CN110981926B

CN110981926B - Purification method of crude product of tylosin

Info

Publication number: CN110981926B
Application number: CN201911271497.XA
Authority: CN
Inventors: 李冀; 黄凯; 刘毅; 李红园; 李金明; 周岩; 田俊岭; 李�杰; 杜永军; 王金军
Original assignee: Hebei Yuanzheng Pharmaceutical Co ltd
Current assignee: Hebei Yuanzheng Pharmaceutical Co ltd
Priority date: 2019-12-12
Filing date: 2019-12-12
Publication date: 2023-05-16
Anticipated expiration: 2039-12-12
Also published as: CN110981926A

Abstract

A purification method of a crude product of tylosin comprises the following steps: adding the crude product of the tylosin into acetonitrile, maintaining the temperature at 20-30 ℃, and stirring until the crude product of the tylosin is dissolved; filtering the acetonitrile solution of the tylosin through a 0.8nm filter element, stirring in a crystallization kettle, and keeping the temperature at 20-30 ℃; under low-speed stirring, maintaining the temperature at 20-30 ℃, adding deionized water with the same volume as acetonitrile into a crystallization kettle within 30min, and stirring for crystallization for 1h; centrifuging, filtering, and drying the filtered solid to obtain a product Luo Xinchun of Taidi; and (5) distilling acetonitrile in the filtrate, and recycling. The method adopts acetonitrile as a solvent, the purity of the purified tylosin reaches more than 99 percent, the water content is low, the quality stability of the product is effectively maintained in the purification process, and the purification time is short.

Description

Purification method of crude product of tylosin

Technical Field

The invention relates to a purification method of a crude product of tylosin, belonging to the technical field of chemicals.

Background

Tylosin is a novel semisynthetic macrolide semisynthetic antibiotic special for animals and is a derivative of tylosin. The composition is used for treating respiratory diseases caused by bacteria such as haemophilus parasuis and actinobacillus pleuropneumoniae, and has better effect than tylosin in inhibiting respiratory pathogens of pigs and cattle. The European Union animal drug Committee (CVMP) approved a market approval for sterile injectable solutions (under the trade name Zupevo) with tylosin as the major ingredient by Intewei corporation, at 3 and 8 days 2011, and would then be approved for sale in the European Union. The Tildipirosin has CAS number of 328898-40-4, molecular formula of C41H 71N 308, molecular weight of 734.02, melting point of 192 deg.C, and slightly soluble in polar organic solvent (such as methanol, acetone, etc.). The tylosin is used for preventing and treating respiratory infectious diseases of pigs and cattle caused by sensitive bacteria, and the whole course of treatment can be provided by single administration. Intramuscular injection of pigs and subcutaneous injection of cattle neck. The medicine has the advantages of rapid absorption, long half-life period, high bioavailability, stable property and good development value.

Currently, patent CN104672287a discloses a purification method of tylosin. The method comprises the steps of acidifying with sulfuric acid, dissolving the tylosin in deionized water, adsorbing with silica gel or activated alumina to remove impurities, washing with a large amount of ethanol and deionized water, alkalizing and crystallizing at 75 ℃, and filtering to obtain the tylosin. The method uses a large amount of silica gel or activated alumina, and uses a large amount of ethanol, so that the purification time is long, the production cost is high, the stability of the tylosin is poor, and impurities can be generated again to reduce the purity when the high-temperature alkaline aqueous solution is crystallized. The solid powder obtained by the acid-base crystallization of the tylosin has strong electrostatic action, so that dust emission phenomenon exists in the production process.

Disclosure of Invention

Aiming at the problems existing in the prior art, the invention provides a purification method of a crude product of tylosin, which adopts acetonitrile as a solvent, the purity of the purified tylosin reaches more than 99 percent, the water content is low, the quality stability of the product is effectively maintained in the purification process, and the purification time is short.

The technical problems described in the invention are solved by the following technical scheme:

a method for purifying crude tylosin, the method comprising the steps of:

a. adding the crude product of the tylosin into acetonitrile, maintaining the temperature at 20-30 ℃, and stirring until the crude product of the tylosin is dissolved;

b. filtering the acetonitrile solution of the tylosin through a 0.8nm filter element, stirring in a crystallization kettle, and keeping the temperature at 20-30 ℃;

c. under low-speed stirring, maintaining the temperature at 20-30 ℃, adding deionized water with the same volume as acetonitrile into a crystallization kettle within 30min, and stirring for crystallization for 1h;

d. centrifuging, filtering, and drying the filtered solid to obtain a product Luo Xinchun of Taidi;

e. and (5) distilling acetonitrile in the filtrate, and recycling.

And d, repeating the purification steps a-d for the pure product of the tylosin Luo Xinxin obtained in the step d when the purity of the crude product of the tylosin is 85-95%, so as to obtain the high-purity product of the tylosin Luo Xinchun.

In the purification method of the crude product of the tylosin, in the step a, the addition volume of acetonitrile is more than 20 times of the mass of the crude product of the tylosin, and the addition volume is calculated by kg/L. The increase of the acetonitrile addition amount is used for ensuring that the crude product of the tylosin can be completely dissolved at 20-30 ℃.

In the step d, the drying is performed by vacuum drying, the drying temperature is 50-60 ℃, the drying pressure is-0.08-0.1 Mpa, and the drying time is 8 hours.

The purification process only adopts acetonitrile as a solvent, and can be recycled, so that the production cost is reduced, and the environmental protection pressure is lightened; the process is simple, the purification condition is easy to control, the operation is simple, the energy consumption is low, the production time is short, the time and the labor cost are reduced, and the production efficiency is improved; the purified tylosin has large particles, good fluidity and no electrostatic effect, avoids dust emission in production, and improves the safety of production; the purity of the purified tylosin reaches more than 99%, the quality of the product is improved, the moisture content is low, and the quality stability of the product can be effectively maintained in the storage process.

Detailed Description

The present invention will be described in further detail and fully with reference to the following examples.

Example 1

Adding 10kg of 95% crude tylosin into 200L of acetonitrile, stirring, controlling the temperature at 25 ℃, stirring and dissolving, filtering the solution to a crystallization kettle through a 0.8nm filter element, stirring, adding 200L of deionized water into the crystallization kettle at the temperature of 25 ℃ under low-speed stirring for 30min, preserving heat, and stirring and crystallizing for 1h. The solid was filtered off and dried in double cone vacuum for 8h. 9.4kg of solid of theirofacitretin is obtained, the purity is 99.4%.

Example 2

10kg of 93% crude tylosin is added into 300L of acetonitrile for stirring, the temperature is controlled at 25 ℃, the solution is stirred and clear, the solution is filtered to a crystallization kettle for stirring, the temperature is 25 ℃, and 300L of deionized water is added into the crystallization kettle for 30min under low-speed stirring. Preserving heat, stirring and crystallizing for 1h. The solid was filtered off and dried in double cone vacuum for 8h. 9.2kg of solid tildipirosin is obtained, the purity of which is 99.3%.

Example 3

10kg of 86% crude tylosin is added into 300L of acetonitrile for stirring, the temperature is controlled at 25 ℃, the solution is stirred and clear, the solution is filtered to a crystallization kettle for stirring, the temperature is 25 ℃, and 300L of deionized water is added into the crystallization kettle for 30min under low-speed stirring. Preserving heat, stirring and crystallizing for 1h. The solid was filtered off and dried in double cone vacuum for 8h. 9kg of solid of thetildipirol is obtained, with a purity of 93.2%.

9kg of the 93.2% tylosin solid is added into 200L of acetonitrile for stirring, the temperature is controlled at 25 ℃, the mixture is stirred and dissolved, the mixture is filtered through a filter element with the thickness of 0.8nm, and the mixture is filtered to a crystallization kettle for stirring, the temperature is 25 ℃, and 200L of deionized water is added into the crystallization kettle under low-speed stirring for 30 min. Preserving heat, stirring and crystallizing for 1h. The solid was filtered off and dried in double cone vacuum for 8h. 8.2kg of solid of thepiroxicam is obtained with the purity of 99.5 percent

Example 4

10kg of 95% crude tylosin is added into 200L of recovered acetonitrile and stirred, the temperature is controlled at 25 ℃, the solution is stirred and clear, the solution is filtered to a crystallization kettle and stirred, the temperature is 25 ℃, and 200L of deionized water is added into the crystallization kettle under low-speed stirring for 30 min. Preserving heat, stirring and crystallizing for 1h. The solid was filtered off and dried in double cone vacuum for 8h. 9.3kg of solid of thepiroxicam is obtained with the purity of 99.5 percent

Example 5

10kg of 93% crude tylosin is added into 300L of recovered acetonitrile for stirring, the temperature is controlled at 25 ℃, the solution is stirred and clear, the solution is filtered to a crystallization kettle for stirring, the temperature is 25 ℃, and 300L of deionized water is added into the crystallization kettle for 30min under low-speed stirring. Preserving heat, stirring and crystallizing for 1h. The solid was filtered off and dried in double cone vacuum for 8h. 9.2kg of solid tildipirosin is obtained, with a purity of 99.5%.

Example 6

10kg of 86% crude tylosin product is added into 300L of recovered acetonitrile for stirring, the temperature is controlled at 25 ℃, the solution is stirred and clear, the solution is filtered by a filter element with the thickness of 0.8nm to a crystallization kettle for stirring, and 300L of deionized water is added into the crystallization kettle under low-speed stirring at the temperature of 25 ℃ within 30 min. Preserving heat, stirring and crystallizing for 1h. The solid was filtered off and dried in double cone vacuum for 8h. 9kg of solid tildipirosin was obtained, with a purity of 94.5%.

9kg of the 94.5% tylosin solid is added into 200L of recovered acetonitrile to be stirred, the temperature is controlled at 25 ℃, the mixture is stirred and dissolved, filtered by a 0.8nm filter element to a crystallization kettle to be stirred, the temperature is 25 ℃, and 200L of deionized water is added into the crystallization kettle under low-speed stirring for 30 min. Preserving heat, stirring and crystallizing for 1h. The solid was filtered off and dried in double cone vacuum for 8h. 8.3kg of tildipirosin solid is obtained, and the purity is 99.3%.

Claims

1. A purification method of a crude product of tylosin is characterized by comprising the following steps: the purification method comprises the following steps:

e. distilling acetonitrile in the filtrate, and recycling;

and d, when the purity of the crude product of the tylosin is 85-95%, repeatedly purifying the pure product of the tylosin Luo Xinxin obtained in the step d to obtain a high-purity product of the tylosin Luo Xinchun.

2. The purification method of crude tylosin according to claim 1, characterized in that: in the step a, the addition volume of acetonitrile is more than 20 times of the mass of the crude product of the tylosin, and the addition volume is calculated in kg/L.

3. The purification method of crude tylosin according to claim 2, characterized in that: in the step d, the drying is performed by vacuum drying, the drying temperature is 50-60 ℃, the drying pressure is-0.08-0.1 Mpa, and the drying time is 8 hours.