than 12.0, washing, controlling the pH value to be 6.0-7.5, and separating the water phase to obtain the amino chloroethane. b, preparing diethylaminoethyl isothiourea hydrochloride, adding thiourea and water into the amino chloroethane in the step a, and maintaining the reaction temperature at 60-80 ℃ for 1.5-2.5 hours to generate 60-70% diethylaminoethyl isothiourea hydrochloride solution. And c, preparing pleuromutilin ester of the toluenesulfonic acid, adding ketone or benzene organic solvents into a reactor, adding pleuromutilin, p-toluenesulfonyl chloride and inorganic base, maintaining the pH value of a reaction system to be equal to or higher than 12, reacting at 50-60 ℃ for 0.5-1 hour, and then separating the water phase to obtain the pleuromutilin ester solution of the toluenesulfonic acid. d, reacting isothiourea salt with pleuromutilin p-toluenesulfonate, adding the diethylaminoethyl isothiourea hydrochloride solution prepared in the step b into the pleuromutilin p-toluenesulfonate solution prepared in the step c, adding tetrabutylammonium bromide and inorganic base, and reacting for 0.5-1 hour at the temperature of 50-60 ℃ to obtain tiamulin reaction solution. e, extraction of tiamulin: the tiamulin reaction liquid is separated into water phases, impurities are removed through alkaline washing, neutral washing, phase inversion and the like in sequence, the pH value of the alkaline washing is not less than 12.0, the pH value of the neutral washing is controlled to be 6.0-7.5, the water phases are transferred into the water phases at the pH value of not less than 3.0, the water phases are then transferred back to the organic phases, diethylaminoethyl isothiourea hydrochloride is 40-45 ℃, the phase separation interface is clear, the impurities are removed through washing by using a proportioning liquid of methanol and water, and finally the solvent is evaporated under reduced pressure for recycling, so that the tiamulin is obtained.
Specifically, in the preparation of the amino chloroethane in the step a, the mol ratio of bromochloroethane to diethylamine is 1:1.0-1.3.
Specifically, in the preparation of diethylaminoethyl isothiourea hydrochloride in the step b, the molar ratio of the addition amount of thiourea to the addition amount of bromochloroethane in the step a is 1:1.0-1.1.
Specifically, the ketone organic solvent is methyl isobutyl ketone or methyl ethyl ketone, and the benzene organic solvent is toluene or xylene.
Specifically, in the preparation of the pleuromutilin ester of the p-toluenesulfonic acid in the step c, the molar ratio of pleuromutilin to p-toluenesulfonyl chloride is 1:1.02-1.10.
Specifically, in the reaction of the isothiourea salt and the pleuromutilin ester of the toluenesulfonic acid in the step d, the mol ratio of the pleuromutilin ester of the toluenesulfonic acid to the diethylaminoethyl isothiourea hydrochloride is 1:1.1-1.3
Specifically, in the preparation of tiamulin by using the isothiourea salt and the pleuromutilin p-toluenesulfonate in the step d, the addition amount of tetrabutylammonium bromide is 0.5-1% of the addition amount of the pleuromutilin p-toluenesulfonate.
Specifically, the inorganic base is 32% of ionic membrane base, in the preparation of the pleuromutilin p-toluenesulfonate in the step c, the adding amount of the 32% of ionic membrane base is 45% -55% of the adding amount of the pleuromutilin, and in the preparation of tiamulin by using the isothiourea salt and the pleuromutilin p-toluenesulfonate in the step d, the adding amount of the 32% of ionic membrane base is 30% -40% of the adding amount of the pleuromutilin p-toluenesulfonate.
Specifically, in the purification of tiamulin in the step e, the addition amount of the proportioning liquid of the methanol and the water is not less than 75% of the tiamulin.
Specifically, the methanol and water mixture contains 10-40% methanol.
The tiamulin is prepared by reacting isothiourea salt with the pleuromutilin p-toluenesulfonate, the use of diethylaminoethanethiol as a monitoring chemical is completely avoided, and the yield of the tiamulin is similar to that of a diethylaminoethanethiol pathway.
Detailed Description
The method adopted by the invention is as follows:
a, preparing the amino chloroethane: bromochloroethane is added into the reactor, the temperature is raised, and then diethylamine is gradually added. The diethylamine feeding time is less than 1 hour, the feeding mole ratio of bromochloroethane and diethylamine is 1:1.0-1.3, the reaction temperature is 80-120 ℃, the reaction time is maintained for 1-3 hours, and the reaction solution is cooled to room temperature. And (3) adjusting the pH value to be not less than 12.0, washing, controlling the pH value to be 6.0-7.5, and separating the water phase to obtain the amino chloroethane.
B, preparation of diethylaminoethyl isothiourea hydrochloride: adding thiourea and water into the amino-chloroethane in the step a, wherein the molar ratio of the addition amount of the thiourea to the addition amount of the bromochloroethane in the step a is 1:1.0-1.1, the reaction temperature is 60-80 ℃, and the reaction time is maintained for 1.5-2.5 hours, thus generating 60-65% diethylaminoethyl isothiourea hydrochloride solution.
C, preparation of pleuromutilin ester of p-toluenesulfonic acid: the ketone or benzene is organic solvent, the ketone can be methyl isobutyl ketone or methyl ethyl ketone, and the benzene can be toluene or xylene. Adding pleuromutilin, p-toluenesulfonyl chloride and inorganic alkali, wherein the feeding molar ratio of the pleuromutilin to the p-toluenesulfonyl chloride is 1:1.02-1.10, the inorganic alkali can be strong alkali such as sodium hydroxide, potassium hydroxide and the like, preferably ionic membrane alkali prepared by electrolysis of an ion exchange membrane method, the adding amount of the ionic membrane alkali is 45-55% of the adding amount of the pleuromutilin, the pH value of a reaction system is maintained to be not less than 12, the reaction temperature is 50-60 ℃, the reaction time is 0.5-1 hour, and the water phase is separated and discarded to obtain the pleuromutilin p-toluenesulfonate solution.
D, reaction of isothiourea salt with pleuromutilin ester of p-toluenesulfonic acid: adding the diethylaminoethyl isothiourea hydrochloride solution prepared in the step b into the pleuromutilin ester solution prepared in the step c, and adding a catalyst tetrabutylammonium bromide and inorganic base, wherein the molar ratio of the pleuromutilin ester to the diethylaminoethyl isothiourea hydrochloride is 1:1.1-1.3, preferably the inorganic base is ionic membrane base, the adding amount of the inorganic base is 30-40% of the adding amount of pleuromutilin, and the reaction time is 0.5-1 hour at the reaction temperature of 50-60 ℃ to obtain the tiamulin reaction solution.
E, extraction of tiamulin: the tiamulin reaction liquid is firstly separated into water phases, then the water phases are sequentially subjected to alkaline washing, neutral washing, phase inversion and the like to extract and remove impurities, the pH value of the alkaline washing is not less than 12.0, the pH value of the neutral washing is controlled to be 6.0-7.5, the water phases are transferred into the water phases under the pH value of not less than 3.0, the water phases are then transferred back to the organic phases, the diethylaminoethyl isothiourea hydrochloride is 40-45 ℃, and the phase separation interface is clear. And washing with methanol and water to remove impurities, wherein the content of methanol is 10-40%, and the addition amount of the methanol and water is not less than 75% of the tiamulin. Finally, the solvent is distilled off under reduced pressure for recycling, and the high-purity tiamulin is obtained. The generated waste liquid is collected to a waste water pool for centralized treatment, and can be recycled for solution preparation or washing.
Example 1
To a 500ml reactor equipped with a stirring and condensing reflux apparatus, 143g of bromochloroethane was charged, and the temperature was raised to 80℃with the gradual addition of 73g of diethylamine over 1 hour, and then the reaction was maintained at 120℃for 1 hour, and the reaction solution was cooled to room temperature. Washing with 250ml of 30% K 2CO3, washing with 50ml of water with pH controlled at 6.0-7.5, and separating the aqueous phase to obtain the amino chloroethane.
80Ml of water and 69.2g of thiourea are added into the amino chloroethane, the reaction temperature is 60-75 ℃, the reaction is maintained for 2 hours, diethylaminoethyl isothiourea hydrochloride solution is generated, and the isothiourea salt content is detected to be 61.21 percent for standby.
200Ml of solvent methyl isobutyl ketone, 30g of pleuromutilin, 16g of p-toluenesulfonyl chloride and 15g of 32% of ionic membrane caustic soda are added into a 500ml reactor with stirring, the pH value of a reaction system is maintained to be not less than 12, the reaction temperature is 50 ℃, the reaction time is 1 hour, the water phase is separated, 228ml of pleuromutilin p-toluenesulfonate solution is obtained, and the content of pleuromutilin p-toluenesulfonate is detected to be 18.28%.
35G of diethylaminoethyl isothiourea hydrochloride solution, 0.3g of tetrabutylammonium bromide serving as a catalyst and 15g of 32% ionic membrane caustic soda are added into a ketone solution of pleuromutilin p-toluenesulfonate, and the reaction temperature is 60 ℃ and the reaction time is 0.5 hour, so that a reaction solution of tiamulin is obtained.
The tiamulin reaction liquid is separated into water phase, the pH value is adjusted to be larger than or equal to 12.0, the washing is carried out, the pH value is adjusted to be controlled within the range of 6.0-7.5, neutral washing is carried out, the water phase is transferred into the organic phase again after the pH value is smaller than or equal to 3.0, the diethylaminoethyl isothiourea hydrochloride is at the temperature of 40-45 ℃, and the phase separation interface is clear. Then, the mixture was washed with 30ml of 25% aqueous methanol solution, and the solvent was distilled off under reduced pressure at 95℃and-0.095 MPa to obtain 36.08g of tiamulin, the purity of which was detected as 96.12%.
Example 2
143G of bromochloroethane was charged into a 500ml reactor equipped with a stirring and condensing reflux apparatus, heated to 80℃and 93g of diethylamine was gradually added over 1 hour, then the reaction was maintained at 100℃for 3 hours, and the reaction solution was cooled to room temperature. Washing with 250ml of 30% K 2CO3, washing with 50ml of water with pH controlled at 6.0-7.5, and separating the aqueous phase to obtain the amino chloroethane.
80Ml of water and 75g of thiourea are added into the amino chloroethane, the reaction temperature is 65-80 ℃, the reaction is maintained for 1.5 hours, diethylaminoethyl isothiourea hydrochloride solution is generated, and the isothiourea salt content is detected to be 62.03 percent for standby.
200Ml of solvent methyl isobutyl ketone, 30g of pleuromutilin, 15.5g of p-toluenesulfonyl chloride and 15g of 32% of ionic membrane caustic soda are added into a 500ml reactor with stirring, the pH value of a reaction system is maintained to be not less than 12, the reaction temperature is 60 ℃, the reaction time is 0.5 hour, the aqueous phase is discarded, 231ml of pleuromutilin p-toluenesulfonate solution is obtained, and the content of pleuromutilin p-toluenesulfonate is detected to be 18.14%.
30G of diethylaminoethyl isothiourea hydrochloride solution, 0.3g of tetrabutylammonium bromide serving as a catalyst and 15g of 32% ionic membrane caustic soda are added into a ketone solution of pleuromutilin p-toluenesulfonate, and the reaction temperature is 50 ℃ and the reaction time is 1 hour, so that a reaction solution of tiamulin is obtained.
The tiamulin reaction liquid is separated into water phase, the pH value is adjusted to be larger than or equal to 12.0, the washing is carried out, the pH value is adjusted to be controlled within the range of 6.0-7.5, neutral washing is carried out, the water phase is transferred into the organic phase again after the pH value is smaller than or equal to 3.0, the diethylaminoethyl isothiourea hydrochloride is at the temperature of 40-45 ℃, and the phase separation interface is clear. Then, the mixture was washed with 26ml of a 35% aqueous methanol solution, and the solvent was distilled off under reduced pressure at 95℃and-0.095 MPa to obtain 35.98g of tiamulin, the purity of which was 96.01%.
Example 3
143G of bromochloroethane was charged into a 500ml reactor equipped with a stirring and condensing reflux apparatus, heated to 80℃and 93g of diethylamine was gradually added over 1 hour, then the reaction was maintained at 100℃for 3 hours, and the reaction solution was cooled to room temperature. Washing with 250ml of 30% K 2CO3, washing with 50ml of water with pH controlled at 6.0-7.5, and separating the aqueous phase to obtain the amino chloroethane.
80Ml of water and 72.6g of thiourea are added into the amino chloroethane, the reaction temperature is 65-80 ℃, the reaction is maintained for 1.5 hours, diethylaminoethyl isothiourea hydrochloride solution is generated, and the isothiourea salt content is detected to be 62.03 percent for standby.
200Ml of toluene solvent, 30g of pleuromutilin, 16g of p-toluenesulfonyl chloride and 15g of 32% of ionic membrane caustic soda are added into a 500ml reactor with stirring, the reaction temperature is 50 ℃, the reaction time is 1 hour, the water phase is separated, 224ml of pleuromutilin p-toluenesulfonate solution is obtained, and the content of pleuromutilin p-toluenesulfonate is detected to be 18.5%.
30G of diethylaminoethyl isothiourea hydrochloride solution, 0.3g of tetrabutylammonium bromide serving as a catalyst and 15g of 32% ionic membrane caustic soda are added into a ketone solution of pleuromutilin p-toluenesulfonate, and the reaction temperature is 50 ℃ and the reaction time is 1 hour, so that a reaction solution of tiamulin is obtained.
The tiamulin reaction liquid is separated into water phase, the pH value is adjusted to be larger than or equal to 12.0, the water phase is washed, the pH value is adjusted to be controlled within the range of 6.0-7.5, neutral washing is carried out, the water phase is transferred to the organic phase again after the pH value is smaller than or equal to 3.0, and the phase separation interface is clear at the temperature of diethylaminoethyl isothiourea hydrochloride of 40-45 ℃. Then, the mixture was washed with 35ml of a 15% aqueous methanol solution, and the solvent was distilled off under reduced pressure at 95℃and-0.095 MPa to obtain 36.33g of tiamulin, the purity of which was detected as 95.83%.
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.

Claims (5)

1. A method for preparing tiamulin from isothiourea salt and p-toluenesulfonic acid pleuromutilin ester, comprising the reaction of diethylamino chloroethane prepared from bromochloroethane and diethylamine with thiourea to react pleuromutilin with p-toluenesulfonyl chloride, characterized in that:
a, preparing diethylamino chloroethane, adding bromochloroethane into a reactor, heating, then gradually adding diethylamine, wherein the diethylamine feeding time is less than 1 hour, the mol ratio of bromochloroethane to diethylamine is 1:1.0-1.3, the reaction temperature is 100-120 ℃, the reaction time is maintained for 1-3 hours, the reaction solution is cooled to room temperature, the pH value is regulated to be more than or equal to 12.0, the reaction solution is washed, the pH value is controlled to be 6.0-7.5, and the diethylamino chloroethane is obtained by separating and discarding water phase;
b, preparing diethylaminoethyl isothiourea hydrochloride, adding thiourea and water into the diethylaminoethyl chloride prepared in the step a, wherein the molar ratio of the addition of the thiourea to the addition of the bromoethyl chloride in the step a is 1:1.0-1.1, the reaction temperature is 60-80 ℃, the reaction time is maintained for 1.5-2 hours, and 60-70% of diethylaminoethyl isothiourea hydrochloride solution is generated;
c, preparing pleuromutilin ester of the p-toluenesulfonic acid, adding ketone or benzene organic solvent which is methyl isobutyl ketone or methyl ethyl ketone into a reactor, adding pleuromutilin, p-toluenesulfonyl chloride and inorganic base, wherein the mol ratio of pleuromutilin to p-toluenesulfonyl chloride is 1:1.02-1.10, maintaining the pH value of a reaction system to be more than or equal to 12, reacting at 50-60 ℃ for 0.5-1 hour, and then separating an aqueous phase to obtain the pleuromutilin ester solution of the p-toluenesulfonic acid;
d, reacting isothiourea salt with pleuromutilin p-toluenesulfonate, adding the diethylaminoethyl isothiourea hydrochloride solution prepared in the step b into the pleuromutilin p-toluenesulfonate solution prepared in the step c, wherein the mol ratio of the pleuromutilin p-toluenesulfonate to the diethylaminoethyl isothiourea hydrochloride is 1:1.1-1.3, adding tetrabutylammonium bromide and inorganic base, and reacting for 0.5-1 hour at the temperature of 50-60 ℃ to obtain a tiamulin reaction solution;
e, extraction of tiamulin: the tiamulin reaction liquid is separated into water phases, then the water phases are sequentially subjected to alkaline washing, neutral washing and phase inversion to remove impurities, the pH value of the alkaline washing is larger than or equal to 12.0, the pH value of the neutral washing is controlled to be 6.0-7.5, the water phases are transferred into the water phases under the pH value of smaller than or equal to 3.0, then the water phases are transferred back to the organic phases, the system temperature is kept at 40-45 ℃ in the whole extraction process, the phase separation interface is clear, the impurities are removed by washing with a proportioning liquid of methanol and water, and finally the solvent is evaporated under reduced pressure for recycling, so that the tiamulin is obtained.
2. A process for the preparation of tiamulin from isothiourea salt and pleuromutilin ester of p-toluenesulfonic acid as claimed in claim 1, characterized in that: in the step d, the isothiourea salt and the pleuromutilin p-toluenesulfonate are added to prepare tiamulin, and the addition amount of tetrabutylammonium bromide is 0.5-1% of the addition amount of the pleuromutilin p-toluenesulfonate.
3. A process for the preparation of tiamulin from isothiourea salt and pleuromutilin ester of p-toluenesulfonic acid as claimed in claim 1, characterized in that: in the preparation of the pleuromutilin p-toluenesulfonate, the inorganic base is 32% of ionic membrane base, the adding amount of the 32% of ionic membrane base is 45% -55% of the adding amount of pleuromutilin, and in the preparation of the tiamulin by using the isothiourea salt and the pleuromutilin p-toluenesulfonate, the adding amount of the 32% of ionic membrane base is 30% -40% of the adding amount of the pleuromutilin p-toluenesulfonate.
4. A process for the preparation of tiamulin from isothiourea salt and pleuromutilin ester of p-toluenesulfonic acid as claimed in claim 1, characterized in that: in the purification of tiamulin in step e, the addition amount of the proportioning liquid of methanol and water is not less than 75% of the tiamulin.
5. A process for the preparation of tiamulin from isothiourea salts and pleuromutilin esters of p-toluenesulfonic acid as claimed in claim 1 or 4, characterized in that: the methanol and water mixture has methanol content of 10-40%.
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