CN112094305B - Preparation process of tylosin alkali - Google Patents
Preparation process of tylosin alkali Download PDFInfo
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- CN112094305B CN112094305B CN202011194913.3A CN202011194913A CN112094305B CN 112094305 B CN112094305 B CN 112094305B CN 202011194913 A CN202011194913 A CN 202011194913A CN 112094305 B CN112094305 B CN 112094305B
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- tylosin
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- alkali
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Abstract
The invention discloses a preparation process of tylosin alkali, which comprises the following steps: 1. preparing a tylosin filtrate; s2, carrying out primary crystallization on the tylosin filtrate obtained in the step S1 to obtain a primary crystallization crude product; s3, stirring and dissolving the primary crystal crude product and dilute sulfuric acid to obtain a primary acid solution; s4, carrying out secondary crystallization on the primary acid solution to obtain a secondary crystallization crude product; s5, mixing and washing the secondary crystallization crude product with alkaline purified water to obtain a tylosin alkali primary product; and S6, sequentially carrying out vacuum drying and crushing on the initial tylosin alkali product to obtain the tylosin alkali product. According to the invention, the tylosin base is generated by combining the tylosin and hydroxyl ions under an alkaline condition, so that the stability of a main component A of the tylosin base can be improved, the biological value of the main component A of the tylosin base is higher, and the mass content of the tylosin base is higher than that of the main component A of the tylosin in the tylosin tartrate because the molecular weight of the tartrate ions is larger than that of the hydroxyl ions.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations for animals, in particular to a preparation process of tylosin base.
Background
Tavermectin, formerly known as acetylisovaleryltylosin, is a macrolide antibiotic. Developed by Iceau animal health products, Inc. in England, the products sold in the market of the tavermectin are tavermectin tartrate, and the molecular structure of the tavermectin tartrate is finally salified by combining the tavermectin with tartaric acid. The tylosin tartrate premix and the soluble powder are approved in China at present and are used for treating swine and mycoplasma gallisepticum infection and swine bloody flux brachyspira and other infections of sensitive bacteria. The tavermectin has the advantages of high efficiency, low toxicity, low residue and the like, does not generate cross drug resistance among macrolide antibiotics, and is a good macrolide antibiotic for treating respiratory tract and digestive tract infection. However, in the extraction and production process of the tylosin raw material, tartaric acid needs to be added, and finally tylosin tartrate is produced through spray drying, the pH of the tylosin tartrate is 3.0-5.0 (2017 edition chemical volume of veterinary drug quality standard), namely the pH of a finished product is acidic, but according to the characteristics of the tylosin product, in the process of producing tartrate, the tartaric acid is used for dissolving crystals, and according to the characteristics of the product, the product is degraded under the acidic (particularly liquid state) condition, particularly, the component A has poor stability and rapid degradation speed under the acidic condition, for example, in the prior art, "CN 107213470B" discloses "tylosin tartrate soluble powder and a preparation method thereof, the tylosin tartrate prepared by the method has poor stability, and the existing problem that the biological value of the tylosin is low.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention provides a preparation process of tylosin alkali with good stability and high biological value.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation process of tylosin base comprises the following steps:
s1, preparing a tylosin filtrate;
s2, carrying out primary crystallization on the tylosin filtrate obtained in the step S1 to obtain a primary crystallization crude product;
s3, stirring and dissolving the primary crystal crude product and dilute sulfuric acid to obtain a primary acid solution;
s4, carrying out secondary crystallization on the primary acid solution to obtain a secondary crystallization crude product;
s5, mixing and washing the secondary crystallization crude product with alkaline purified water to obtain a tylosin alkali primary product;
and S6, sequentially carrying out vacuum drying and crushing on the initial tylosin alkali product to obtain the tylosin alkali product.
Further, in the step S1, the temperature of the tylosin fermentation liquor is reduced to 20-24 ℃, dilute sulfuric acid is added into the tylosin fermentation liquor for acidification, so that the pH value of the tylosin fermentation liquor is 4.2-4.5, and then the tylosin fermentation liquor is filtered to obtain a tylosin filtrate.
Specifically, the concentration of the dilute sulfuric acid is 5-8%.
Further, in the step S2, sodium hydroxide is added into the tylosin filtrate, the pH value of the tylosin filtrate is adjusted to 5.0-5.5, the feed liquid is heated in a water bath by hot water at the temperature of 80-90 ℃, the feed liquid is heated to 50-55 ℃, and the feed liquid is kept stand for 13-15 hours, so that a primary crystalline crude product is obtained.
Specifically, the concentration of the sodium hydroxide is 10-12%.
Further, in the step S3, the primary crystallized crude product is cooled to 20 to 24 ℃, and then stirred and dissolved with dilute sulfuric acid with a concentration of 8 to 12% to obtain a primary acid solution.
Further, in the step S4, sodium hydroxide is added into the primary acid solution, the pH value of the primary acid solution is adjusted to 5.0-5.5, the feed liquid is heated in a water bath by hot water at 80-90 ℃ to raise the temperature of the feed liquid to 50-55 ℃, and the feed liquid is left to stand for 14-16 hours to obtain a secondary crystal crude product.
Specifically, the concentration of the sodium hydroxide is 10-12%.
Further, in the step S5, the secondary crystallization crude product is washed and stirred for 6-8 times by alkaline purified water with the pH value of 8.0-9.0, and the stirring time of each mixing and washing is 1.5-2.5 h, wherein the volume ratio of the secondary crystallization crude product to the alkaline purified water of each mixing and washing is 1: 10-12.
Further, the step S6 is to perform vacuum drying on the primary finished tylosin alkali product at a vacuum degree of-0.06-0.08 Mpa and a temperature of 65-70 ℃ for 8-12 h, and then pulverize the dried tylosin alkali product to obtain the tylosin alkali product.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the method, a tylosin fermentation liquor is sequentially acidified and filtered to obtain a tylosin filtrate, the pH value of the tylosin filtrate is adjusted by sodium hydroxide to obtain a primary crystallization crude product, the primary crystallization crude product is dissolved and filtered by dilute sulfuric acid, impurities are removed, secondary crystallization is carried out, the secondary crystallization crude product and the crude product are mixed and washed by alkaline purified water with the pH value of 8.0-9.0 to obtain the tylosin alkali.
(2) According to the invention, the tylosin base is generated by combining tylosin and hydroxyl ions under an alkaline condition, so that the content of a main component of the tylosin can be increased, the stability of a component A is increased, and the biological value of the main component A of the tylosin base prepared by the method is higher; in addition, because the molecular weight of the tartrate radical is larger than that of hydroxide radical ions, the content of the tylosin base is higher than that of a tylosin main component A in the tylosin tartrate.
(3) The tylosin alkali product can be obtained by vacuum drying and crushing, and better stability is kept.
Detailed Description
The present invention is further illustrated by the following examples, which include, but are not limited to, the following examples.
A preparation process of tylosin base comprises the following steps:
s1, cooling the tylosin fermentation liquor to 20-24 ℃, adding dilute sulfuric acid with the concentration of 5-8% into the tylosin fermentation liquor for acidification to enable the pH value of the tylosin fermentation liquor to be 4.2-4.5, and then filtering the tylosin fermentation liquor to obtain a tylosin filtrate;
s2, adding 10-12% sodium hydroxide into the tylosin filtrate obtained in the step S1, adjusting the pH value of the tylosin filtrate to 5.0-5.5, heating the feed liquid in water bath by using hot water at 80-90 ℃ to enable the feed liquid to be heated to 50-55 ℃, standing for 13-15 hours, and obtaining a primary crystallization crude product;
s3, cooling the primary crystallization crude product to 20-24 ℃, and stirring and dissolving the primary crystallization crude product and dilute sulfuric acid with the concentration of 8-12% to obtain a primary acid solution;
s4, adding 10-12% sodium hydroxide into the primary acid solution, adjusting the pH value of the primary acid solution to 5.0-5.5, heating the feed liquid in water bath by using hot water at 80-90 ℃ to enable the feed liquid to be heated to 50-55 ℃, and standing for 14-16 hours to obtain a secondary crystallization crude product;
s5, washing and stirring the secondary crystallization crude product with alkaline purified water with the pH value of 8.0-9.0 for 6-8 times, wherein the washing and stirring time for each time is 1.5-2.5 h, and thus obtaining a tylosin alkali primary product, wherein the volume ratio of the secondary crystallization crude product to the alkaline purified water for each washing is 1: 10-12;
s6, drying the initial tylosin alkali product in vacuum at-0.06-0.08 Mpa and 65-70 ℃ for 8-12 h, crushing and sieving to obtain the tylosin alkali product.
Example 1
Preparing the tylosin base.
Cooling the tylosin fermentation liquor to 22 ℃, adding 7% dilute sulfuric acid into the tylosin fermentation liquor for acidification to enable the pH value of the tylosin fermentation liquor to be 4.2-4.5, and then filtering the tylosin fermentation liquor to obtain a tylosin filtrate; adding 11% sodium hydroxide into a tylosin filtrate, adjusting the pH value of the tylosin filtrate to 5.2, heating the feed liquid in a water bath by using 85 ℃ hot water, heating the feed liquid to 54 ℃, standing for 14h to obtain a primary crystallization crude product, performing primary crystallization to obtain a primary crystallization crude product, cooling the primary crystallization crude product to 20 ℃, stirring and dissolving the primary crystallization crude product with 10% dilute sulfuric acid to obtain a primary acid solution, adding 11% sodium hydroxide into the primary acid solution, adjusting the pH value of the primary acid solution to 5.3, heating the feed liquid in a water bath by using 80-90 ℃ hot water, heating the feed liquid to 54 ℃, standing for 15h to obtain a secondary crystallization crude product, mixing, washing and stirring the secondary crystallization crude product with alkaline purified water with the pH value of 8.8 and the volume ratio of 1: 10-12 for 6 times, mixing, washing and stirring for 2h each time, and placing the tylosin base crude product in a vacuum degree of-0.06 Mpa, Vacuum drying at 65 deg.C for 10 hr, pulverizing, and sieving to obtain tylosin base product.
Example 2
And (5) verifying the effect of the tylosin alkali.
And taking three batches of products for normally producing the tylosin tartrate, taking part of filter cakes from secondary crystallization crude products, wherein the taken filter cakes are used for producing the tylosin alkali, and the rest of the filter cakes are subjected to tylosin tartrate production according to the original process to obtain finished products, and then respectively detecting and accelerating the test, and comparing the detection results. The results are shown in Table 1.
TABLE 1
As can be seen from the table above, the A component of the 3 batches of tests is improved by 1.99% compared with the control group, the dry-break biological potency is improved by 3.78%, the degradation rate of the three-month accelerated stability test (accelerated test is carried out by using a stability test box) is reduced by 77.6%, and the content of the A component can be effectively improved by preparing the tavernine, so that more A components are stored, and the biological potency of the prepared tavernine is higher.
Example 3
The detection result of the tylosin alkali under the condition of alkaline purified water with different pH values and the comparison with the tylosin tartrate.
Taking a batch of products normally producing the tylosin tartrate, adding a secondary crystallization crude product to obtain a part of filter cakes, wherein the obtained filter cakes are used for producing the tylosin alkali, mixing and washing the produced tylosin alkali in alkaline purified water with the pH values of 7.95, 8.25, 8.7 and 9.5 respectively, and detecting the residual filter cakes after the tylosin tartrate is produced according to the original process to obtain finished products respectively, wherein the detection results are shown in Table 2.
TABLE 2
According to table 2, the content and the biological potency of the component A of the generated tylosin alkali are highest by mixing and washing with alkaline purified water with the pH value of 8.0-9.0 and reacting with the crystals, and the content of the component A changes less than three months ago in an accelerated test of three months, which shows that the tylosin alkali prepared by the method has better stability, and meanwhile, the tylosin alkali prepared by the method has more retained component A and higher biological potency in a detection result of tylosin tartrate.
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or changes made within the spirit and scope of the main design of the present invention, which still solve the technical problems consistent with the present invention, should be included in the scope of the present invention.
Claims (4)
1. A preparation process of tylosin base is characterized by comprising the following steps:
s1, preparing a tylosin filtrate: cooling the tylosin fermentation liquor to 20-24 ℃, adding dilute sulfuric acid into the tylosin fermentation liquor for acidification to enable the pH value of the tylosin fermentation liquor to be 4.2-4.5, and then filtering the tylosin fermentation liquor to obtain a tylosin filtrate;
s2, carrying out primary crystallization on the tylosin filtrate obtained in the step S1 to obtain a primary crystallization crude product: adding sodium hydroxide into the tylosin filtrate, adjusting the pH value of the tylosin filtrate to 5.0-5.5, heating the feed liquid in water bath by using hot water at the temperature of 80-90 ℃, heating the feed liquid to 50-55 ℃, standing for 13-15 h, and obtaining a primary crystallization crude product;
s3, stirring and dissolving the primary crystal crude product and dilute sulfuric acid to obtain a primary acid solution: firstly, cooling the primary crystallization crude product to 20-24 ℃, and then stirring and dissolving the primary crystallization crude product and dilute sulfuric acid with the concentration of 8-12% to obtain a primary acid solution;
s4, carrying out secondary crystallization on the primary acid solution to obtain a secondary crystallization crude product: adding sodium hydroxide into the primary acid solution, adjusting the pH value of the primary acid solution to 5.0-5.5, heating the feed liquid in water bath by using hot water at the temperature of 80-90 ℃, heating the feed liquid to 50-55 ℃, standing for 14-16 h, and obtaining a secondary crystallization crude product;
s5, mixing and washing the secondary crystallization crude product with alkaline purified water to obtain a tylosin alkali primary product; washing and stirring the secondary crystallization crude product with alkaline purified water with the pH value of 8.0-9.0 for 6-8 times, wherein the stirring time of each mixing and washing is 1.5-2.5 h, and the volume ratio of the secondary crystallization crude product to the alkaline purified water of each mixing and washing is 1: 10-12;
s6, drying the initial tylosin alkali product in vacuum at-0.06-0.08 Mpa and 65-70 ℃ for 8-12 h, and then crushing to obtain the tylosin alkali product.
2. The process of claim 1, wherein the concentration of dilute sulfuric acid in step S1 is 5-8%.
3. The process of claim 1, wherein the concentration of sodium hydroxide in step S2 is 10-12%.
4. The process of claim 1, wherein the concentration of sodium hydroxide in step S4 is 10-12%.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1374406A (en) * | 2000-09-30 | 2002-10-16 | 徐月清 | Extraction process of tylan |
| CN1432575A (en) * | 2002-01-14 | 2003-07-30 | 徐兵 | Tylan purifying process |
| CN101381756A (en) * | 2007-09-07 | 2009-03-11 | 中牧实业股份有限公司 | Purification method of super tylosin |
| CN103408623A (en) * | 2013-08-27 | 2013-11-27 | 宁夏泰瑞制药股份有限公司 | Extraction process of acetylisovaleryltylosin |
| CN103923140A (en) * | 2014-04-14 | 2014-07-16 | 宁夏泰瑞制药股份有限公司 | Preparation method of acetylisovaleryltylosin tartrate |
| CN108358979A (en) * | 2018-05-22 | 2018-08-03 | 中牧实业股份有限公司 | The purification process of safe ten thousand rhzomorphs |
-
2020
- 2020-10-30 CN CN202011194913.3A patent/CN112094305B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1374406A (en) * | 2000-09-30 | 2002-10-16 | 徐月清 | Extraction process of tylan |
| CN1432575A (en) * | 2002-01-14 | 2003-07-30 | 徐兵 | Tylan purifying process |
| CN101381756A (en) * | 2007-09-07 | 2009-03-11 | 中牧实业股份有限公司 | Purification method of super tylosin |
| CN103408623A (en) * | 2013-08-27 | 2013-11-27 | 宁夏泰瑞制药股份有限公司 | Extraction process of acetylisovaleryltylosin |
| CN103923140A (en) * | 2014-04-14 | 2014-07-16 | 宁夏泰瑞制药股份有限公司 | Preparation method of acetylisovaleryltylosin tartrate |
| CN108358979A (en) * | 2018-05-22 | 2018-08-03 | 中牧实业股份有限公司 | The purification process of safe ten thousand rhzomorphs |
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