CN114133417A - Production method for improving quality of tilmicosin phosphate - Google Patents
Production method for improving quality of tilmicosin phosphate Download PDFInfo
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- CN114133417A CN114133417A CN202111552221.6A CN202111552221A CN114133417A CN 114133417 A CN114133417 A CN 114133417A CN 202111552221 A CN202111552221 A CN 202111552221A CN 114133417 A CN114133417 A CN 114133417A
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- C07H1/00—Processes for the preparation of sugar derivatives
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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Abstract
The invention relates to a production method for improving the quality of tilmicosin phosphate, which is characterized in that after butyl acetate is extracted for 20-40min and before amine is synthesized, anhydrous sodium sulfate is added into extract liquid for stirring treatment, so that on one hand, the time for extracting, standing and water dividing of butyl acetate is greatly shortened, 5-6 hours are needed for extracting, standing and water dividing in the original process, and the time for water dividing is 30-60min after the anhydrous sodium sulfate is added, thereby reducing the production time. On the other hand, the water in the extraction liquid is greatly removed, and a specific amount of anhydrous sodium sulfate is added at a specific time, so that the water in the extraction liquid is lower than 2.0 percent, the insufficient subsequent amination reaction is avoided, the amination reaction is thorough, the quality of the tilmicosin phosphate is improved, and the total impurity is reduced by 3.0 percent.
Description
Technical Field
The invention relates to a production method for improving the quality of tilmicosin phosphate, belonging to the technical field of biological veterinary drug preparation.
Background
Tilmicosin phosphate is a phosphate formed by Tilmicosin (Tilmicosin) and phosphoric acid; the structural formula is shown as the following formula I, the antibiotic is a macrolide antibiotic specially used for livestock and poultry semi-synthesized by tylosin and developed successfully by British corporation in 80 th century, and due to the special antibacterial activity and pharmacokinetic characteristics of the antibiotic, the antibiotic is approved to be clinically used for preventing and treating infectious diseases of animals such as cows, goats, sheep, cows, pigs, chickens and the like, particularly respiratory diseases of the livestock and the poultry, such as actinobacillary pleuropneumonia, pasteurellosis, gallinaceous mycoplasmosis and the like and mastitis of lactating animals; has similar molecular structure and antibacterial spectrum with tylosin, but has stronger antibacterial activity to some pathogenic bacteria than tylosin, in recent years, the synthetic route of tilmicosin phosphate is mature, and the main starting materials are tylosin tartrate and tylosin phosphate.
At present, two main synthetic routes of tilmicosin are available in China. One is that tylosin fermentation broth is pretreated, then is subjected to formyl amination reduction, and then is hydrolyzed under an acidic condition to generate tilmicosin, for example, a method for synthesizing tilmicosin and tilmicosin phosphate by utilizing the tylosin fermentation broth disclosed in Chinese patent CN102659878A is disclosed. And the other is that tylosin phosphate is firstly hydrolyzed in an acidic aqueous solution and then undergoes amination reaction with 3, 5-dimethylpiperidine, for example, CN105837648A discloses a preparation method of tilmicosin phosphate, which takes tylosin tartrate as a raw material, and the raw material is hydrolyzed, alkalized and extracted, aminated, added with phosphorus pentoxide and a small amount of water for phosphorylation under an acidic condition, fully stirred to form salt, centrifugally separated after solid is completely separated out, and dried in vacuum to obtain tilmicosin phosphate.
In the two methods, before amination, amination is performed after natural layering through organic solvent extraction, the operation time is long, the residual amount of water in butyl acetate is large, and finally the finished product has more impurities and low purity; meanwhile, the entrainment of the organic solvent for extraction can influence the amination reaction, and further lead to more impurities in the finished product.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the production method for improving the quality of the tilmicosin phosphate, the method can effectively reduce impurities and improve the purity of the tilmicosin phosphate, the method has the advantages of simple process, low cost, short working procedure and easy popularization and utilization, and the total impurities of the tilmicosin phosphate can be reduced by 3.0 percent on average; the content is improved by 4 percent on average.
The invention is realized by the following technical scheme:
a production method for improving the quality of tilmicosin phosphate comprises the steps of extracting tylosin tartrate concentrated solution by butyl acetate, synthesizing amine, carrying out acid extraction and hydrolysis, decoloring, crystallizing, extracting by phosphoric acid, and carrying out vacuum drying to obtain tilmicosin;
the butyl acetate extraction is that butyl acetate is used as an extractant to carry out countercurrent extraction on tylosin tartrate concentrated solution, extract liquor is collected, and the volume ratio of the tylosin tartrate concentrated solution to the butyl acetate is 10-11: 4-4.5, the extraction temperature is 40-50 ℃, and the extraction pH is controlled to be 7.0-10.0;
the amination synthesis is carried out by adding 3, 5-dimethylpiperidine, formic acid and organic solvent for amination reaction;
after butyl acetate is extracted for 20-40min and before amine synthesis, anhydrous sodium sulfate is added into the extract liquid for stirring treatment, then the anhydrous sodium sulfate is removed by filtration, and then the amine synthesis is carried out.
According to the invention, the amount of anhydrous sodium sulfate added is preferably 5.0-12.0% by mass of the extract.
Most preferably, the amount of anhydrous sodium sulfate added is 8.0% of the mass of the extract.
According to the invention, the stirring treatment time is preferably 30 to 60 min.
Most preferably, the stirring treatment time is 50 min.
According to the invention, the molar ratio of tylosin to 3, 5-dimethylpiperidine in amination synthesis is preferably 1: 1-1.5.
According to the invention, the molar ratio of tylosin to formic acid in amination synthesis is preferably 1: 1-1.5.
According to the invention, in the amination synthesis, the mass ratio of formic acid to the organic solvent is 1: 10-15, and the organic solvent is ethyl acetate.
According to the optimization of the invention, the reaction temperature in the amination synthesis is 60-80 ℃.
According to the invention, the reaction time in the amination synthesis is preferably 2-4 hours.
According to the invention, after butyl acetate is extracted for 20-40min and before amine synthesis, anhydrous sodium sulfate is added into the extract for stirring treatment, so that on one hand, the time for extracting and statically dividing water of butyl acetate is greatly shortened, on the other hand, the moisture in the extract is greatly removed, a specific amount of anhydrous sodium sulfate is added at a specific time, so that the moisture in the extract is lower than 2.0%, the problem of insufficient subsequent amination reaction is avoided, the amination reaction is thorough, the quality of tilmicosin phosphate is improved, the tylosin conversion rate in the amine synthesis reaction can reach 99.5%, and even if the reaction is not affected by the entrainment of the anhydrous sodium sulfate, the tilmicosin phosphate powder total impurities can be removed by washing with water, so that the total impurities of the tilmicosin phosphate powder can be reduced by 3.0%.
When the addition amount of the anhydrous sodium sulfate is too large, a large amount of cost is generated, equipment is blocked, the production progress is influenced, and the like. When the amount of the amine compound is too small, the water in the butyl acetate cannot be sufficiently removed, and the amine compound reaction is ensured to be sufficiently reacted. Thereby failing to achieve the object of reducing impurities and improving quality.
The invention has the technical characteristics and advantages that:
1. according to the invention, after butyl acetate is extracted for 20-40min and before amine is combined, anhydrous sodium sulfate is added into the extract liquid for stirring treatment, so that on one hand, the time for extracting stationary water division of butyl acetate is greatly shortened, 5-6 hours are required for extracting stationary water division in the original process, and the water division time is 30-60min after the anhydrous sodium sulfate is added, so that the production working hours are reduced. On the other hand, the water in the extraction liquid is greatly removed, and a specific amount of anhydrous sodium sulfate is added at a specific time, so that the water in the extraction liquid is lower than 2.0 percent, the insufficient subsequent amination reaction is avoided, the amination reaction is thorough, the quality of the tilmicosin phosphate is improved, and the total impurity is reduced by 3.0 percent.
2. The method of the invention does not cause conflict to the existing production process and equipment, and has the advantages of simple operation, easy execution and low raw material cost.
Detailed Description
The present invention is further illustrated by, but is not limited to, the following specific examples.
Example 1
A production method for improving the quality of tilmicosin phosphate comprises the following steps:
1) carrying out countercurrent extraction on the tylosin tartrate concentrated solution by taking butyl acetate as an extractant, and collecting extract liquor, wherein the volume ratio of the tylosin tartrate concentrated solution to the butyl acetate is 10: 4, the extraction temperature is 45 ℃, and the extraction pH is controlled to be 7.0;
2) adding butyl acetate, extracting, standing for 35min, discarding water phase to obtain butyl acetate extractive solution 5m3；
3) Adding anhydrous sodium sulfate into the extract, stirring for 50min, filtering to remove anhydrous sodium sulfate, and performing amination synthesis; the addition of anhydrous sodium sulfate is 8.0 percent of the mass of the extraction liquid;
4) adding 3, 5-dimethylpiperidine, formic acid and ethyl acetate into the system to carry out amination reaction, wherein the molar ratio of the tylosin to the 3, 5-dimethylpiperidine is 1: 1; the molar ratio of the tylosin to the formic acid is 1:1, and the mass ratio of the formic acid to the organic solvent is 1: 10; the reaction temperature was 70 ℃ and the reaction time was 3 hours.
5) And after the amination reaction is finished, performing acid extraction hydrolysis, decoloring, crystallization centrifugation, phosphoric acid extraction, and drying the phosphoric acid extract by using a high-speed centrifugal spray dryer to obtain tilmicosin phosphate powder.
Example 2
A production method for improving the quality of tilmicosin phosphate comprises the following steps:
1) carrying out countercurrent extraction on the tylosin tartrate concentrated solution by taking butyl acetate as an extractant, and collecting extract liquor, wherein the volume ratio of the tylosin tartrate concentrated solution to the butyl acetate is 10: 4.5, the extraction temperature is 45 ℃, and the extraction pH is controlled to be 7.0;
2) adding butyl acetate, extracting, standing for 30min, discarding water phase to obtain butyl acetate extractive solution 5m3；
3) Adding anhydrous sodium sulfate into the extract, stirring for 40min, filtering to remove anhydrous sodium sulfate, and performing amination synthesis; the addition of anhydrous sodium sulfate is 10.0 percent of the mass of the extraction liquid;
4) adding 3, 5-dimethylpiperidine, formic acid and ethyl acetate into the system to carry out amination reaction, wherein the molar ratio of the tylosin to the 3, 5-dimethylpiperidine is 1: 1.5; the mol ratio of the tylosin to the formic acid is 1:1.5, and the mass ratio of the formic acid to the organic solvent is 1: 12; the reaction temperature was 70 ℃ and the reaction time was 3 hours.
5) And after the amination reaction is finished, performing acid extraction hydrolysis, decoloring, crystallization centrifugation, phosphoric acid extraction, and drying the phosphoric acid extract by using a high-speed centrifugal spray dryer to obtain tilmicosin phosphate powder.
Example 3
A production method for improving the quality of tilmicosin phosphate comprises the following steps:
1) carrying out countercurrent extraction on the tylosin tartrate concentrated solution by taking butyl acetate as an extractant, and collecting extract liquor, wherein the volume ratio of the tylosin tartrate concentrated solution to the butyl acetate is 11: 4.5, the extraction temperature is 45 ℃, and the extraction pH is controlled to be 7.0;
2) adding butyl acetate, extracting, standing for 25min, discarding water phase to obtain butyl acetate extractive solution 5m3；
3) Adding anhydrous sodium sulfate into the extract, stirring for 45min, filtering to remove anhydrous sodium sulfate, and performing amination synthesis; the addition of anhydrous sodium sulfate is 7.0 percent of the mass of the extraction liquid;
4) adding 3, 5-dimethylpiperidine, formic acid and ethyl acetate into the system to carry out amination reaction, wherein the molar ratio of the tylosin to the 3, 5-dimethylpiperidine is 1: 1.5; the mol ratio of the tylosin to the formic acid is 1:1.5, and the mass ratio of the formic acid to the organic solvent is 1: 12; the reaction temperature was 70 ℃ and the reaction time was 3 hours.
5) And after the amination reaction is finished, performing acid extraction hydrolysis, decoloring, crystallization centrifugation, phosphoric acid extraction, and drying the phosphoric acid extract by using a high-speed centrifugal spray dryer to obtain tilmicosin phosphate powder.
Comparative example 1
PhosphorusThe tilmicosin hydrochloride is prepared through conventional process including adding butyl acetate into concentrated tylosin tartrate solution, extracting, discarding water phase to obtain butyl acetate extractive solution of 5m3Carrying out amine synthesis reaction, acid extraction hydrolysis, decoloring, crystallization centrifugation, phosphoric acid extraction, and drying the phosphoric acid extract by using a spray centrifugal drying tower to obtain tilmicosin phosphate powder.
Experimental example:
the method of example 1 and comparative example 1 was adopted to perform 3 comparison productions using different tylosin tartrate concentrated solutions, and the products after each secondary production were taken for testing.
The detection test results are shown in the following tables 1, 2 and 3:
TABLE 1
| Single and mixed% | Total miscellaneous% | Water content% | Content% | |
| Example 1 | 2.1 | 5.5 | 3.1 | 83.98 |
| Comparative example 1 | 2.3 | 8.6 | 3.2 | 78.90 |
TABLE 2
| Single and mixed% | Total miscellaneous% | Water content% | Content% | |
| Example 1 | 1.6 | 4.9 | 3.1 | 84.23 |
| Comparative example 1 | 1.8 | 8.0 | 3.0 | 79.90 |
TABLE 3
| Single and mixed% | Total miscellaneous% | Water content% | Content% | |
| Example 1 | 2.4 | 5.4 | 3.0 | 83.45 |
| Comparative example 1 | 2.6 | 8.7 | 3.2 | 78.33 |
As can be seen from the comparison of the 3 batches of production, the total heterosis of the invention in example 1 is reduced by 3.16% compared with that in comparative example 1; the content is averagely improved by 4.84 percent, the effect is obvious, the time of extracting, standing and water dividing of butyl acetate is greatly shortened, and the quality of tilmicosin phosphate is improved.
Claims (10)
1. A production method for improving the quality of tilmicosin phosphate comprises the steps of extracting tylosin tartrate concentrated solution by butyl acetate, synthesizing amine, carrying out acid extraction and hydrolysis, decoloring, crystallizing, extracting by phosphoric acid, and carrying out vacuum drying to obtain tilmicosin;
the butyl acetate extraction is that butyl acetate is used as an extractant to carry out countercurrent extraction on tylosin tartrate concentrated solution, extract liquor is collected, and the volume ratio of the tylosin tartrate concentrated solution to the butyl acetate is 10-11: 4-4.5, the extraction temperature is 40-50 ℃, and the extraction pH is controlled to be 7.0-10.0;
the amination synthesis is carried out by adding 3, 5-dimethylpiperidine, formic acid and organic solvent for amination reaction;
after butyl acetate is extracted for 20-40min and before amine synthesis, anhydrous sodium sulfate is added into the extract liquid for stirring treatment, then the anhydrous sodium sulfate is removed by filtration, and then the amine synthesis is carried out.
2. The production method according to claim 1, wherein the amount of the anhydrous sodium sulfate added is 5.0 to 12.0% by mass of the extract.
3. The production method according to claim 1, wherein the amount of anhydrous sodium sulfate added is 8.0% by mass of the extract.
4. The production method according to claim 1, wherein the stirring treatment time is 30 to 60 min.
5. The production method according to claim 1, wherein the stirring treatment time is 50 min.
6. The production method according to claim 1, wherein the molar ratio of tylosin to 3, 5-dimethylpiperidine in the amination synthesis is 1:1 to 1.5.
7. The production method according to claim 1, wherein the molar ratio of tylosin to formic acid in the amination synthesis is 1:1 to 1.5.
8. The production method according to claim 1, wherein in the amination synthesis, the mass ratio of formic acid to the organic solvent is 1: 10-15, and the organic solvent is ethyl acetate.
9. The production method according to claim 1, wherein the reaction temperature in the amination synthesis is 60 to 80 ℃.
10. The production method according to claim 1, wherein the reaction time in the amination synthesis is 2 to 4 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115626941A (en) * | 2022-12-20 | 2023-01-20 | 山东久隆恒信药业有限公司 | Synthesis method of tilmicosin phosphate |
| CN115925772A (en) * | 2022-12-20 | 2023-04-07 | 山东久隆恒信药业有限公司 | Synthesis method of tilmicosin |
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| CN102659878A (en) * | 2012-04-11 | 2012-09-12 | 宁夏泰瑞制药股份有限公司 | Method for synthesizing tilmicosin and tilmicosin phosphate through using tylosin broth |
| CN105837648A (en) * | 2015-11-02 | 2016-08-10 | 湖北龙翔药业科技股份有限公司 | Tilmicosin phosphate preparation method |
| CN108864227A (en) * | 2018-06-07 | 2018-11-23 | 中牧实业股份有限公司 | The method for producing Tilmicosin and tilmicosin phosphate using tylosin broth |
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2021
- 2021-12-17 CN CN202111552221.6A patent/CN114133417A/en active Pending
Patent Citations (3)
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| CN102659878A (en) * | 2012-04-11 | 2012-09-12 | 宁夏泰瑞制药股份有限公司 | Method for synthesizing tilmicosin and tilmicosin phosphate through using tylosin broth |
| CN105837648A (en) * | 2015-11-02 | 2016-08-10 | 湖北龙翔药业科技股份有限公司 | Tilmicosin phosphate preparation method |
| CN108864227A (en) * | 2018-06-07 | 2018-11-23 | 中牧实业股份有限公司 | The method for producing Tilmicosin and tilmicosin phosphate using tylosin broth |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115626941A (en) * | 2022-12-20 | 2023-01-20 | 山东久隆恒信药业有限公司 | Synthesis method of tilmicosin phosphate |
| CN115925772A (en) * | 2022-12-20 | 2023-04-07 | 山东久隆恒信药业有限公司 | Synthesis method of tilmicosin |
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