CN117903026A - Preparation method of tiamulin - Google Patents

Preparation method of tiamulin Download PDF

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Publication number
CN117903026A
CN117903026A CN202410055809.8A CN202410055809A CN117903026A CN 117903026 A CN117903026 A CN 117903026A CN 202410055809 A CN202410055809 A CN 202410055809A CN 117903026 A CN117903026 A CN 117903026A
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acetate
reaction
tiamulin
mutilin
preparation
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沈敏祥
许冰白
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Xinjiang Shangni Biotechnology Co ltd
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Xinjiang Shangni Biotechnology Co ltd
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Abstract

The application discloses a preparation method of tiamulin, which comprises the following steps: and carrying out transesterification on diethylaminoethyl thiomethyl acetate and Mutilin to obtain tiamulin. The application avoids using the second monitoring chemical 2-diethylaminoethanethiol and mercaptoethanol with high toxicity and high pungent smell, the preparation method is environment-friendly, and simultaneously, the yield of tiamulin is close to that of the traditional method using diethylaminoethanethiol, thus being suitable for industrial production.

Description

Preparation method of tiamulin
Technical Field
The application relates to the technical field of synthesis of veterinary bulk drugs, in particular to a preparation method of tiamulin.
Background
In 1951, kav.F found pleuromutilin (pleuromutilin) for the first time in Pleurotus genus of Basidiomycetes class, and Kav.F found that the fungal fermentation broth had activity against Staphylococcus aureus. In the 70 s of the 20 th century, sandoz developed a veterinary antibiotic, a pleuromutilin derivative, which was used clinically mainly in the form of tiamulin fumarate. Tiamulin fumarate is a veterinary drug with similar antibacterial spectrum as macrolide, can be rapidly absorbed by animals and can be well distributed in the body, and is mainly used for preventing and treating chronic respiratory diseases of chickens, mycoplasma hyopneumoniae of pigs and the like.
At present, the synthesis steps generally adopted in the related art for producing tiamulin fumarate are as follows: the C22 hydroxyl of pleuromutilin is subjected to p-toluenesulfonylation to generate pleuromutilin p-toluenesulfonyl ester, the intermediate product and 2-diethylaminoethanethiol are subjected to tiamulin generation, and finally the intermediate product and fumaric acid are subjected to salification to generate tiamulin fumarate. In the method, the molar yield of the tiamulin prepared from the pleuromutilin can reach about 93 percent. However, the important raw material 2-diethylaminoethanethiol used in the method has malodorous smell, and is listed into a second class of monitoring chemicals by OPCW, so that the application is limited internationally, and the production of tiamulin is not facilitated; it has also been reported in the related art that p-toluenesulfonic acid pleuromutilin ester, diethylamine and ethylene oxide are directly mixed together for reaction by a "one pot method". The method avoids directly using diethylaminoethanethiol, but the impurities generated by the method are more and cannot be separated, the tiamulin yield is extremely low, the method stays in the laboratory research stage all the time, and the method has no significance in industrial production. Therefore, how to provide a high-yield and environment-friendly synthesis method of tiamulin has very important research significance.
Disclosure of Invention
In view of the above-mentioned drawbacks or shortcomings in the prior art, the present application provides a preparation method of tiamulin, which avoids the use of 2-diethylaminoethanethiol, which is a second type of monitoring chemical, and mercaptoethanol having a high toxicity and a high pungent odor, and which is environmentally friendly, while also enabling the tiamulin yield to be close to the conventional method using 2-diethylaminoethanethiol.
In one aspect, the application provides a method for preparing tiamulin, comprising the steps of:
And carrying out transesterification on diethylaminoethyl thiomethyl acetate and Mutilin to obtain tiamulin.
Alternatively, before the diethylaminoethyl thiomethyl acetate and Mutilin are subjected to transesterification to obtain tiamulin, the preparation method further comprises:
preparing diethylaminoethyl thiomethyl acetate from methyl thioglycolate, bromochloroethane and diethylamine;
The pleuromutilin and alkali liquor are reacted in toluene or methyl isobutyl ketone solution to prepare Mutilin.
Alternatively, the preparation of diethylaminoethyl thiomethyl acetate from methyl thioglycolate, bromochloroethane and diethylamine comprises:
After methyl thioglycolate is dissolved in a solvent, bromochloroethane is added for condensation reaction to obtain a first product;
and (3) carrying out condensation reaction on the first product and diethylamine to obtain diethylaminoethylthio methyl acetate.
As an alternative scheme, after methyl thioglycolate is dissolved in a solvent, bromochloroethane is added for condensation reaction, and the feeding mole ratio of the methyl thioglycolate to the bromochloroethane is 1: (1.0-2.0), wherein the solvent is methanol, and the temperature of the condensation reaction is 20-30 ℃.
As an alternative scheme, in the process of carrying out condensation reaction on the first product and diethylamine, the feeding molar ratio of methyl thioglycolate to diethylamine is 1: (1.3-2.5), the reaction temperature is 50-60 ℃, and the catalyst is KI.
Alternatively, the preparation method further comprises removing the solvent after the condensation reaction of the first product and diethylamine is completed.
As an alternative scheme, pleuromutilin and alkali liquor are reacted in toluene or methyl isobutyl ketone solution, and the reaction temperature is 50-60 ℃ in the process of preparing Mutilin.
As an alternative scheme, the diethylaminoethyl thiomethyl acetate and Mutilin are subjected to transesterification, and in the process of obtaining tiamulin, the reaction conditions are as follows: the reaction temperature is 70-100 ℃, and nitrogen is filled in the reaction process; preferably, the reaction temperature is from 85℃to 100 ℃.
Alternatively, methyl diethylaminoethyl thioacetate and Mutilin undergo transesterification under basic or acidic conditions; preferably, the diethylaminoethyl thiomethyl acetate and Mutilin are transesterified under basic conditions.
As an alternative scheme, the feeding mole ratio of Mutilin to diethylaminoethylthiomethyl acetate is 1: (1.0-1.1).
According to the preparation method of tiamulin, provided by the application, the tiamulin is obtained by carrying out transesterification on diethylaminoethyl thiomethyl acetate and Mutilin. The method avoids the use of the second monitoring chemical 2-diethylaminoethanethiol and mercaptoethanol with high toxicity and high pungent smell, is environment-friendly and safe to operate, and the tiamulin prepared by the transesterification has higher yield, which is similar to the yield of the tiamulin prepared by using diethylaminoethanethiol.
Drawings
FIG. 1 is a high performance liquid chromatogram of example 1 of the present application;
FIG. 2 is a high performance liquid chromatogram of example 2 of the present application;
FIG. 3 is a high performance liquid chromatogram of example 3 of the present application;
Detailed Description
The application is described in further detail below with reference to the drawings and examples. It is to be understood that the specific embodiments described herein are merely illustrative of the application and are not limiting of the application.
It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other.
It should be noted that endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and that such range or value should be understood to include values approaching such range or value. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The source of the raw materials according to the present application is not particularly limited, and may be commercially available or prepared according to conventional methods well known to those skilled in the art. The purity of all the raw materials of the present application is not particularly limited, and it is preferable to use the purity of the raw materials as industrially pure or as usual in the art.
The application provides a preparation method of tiamulin, which comprises the following steps:
And (3) carrying out transesterification on diethylaminoethyl thiomethyl acetate and Mutilin (mutilin) to obtain tiamulin.
It should be noted that, the diethylaminoethyl thio methyl acetate may be prepared by any existing method, for example, but not limited to, esterification reaction, condensation reaction, substitution reaction, addition reaction, etc.; of course, methyl diethylaminoethyl thioglycolate may also be a direct purchase commercial product; mutilin is obtained by treating pleuromutilin in an alkaline solution, wherein the reaction can be carried out in a methanol solution or in a toluene or methyl isobutyl ketone solution.
It can be understood that the diethylaminoethyl thiomethyl acetate and Mutilin are subjected to transesterification, so that the method has the advantages of less side reaction, high yield, easy control of the specific volume of the fed material, convenient operation and suitability for large-scale industrial production.
The embodiment of the application solves the problems of toxic and harmful substances and low yield in the synthesis of tiamulin in the prior art, and obtains the tiamulin by carrying out transesterification on diethylaminoethyl thiomethyl acetate and Mutilin. The method avoids the use of a second monitoring chemical 2-diethylaminoethanethiol and mercaptoethanol with high toxicity and high pungent smell, is environment-friendly and safe to operate, and the tiamulin prepared by transesterification has higher yield, which is similar to the yield of the tiamulin prepared by using diethylaminoethanethiol conventionally
In some embodiments, the method of making further comprises:
preparing diethylaminoethyl thiomethyl acetate from methyl thioglycolate, bromochloroethane and diethylamine;
The pleuromutilin and alkali liquor are reacted in toluene or methyl isobutyl ketone solution to prepare Mutilin.
In some embodiments, the preparation of diethylaminoethyl thiomethyl acetate from methyl thioglycolate, bromochloroethane, and diethylamine comprises:
After methyl thioglycolate (compound 1) is dissolved in a solvent, bromochloroethane (compound 2) is added for condensation reaction to obtain a first product (compound 3);
The reaction mechanism is as follows:
in some embodiments, an acid-binding agent may be added, and the acid-binding agent and methyl thioglycolate are dissolved in a solvent together and then subjected to condensation reaction with bromochloroethane;
The acid-binding agent can be any alkaline substance, such as but not limited to potassium carbonate, and is mainly used for neutralizing hydrogen bromide in the product, so that the reaction is facilitated, and the yield is improved; the solvent may be any organic solvent such as, but not limited to, methanol.
The first product (compound 3) and diethylamine are subjected to condensation reaction under the action of a catalyst to obtain diethylaminoethylthio methyl acetate (compound 4).
Wherein, the catalyst can be KI, and the addition of potassium iodide is beneficial to promoting the reaction.
The reaction mechanism is as follows:
In the embodiment, diethylaminoethylthio methyl acetate is obtained by condensation reaction, the product is single, the occurrence of side reaction is effectively avoided, and the yield is improved.
In a preferred embodiment, after the methyl thioglycolate and the acid binding agent are dissolved in a solvent, adding bromochloroethane for condensation reaction, wherein the feeding mole ratio of the methyl thioglycolate to the bromochloroethane is 1: (1.0-2.0), wherein the solvent is methanol, the temperature of the condensation reaction is 20-30 ℃, and the time of the condensation reaction is 0.5-1 h.
In the embodiment of the application, the material ratio of the methyl thioglycolate and the bromochloroethane is favorable for ensuring the full reaction of the methyl thioglycolate, the temperature and time conditions of the condensation reaction are mild, and the occurrence of side reactions can be effectively avoided.
Specifically, the feeding molar ratio of methyl thioglycolate to bromochloroethane is 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8 or 1:2.0, etc.; when bromochloroethane is too little, methyl thioglycolate cannot react sufficiently, and chlorine atoms on bromochloroethane are condensed to form unnecessary side reaction products; when the bromochloroethane is excessive, bromochloroethane is wasted, and other unnecessary side reactions can be generated; the condensation reaction temperature is 20 ℃,22 ℃, 24 ℃, 26 ℃, 28 ℃ or 30 ℃ and the like; the condensation reaction time is 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1.0h, etc.
In some embodiments, in the condensation reaction of the first product and diethylamine in the presence of a catalyst, the molar ratio of methyl thioglycolate to diethylamine is 1: (1.3-2.5), the reaction temperature is 50-60 ℃, the reaction time is 4-8 h, and the catalyst is KI.
The feeding molar ratio of the methyl thioglycolate to the diethylamine in the embodiment is beneficial to promoting the synthesis of the diethylaminoethyl thioglycolate by the first product, improves the conversion rate and does not cause the waste of the first product; the reaction temperature in this example was increased, which was advantageous in accelerating the reaction and promoting the forward progress of the reaction.
Specifically, the molar ratio of methyl thioglycolate to diethylamine can be, but is not limited to, 1:1.3, 1:1.5, 1:1.7, 1:1.9, 1:2.1, or 1:2.3, etc.; when the amount of diethylamine is too small, the first product cannot react completely, so that waste is caused, and the cost is increased; when the amount of the diethylamine is excessive, the diethylamine is wasted, and the environment is not protected; the reaction temperature may be, but is not limited to, 50 ℃, 52 ℃, 54 ℃, 56 ℃, 60 ℃, or the like; when the reaction temperature is too high, unsafe hidden danger is caused, and when the reaction temperature is too low, the reaction efficiency is reduced.
In some embodiments, the method further comprises removing the solvent after the first product and diethylamine are subjected to the addition reaction over the catalyst.
In some embodiments, the temperature of the reaction during the preparation of Mutilin (mutilin, compound 6) by reacting pleuromutilin (compound 5) with an alkaline solution in toluene or methyl isobutyl ketone is 50-55 ℃.
The reaction mechanism for preparation Mutilin is as follows:
Of course, the reaction may be performed in a methanol solution, but the tiamulin synthesis reaction is performed in toluene or methyl isobutyl ketone (MIBK) solution, and if the compound Mutilin is synthesized in a methanol solution, the methanol solvent is removed before use.
In some embodiments, the transesterification of methyl diethylaminoethyl thioacetate (compound 4) and Mutilin (compound 6) to obtain tiamulin (compound 7) is performed under the following reaction conditions: the reaction temperature is 70-100 ℃, the reaction time is 2-4 hours, and nitrogen is filled in the reaction process; preferably, the reaction temperature is from 85℃to 100 ℃.
The reaction temperature in this example is beneficial to promote the discharge of the product methanol and promote the reaction;
concretely, diethylaminoethylthio methyl acetate (compound 4) and Mutilin (compound 6) are subjected to transesterification in toluene or MIBK solution, the reaction temperature can be, but is not limited to, 70 ℃, 75 ℃,80 ℃, 85 ℃, 90 ℃, 95 ℃ or 100 ℃, and the like, and the excessive reaction temperature can cause MIBK or toluene to boil, so that the unsafe hidden danger is increased; too low a temperature results in low reaction efficiency.
It can be understood that the hydroxyl group on the compound 6 is easily oxidized, so that nitrogen is introduced in the reaction process, which is favorable for avoiding the oxidation of the hydroxyl group on the compound 6, reducing side reactions, promoting the discharge of methanol gas, promoting the proceeding of transesterification reaction and improving the yield of tiamulin.
In some embodiments, the diethylaminoethylthiomethyl acetate and Mutilin undergo transesterification under basic or acidic conditions; preferably, the diethylaminoethyl thiomethyl acetate and Mutilin are transesterified under basic conditions.
The reaction mechanism is as follows:
In some embodiments, the molar ratio of Mutilin to methyl diethylaminoethylthioacetate is 1: (1.0-1.1).
In the embodiment, the diethylaminoethyl thiomethyl acetate is slightly excessively fed, which is favorable for ensuring Mutilin complete reaction and improving the conversion rate of the reaction.
For further explanation of the present application, the following describes in detail a synthesis method of diethylaminoethanethiol according to the present application with reference to examples, but it should be understood that these examples are implemented on the premise of the technical scheme of the present application, and detailed implementation and specific operation procedures are given, only for further explanation of the features and advantages of the present application, and not limitation of the claims of the present application, and the scope of protection of the present application is not limited to the following examples.
Example 1
(1) Preparation of diethylaminoethyl thiomethyl acetate:
40g of methyl thioglycolate and 53g of K 2CO3 are added into a 1000mL reactor, dissolved by 400mL of methanol, 81g of bromochloroethane is gradually added in 0.5h at 25 ℃, and stirring reaction is carried out for 2h at 25 ℃ to obtain a compound (3);
then adding 2.5gKI and 45g of diethylamine into the product, heating to 55 ℃, stirring and reacting for 6 hours, ending the reaction, continuously heating to 75 ℃ at most, and distilling methanol until no distillate exists, thus obtaining a compound (4);
Cooling the reaction solution to room temperature, adding 100ml of H 2 O and 200mlMIBK, stirring uniformly, standing for layering, discarding the water phase, and washing with 50ml of deionized water for 3 times for later use;
When 65.1g of diethylaminoethylthiomethyl acetate (Compound 4) was contained in the above MIBK solution, the yield of diethylaminoethylthiomethyl acetate prepared from thiomethyl acetate was about 84.1%.
(2) Preparation Mutilin:
120g of pleuromutilin and 400mLMIBK g of pleuromutilin are added into a 1000mL reactor, then 20g of KOH is added, the temperature is raised to 55 ℃, the reaction time is 3.0h, 150mL of water is added into the reaction liquid, the mixture is stirred uniformly, the mixture is kept still for layering, the water phase is discarded, and the mixture is washed 3 times with 50mL of deionized water, so that the compound (6) is obtained for standby.
(3) Preparation of tiamulin
Adding the compound (4) into the compound (6), adding 40g of 32% NaOH, stirring at 90 ℃ for reaction for 2 hours, simultaneously filling a small amount of nitrogen for reaction, cooling to room temperature after the reaction is finished, and washing with deionized water for 5 times (80 ml each time) until the PH is less than 7.5, thus obtaining a stable tiamulin MIBK solution.
The detection spectrum of the tiamulin product is shown in figure 1, the chromatographic purity of the tiamulin is 94.53 percent, the tiamulin is 141.5g, and the yield from the pleuromutilin to the tiamulin is about 90.40 percent.
Example 2
Unlike example 1, the following is:
The feeding mole ratio of methyl thioglycolate to bromochloroethane is 1:1, the feeding mole ratio of methyl thioglycolate to diethylamine is 1:2, and the reaction temperature of adding the compound (4) into the compound (6) is 100 ℃.
The yield of diethylaminoethyl thiomethyl acetate prepared from methyl thioglycolate was about 82.8%.
The detection spectrum of the tiamulin product is shown in figure 2, the chromatographic purity of the tiamulin is 93.79 percent, the purity of the tiamulin is 140.7g, and the yield from the pleuromutilin to the tiamulin is about 89.89 percent.
Example 3
Unlike example 1, the following is:
The feeding mole ratio of methyl thioglycolate to bromochloroethane is 1:2, the feeding mole ratio of methyl thioglycolate to diethylamine is 1:2.5, and the reaction temperature of adding the compound (4) into the compound (6) is 85 ℃;
the yield of diethylaminoethylthiomethyl acetate prepared from methyl thioglycolate was about 87.7%.
The tiamulin product detection spectrum is shown in figure 3, the chromatographic purity of the tiamulin is 94.21%, the tiamulin is 144.3g, and the yield from pleuromutilin to tiamulin is about 92.19%.
The above description is only illustrative of the preferred embodiments of the present application and of the principles of the technology employed. It will be appreciated by persons skilled in the art that the scope of the application referred to in the present application is not limited to the specific combinations of the technical features described above, but also covers other technical features formed by any combination of the technical features described above or their equivalents without departing from the inventive concept. Such as the above-mentioned features and the technical features disclosed in the present application (but not limited to) having similar functions are replaced with each other.

Claims (10)

1. The preparation method of tiamulin is characterized by comprising the following steps:
And carrying out transesterification on diethylaminoethyl thiomethyl acetate and Mutilin to obtain tiamulin.
2. The preparation method according to claim 1, wherein before the transesterification of diethylaminoethylthiomethyl acetate and Mutilin to obtain tiamulin, the preparation method further comprises:
preparing diethylaminoethyl thiomethyl acetate from methyl thioglycolate, bromochloroethane and diethylamine;
The pleuromutilin and alkali liquor are reacted in toluene or methyl isobutyl ketone solution to prepare Mutilin.
3. The method according to claim 2, wherein the preparation of diethylaminoethyl thiomethyl acetate from methyl thioglycolate, bromochloroethane and diethylamine comprises:
After methyl thioglycolate is dissolved in a solvent, bromochloroethane is added for condensation reaction to obtain a first product;
and (3) carrying out condensation reaction on the first product and diethylamine to obtain diethylaminoethylthio methyl acetate.
4. The preparation method according to claim 3, wherein in the condensation reaction process of adding bromochloroethane after dissolving methyl thioglycolate in a solvent, the feeding mole ratio of the methyl thioglycolate to the bromochloroethane is 1: (1.0-2.0), wherein the solvent is methanol, and the temperature of the condensation reaction is 20-30 ℃.
5. The method according to claim 3, wherein in the condensation reaction of the first product and diethylamine, the molar ratio of the methyl thioglycolate to the diethylamine is 1: (1.3-2.5), the reaction temperature is 50-60 ℃, and the catalyst is KI.
6. The process according to claim 3, wherein after the condensation reaction of the first product with diethylamine is completed, the process further comprises removing the solvent.
7. The preparation method according to claim 2, wherein the reaction temperature is 50-60 ℃ in the process of preparing Mutilin by reacting pleuromutilin and alkali liquor in toluene or methyl isobutyl ketone solution.
8. The preparation method according to any one of claims 1 to 7, wherein in the process of transesterification of diethylaminoethyl thiomethyl acetate and Mutilin to obtain tiamulin, the reaction conditions are as follows: the reaction temperature is 70-100 ℃, and nitrogen is filled in the reaction process; preferably, the reaction temperature is from 85℃to 100 ℃.
9. The method according to claim 8, wherein the diethylaminoethyl thiomethyl acetate and Mutilin undergo transesterification under basic or acidic conditions; preferably, the diethylaminoethyl thiomethyl acetate and Mutilin are transesterified under basic conditions.
10. The method according to claim 8, wherein the Mutilin and diethylaminoethylthio methyl acetate are fed in a molar ratio of 1: (1.0-1.1).
CN202410055809.8A 2024-01-12 2024-01-12 Preparation method of tiamulin Pending CN117903026A (en)

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