CN110437248B - Production method of milbemycins capable of shortening production cycle - Google Patents
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Abstract
The invention provides a production method of milbemycins capable of shortening the production period, which comprises the following steps: step 1: dissolving the milbemycin extract by using a first solvent to obtain a first milbemycin solution; step 2: adding a second solvent into the first milbemycin dissolving solution obtained in the step (1), and then stirring for crystallization to obtain crude crystal powder; and step 3: dissolving the coarse crystal powder obtained in the step (2) by using a first solvent to obtain a second milbemycin solution; and 4, step 4: adding a second solvent into the second milbemycin dissolving solution obtained in the step (3) for stirring and recrystallizing to obtain milbemycin recrystallization powder; the first solvent is acetone; the second solvent is any one of n-hexane, n-heptane and n-octane. The production method has the advantages of simple process, short production period, low solvent recovery amount and high purity of the prepared milbemycins.
Description
The application is divided into separate applications by taking an invention patent with the application date of 2017, 04, 19 and the application number of 201710258658.6, namely a production method of milbemycins as a parent.
Technical Field
The invention relates to the field of biological pharmacy, in particular to a production method of milbemycin.
Background
The milbemycins are a mixture with hexadecanolide structure separated from milbemycins fermentation liquor. The milbemycins are one of insecticides with the highest activity, are used as novel biological pesticides, have broad spectrum, high efficiency and low toxicity; meanwhile, milbemycin is a direct raw material for synthesizing milbemycin oxime, and milbemycin oxime is a novel synthetic macrolide insect repellent and has good effects on controlling and preventing most of parasitic diseases.
At present, the production method of the milbemycins comprises the steps of filtering out bacteria from fermentation liquorExtracting the mushroom dregs with acetone or ethanol to obtain milbemycin extract; adding water with the same volume as the milbemycin extract into the milbemycin extract for dilution, adsorbing the diluted milbemycin extract (column loading liquid) by using resin, and eluting by using ethanol-water or acetone-water to obtain eluent; concentrating the eluate to obtain concentrated solution, and extracting with n-heptane to obtain extractive solution; and concentrating the extract until the volume content of the liquid is 20-30% to obtain the milbemycin. The production method generally takes 3 days for the resin separation process, the usage amount of the solvent is large, and about 15m is needed for separating 10kg of milbemycin in the production3Namely 15000L of acetone or ethanol, the recovery amount of the solvent is large, the energy consumption is high, the purity of the milbemycin obtained by resin separation is 70-80%, and the obtained milbemycin is pasty and has poor stability and is difficult to store.
Therefore, it is necessary to invent a method for producing milbemycins which can produce high purity milbemycins.
Disclosure of Invention
The invention aims to overcome the defects and provide a method for producing the milbemycins with high purity.
In order to solve the technical problems, the invention adopts the technical scheme that:
the invention provides a production method of milbemycin, which comprises the following steps:
step 1: dissolving the milbemycin extract by using a first solvent to obtain a first milbemycin solution;
step 2: adding a second solvent into the first milbemycin dissolving solution obtained in the step (1), and then stirring for crystallization to obtain crude crystal powder;
and step 3: dissolving the coarse crystal powder obtained in the step (2) by using a first solvent to obtain a second milbemycin solution;
and 4, step 4: adding a second solvent into the second milbemycin dissolving solution obtained in the step (3) for stirring and recrystallizing to obtain milbemycin recrystallization powder;
the first solvent is any one of ethanol, acetone, ethyl acetate or isopropanol; the second solvent is any one of n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane or n-dodecane.
The invention also provides a production method of the milbemycin, which comprises the following steps:
step a: filtering the milbemycin fermentation liquor to obtain mushroom dregs;
step b: adding acetone or ethanol into the mushroom dregs obtained in the step a, stirring and extracting, wherein the liquid-material ratio of the acetone or the ethanol to the mushroom dregs is 6-10L: 3kg, the stirring time is 5-7 h, and then filtering to obtain a milbemycin extracting solution;
step c: concentrating the milbemycin extracting solution in the step b until the volume content of acetone or the volume content of ethanol is 20-30% to obtain a milbemycin extract;
step d: dissolving the milbemycin extract obtained in the step c by using a first solvent to obtain a first milbemycin solution, wherein the ratio of the addition amount of the first solvent to the bacterial residues in the step b is 9-11L: 150 kg;
step e: adding a second solvent into the first milbemycin dissolving solution obtained in the step d, and then stirring and crystallizing to obtain crude crystal powder, wherein the adding amount of the second solvent and the bacterial slag obtained in the step b are in a ratio of 24-26L: 75kg, the flow rate of the added second solvent is 5.3-8.7L/min, the stirring time is 4.5-5.5 h, and the reaction temperature is controlled to be 20-30 ℃;
step f: dissolving the coarse crystal powder obtained in the step e by using a first solvent to obtain a second milbemycin solution, wherein the ratio of the addition amount of the first solvent to the bacterial slag obtained in the step b is 9-11L: 150 kg;
step g: adding a second solvent into the second milbemycin dissolving solution obtained in the step f, and stirring and recrystallizing to obtain milbemycin recrystallization powder, wherein the addition amount of the second solvent, the flow rate of adding the second solvent, the stirring time and the reaction temperature are the same as those in the step e;
the first solvent is acetone; the second solvent is n-heptane.
The invention has the beneficial effects that: (1) the milbemycin is purified by a crystallization method to obtain white crystal powder of the milbemycin, and compared with the pasty milbemycin (the purity is 70-80%) prepared by the traditional resin separation method, the milbemycin has the advantages of purity of over 95%, higher purity, better stability and convenient storage; (2) compared with the traditional resin separation method (period is 3 days), the method adopts a crystallization method to purify the milbemycins, has simpler process, only needs 1 day for the period, greatly shortens the production period, and effectively improves the production efficiency; (3) the crystallization method of the invention is to recycle the solvent from the concentrated milbemycins extract for crystallization and purification, the consumed solvent is less, even if the solvent used for preparing the milbemycins extract by the mushroom dregs is added, only about 1500L of solvent is needed for producing 10kg of milbemycins, the solvent recovery amount is one tenth of that of the traditional method, the energy consumption is low, and the production cost is effectively reduced.
Detailed Description
In order to explain technical contents, structural features, and objects and effects of the present invention in detail, the following description is given in detail with reference to the embodiments.
The most key concept of the invention is as follows: the milbemycin is purified by adopting a crystallization method to prepare the high-purity milbemycin.
The invention provides a production method of milbemycin, which comprises the following steps:
step 1: dissolving the milbemycin extract by using a first solvent to obtain a first milbemycin solution;
step 2: adding a second solvent into the first milbemycin dissolving solution obtained in the step (1), and then stirring for crystallization to obtain crude crystal powder;
and step 3: dissolving the coarse crystal powder obtained in the step (2) by using a first solvent to obtain a second milbemycin solution;
and 4, step 4: adding a second solvent into the second milbemycin dissolving solution obtained in the step (3) for stirring and recrystallizing to obtain milbemycin recrystallization powder;
the first solvent is any one of ethanol, acetone, ethyl acetate or isopropyl ketone; the second solvent is any one of n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane or n-dodecane.
The principle of the invention is as follows: in view of the fact that the milbemycin has high solubility in the first solvent, low solubility in the second solvent and high solubility of impurities in the first solvent and the second solvent, the milbemycin extract is dissolved by the first solvent, the second solvent is added, the solubility of the milbemycin is reduced, the purpose of crystallization is achieved, and the impurities exist in the mother liquor in a large amount, so that the effect of purifying the milbemycin crystals is achieved.
From the above description, the beneficial effects of the present invention are: (1) the milbemycin is purified by a crystallization method to obtain white crystal powder of the milbemycin, and compared with the pasty milbemycin (the purity is 70-80%) prepared by the traditional resin separation method, the milbemycin has the advantages of purity of over 95%, higher purity, better stability and convenient storage; (2) compared with the traditional resin separation method (period is 3 days), the method adopts a crystallization method to purify the milbemycins, has simpler process, only needs 1 day for the period, greatly shortens the production period, and effectively improves the production efficiency; (3) the crystallization method of the invention is to recycle the solvent from the concentrated milbemycins extract for crystallization and purification, the consumed solvent is less, even if the solvent used for preparing the milbemycins extract by the mushroom dregs is added, only about 1500L of solvent is needed for producing 10kg of milbemycins, the solvent recovery amount is one tenth of that of the traditional method, the energy consumption is low, and the production cost is effectively reduced.
Further, the first solvent is ethanol, and the second solvent is n-hexane or n-heptane.
As can be seen from the above description, experiments prove that the milbemycin crystal powder prepared by using ethanol as the first solvent and n-hexane or n-heptane as the second solvent has higher purity, which is higher than 90%.
Further, the first solvent is ethyl acetate, and the second solvent is any one of n-hexane, n-heptane or n-octane.
As can be seen from the above description, experiments prove that the milbemycin crystal powder prepared by using ethyl acetate as the first solvent and any one of n-hexane, n-heptane or n-octane as the second solvent has higher purity, and the purity is more than 90%.
Further, the first solvent is acetone, and the second solvent is any one of n-hexane, n-heptane, n-octane, n-nonane, n-decane or n-undecane.
As can be seen from the above description, experiments prove that the milbemycin crystal powder prepared by using acetone as the first solvent and any one of n-hexane, n-heptane, n-octane, n-nonane, n-decane or n-undecane as the second solvent has a purity of more than 92%.
Further, the first solvent is acetone, and the second solvent is n-heptane.
As can be seen from the above description, experiments prove that the purity of the milbemycin crystal powder prepared by using acetone as the first solvent and n-heptane as the second solvent is more than 97%.
Further, the preparation method also comprises the preparation of the milbemycin extract, and the preparation of the milbemycin extract comprises the following steps:
step A: filtering the milbemycin fermentation liquor to obtain mushroom dregs;
and B: adding acetone or ethanol into the fungus dregs obtained in the step A for extraction to obtain a milbemycin extracting solution;
and C: and D, concentrating the milbemycin extracting solution in the step B until the volume content of acetone or the volume content of ethanol is 20-30%, and obtaining the milbemycin extract.
According to the above description, the quality of the milbemycin extract obtained by preparing the milbemycin extract by the method is relatively stable, and the preparation of high-purity milbemycin in the later period is facilitated.
Further, the specific operation of step B is: and C, adding acetone or ethanol into the mushroom dregs obtained in the step A, stirring and extracting, wherein the liquid-material ratio of the acetone or the ethanol to the mushroom dregs is 6-10L: 3kg, the stirring time is 5-7 h, and then filtering to obtain a milbemycin extracting solution.
From the above description, controlling the liquid-material ratio of the extraction reagent (acetone or ethanol) to the mushroom dregs and the stirring time is beneficial to completely extracting the milbemycins in the mushroom dregs, so that the raw materials are fully utilized.
Further, the flow rate of the second solvent added in the step 2 and the step 4 is controlled to be 5.3-8.7L/min, and the stirring time of the step 2 and the step 4 is 4.5-5.5 h; controlling the reaction temperature of the step 2 and the step 4 to be 20-30 ℃.
From the above description, the flow rate of the second solvent, the stirring time and the reaction temperature are controlled so as to dissolve and react the components, thereby increasing the yield of the final milbemycin.
The invention also provides a production method of the milbemycin, which comprises the following steps:
step a: filtering the milbemycin fermentation liquor to obtain mushroom dregs;
step b: adding acetone or ethanol into the mushroom dregs obtained in the step a, stirring and extracting, wherein the liquid-material ratio of the acetone or the ethanol to the mushroom dregs is 6-10L: 3kg, the stirring time is 5-7 h, and then filtering to obtain a milbemycin extracting solution;
step c: concentrating the milbemycin extracting solution in the step b until the volume content of acetone or the volume content of ethanol is 20-30% to obtain a milbemycin extract;
step d: dissolving the milbemycin extract obtained in the step c by using a first solvent to obtain a first milbemycin solution, wherein the ratio of the addition amount of the first solvent to the bacterial residues in the step b is 9-11L: 150 kg;
step e: adding a second solvent into the first milbemycin dissolving solution obtained in the step d, and then stirring and crystallizing to obtain crude crystal powder, wherein the adding amount of the second solvent and the bacterial slag obtained in the step b are in a ratio of 24-26L: 75kg, the flow rate of the added second solvent is 5.3-8.7L/min, the stirring time is 4.5-5.5 h, and the reaction temperature is controlled to be 20-30 ℃;
step f: dissolving the coarse crystal powder obtained in the step e by using a first solvent to obtain a second milbemycin solution, wherein the ratio of the addition amount of the first solvent to the bacterial slag obtained in the step b is 9-11L: 150 kg;
step g: adding a second solvent into the second milbemycin dissolving solution obtained in the step f, and stirring and recrystallizing to obtain milbemycin recrystallization powder, wherein the addition amount of the second solvent, the flow rate of adding the second solvent, the stirring time and the reaction temperature are the same as those in the step e;
the first solvent is acetone; the second solvent is n-heptane.
From the above description, the beneficial effects of the present invention are: (1) the milbemycin is purified by a crystallization method to obtain white crystal powder of the milbemycin, and compared with the pasty milbemycin (the purity is 70-80%) prepared by the traditional resin separation method, the milbemycin has the advantages of purity of over 95%, higher purity, better stability and convenient storage; (2) compared with the traditional resin separation method (period is 3 days), the method adopts a crystallization method to purify the milbemycins, has simpler process, only needs 1 day for the period, greatly shortens the production period, and effectively improves the production efficiency; (3) the crystallization method of the invention is to recycle the solvent from the concentrated milbemycins extract for crystallization and purification, the consumed solvent is less, even if the solvent used for preparing the milbemycins extract by the mushroom dregs is added, only about 1500L of solvent is needed for producing 10kg of milbemycins, the solvent recovery amount is one tenth of that of the traditional method, the energy consumption is low, and the production cost is effectively reduced.
Example 1
A method for producing milbemycins comprises the following steps:
the invention also provides a production method of the milbemycin, which comprises the following steps:
step a: filtering the milbemycin fermentation liquor to obtain mushroom dregs;
step b: adding acetone or ethanol into the mushroom dregs obtained in the step a, stirring and extracting, wherein the liquid-material ratio of the acetone or the ethanol to the mushroom dregs is 6-10L: 3kg, the stirring time is 5-7 h, and then filtering to obtain a milbemycin extracting solution;
step c: concentrating the milbemycin extracting solution in the step b until the volume content of acetone or the volume content of ethanol is 20-30% to obtain a milbemycin extract;
step d: dissolving the milbemycin extract obtained in the step c by using a first solvent to obtain a first milbemycin solution, wherein the ratio of the addition amount of the first solvent to the bacterial residues in the step b is 9-11L: 150 kg;
step e: adding a second solvent into the first milbemycin dissolving solution obtained in the step d, and then stirring and crystallizing to obtain crude crystal powder, wherein the adding amount of the second solvent and the bacterial slag obtained in the step b are in a ratio of 24-26L: 75kg, the flow rate of the added second solvent is 5.3-8.7L/min, the stirring time is 4.5-5.5 h, and the reaction temperature is controlled to be 20-30 ℃;
step f: dissolving the coarse crystal powder obtained in the step e by using a first solvent to obtain a second milbemycin solution, wherein the ratio of the addition amount of the first solvent to the bacterial slag obtained in the step b is 9-11L: 150 kg;
step g: adding a second solvent into the second milbemycin dissolving solution obtained in the step f, and stirring and recrystallizing to obtain milbemycin recrystallization powder, wherein the addition amount of the second solvent, the flow rate of adding the second solvent, the stirring time and the reaction temperature are the same as those in the step e;
the first solvent is any one of ethanol, acetone, ethyl acetate or isopropyl ketone; the second solvent is any one of n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane or n-dodecane; randomly combining the first solvent and the second solvent into different solvent systems for the steps, wherein the purity of the prepared milbemycins is shown in table 1;
TABLE 1 Effect of different vehicle systems on the purity of milbemycins
Example 2
A production method of milbemycins (750 kg of mushroom dregs are used as raw materials for production, and the milbemycins are about 20kg) comprises the following steps:
step a: filtering the milbemycin fermentation liquor to obtain mushroom dregs;
step b: taking 750kg of fungus residues, putting the fungus residues into an extraction tank, adding 2000L of acetone, stirring for 6 hours, and then filtering to obtain a milbemycin extracting solution;
step c: concentrating the milbemycin extracting solution in the step b until the volume content of acetone is 20-30% to obtain a milbemycin extract;
step d: c, adding 50L of acetone into the milbemycin extract obtained in the step c for dissolving to obtain a first milbemycin dissolving solution;
step e: slowly adding 250L of n-heptane into the first milbemycin dissolving solution obtained in the step d, controlling the flow rate of the n-heptane to be 5.3-8.7L/min (the n-heptane is added within 30-45 min), controlling the temperature to be 20-30 ℃, stirring for crystallization for 5h, and filtering by using a filter membrane with the filter diameter of 0.8mm to obtain crude crystal powder;
step f: dissolving the coarse crystal powder obtained in the step e by using 50L of acetone to obtain a second milbemycin solution;
step g: and f, slowly adding 250L of n-heptane into the second milbemycin dissolving solution in the step f, controlling the flow rate of the n-heptane to be 5.3-8.7L/min (the n-heptane is added within 30-45 min), controlling the temperature to be 20-30 ℃, stirring and recrystallizing for 5 hours, and filtering by using a filter membrane with the filter diameter of 0.6mm to obtain 16.8kg of milbemycin recrystallization powder.
The purity of the obtained milbemycin recrystallized powder was 97.2% by HPLC, and the yield was about 85%. (the yield was calculated according to the following formula: amount of milbemycins in recrystallized powder ÷ total content of milbemycins in mushroom dregs).
Example 3
A method for producing milbemycins (750 kg of mushroom dregs are used as raw materials for production), which has the same operation steps as the example 2, except that the acetone adding amount in the step b is changed to 1500L, and the stirring time is changed to 5 h; the addition amount of acetone in the step d and the step f is changed to 45L; the adding amount of the n-heptane in the step e and the step g is changed to 240L, and the stirring crystallization time is changed to 4.5 h. 16.5kg of milbemycin recrystallization powder is obtained.
The purity of the obtained milbemycin recrystallized powder was 97.3% by HPLC, and the yield was about 82.5%. The yield was calculated in the same manner as in example 1.
Example 4
A method for producing milbemycins (750 kg of mushroom dregs are used as raw materials for production, about 20kg of milbemycins are contained), the operation steps are the same as the example 2, except that the addition amount of acetone in the step b is changed to 2500L, and the stirring time is changed to 7 h; the addition amount of acetone in the step d and the step f is changed to 55L; the adding amount of the n-heptane in the step e and the step g is changed to 260L, and the stirring crystallization time is changed to 5.5 h. 16.9kg of milbemycin recrystallization powder is obtained.
The purity of the resulting crystalline powder of milbemycin was determined by HPLC to be 98.2%, and the yield was about 84.5% in the same manner as in example 1.
Example 5
A method for producing milbemycins (750 kg of mushroom dregs are used as raw materials to produce the milbemycins, about 20kg), the operation steps are the same as the example 2, except that acetone in the example is changed into ethanol to prepare 17.0kg of milbemycins recrystallization powder.
The obtained milbemycin recrystallized powder had a purity of 92.3% by HPLC and a yield of about 85%. The yield was calculated in the same manner as in example 1.
Example 6
Influence of the purity of milbemycins on the stability of milbemycins, milbemycins with different initial purities were subjected to purity measurement by HPLC method every week in an environment of 25. + -. 2 ℃ and the results are shown in Table 2,
TABLE 2 variation in purity of milbemycins of different initial purities after storage for a certain period of time
As can be seen from the above table, when the initial purity of milbemycins is less than 90% at the same temperature, the purity of milbemycins decreases rapidly with the increase of storage time, and the higher the initial purity of milbemycins, the more stable the quality, and thus, it is important to prepare high-purity milbemycins.
Comparative example 1
Resin separation and purification: 750kg of mushroom dregs (containing 20kg of milbemycins) are taken and put into an extraction tank, 2m3(2000L) of ethanol is added, the mixture is stirred for 6 hours and filtered, the filtrate is diluted by 2m3(2000L) of water and is adsorbed by macroporous resin, 60 percent ethanol-water of 34.5m3 is used for elution, the eluent is concentrated and then is added with 500L of n-heptane for extraction, and the n-heptane layer is concentrated and dried to obtain a milbemycins paste which contains 15kg of milbemycins, has the purity of 75.2 percent and the yield of 75 percent (the content of the milbemycins in the paste divided by the total content of the milbemycins in the mushroom dregs).
Comparative example 2
Resin separation and purification: 750kg of mushroom dregs are taken and put into an extraction tank, 2m3(2000L) acetone is added, stirring is carried out for 6h, filtering is carried out, 2m3(2000L) water is added into filtrate for dilution, macroporous resin adsorption is carried out, 60% acetone-water of 35m is used for elution, 500L of n-heptane is added for extraction after eluent is concentrated, and after the n-heptane layer is concentrated and dried, 15.2kg of milbemycins paste is obtained, the purity is 73.8%, and the yield is about 75.1% -the milbemycins amount of the paste and the milbemycins amount in the mushroom dregs.
In conclusion, according to the production method of the milbemycins, provided by the invention, the milbemycins are purified by a crystallization method to obtain white crystal powder of the milbemycins, and compared with the paste milbemycins (the purity is 70-80%) prepared by a traditional resin separation method, the milbemycins have the purity of over 95%, are higher in purity and better in stability, and are convenient to store; compared with the traditional resin separation method (period is 3 days), the method adopts a crystallization method to purify the milbemycins, has simpler process, only needs 1 day for the period, greatly shortens the production period, and effectively improves the production efficiency; the crystallization method of the invention is to recycle the solvent from the concentrated milbemycins extract for crystallization and purification, the consumed solvent is less, even if the solvent used for preparing the milbemycins extract by the mushroom dregs is added, only about 1500L of solvent is needed for producing 10kg of milbemycins, the solvent recovery amount is one tenth of that of the traditional method, the energy consumption is low, and the production cost is effectively reduced.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (3)
1. A production method of milbemycins capable of shortening the production cycle is characterized by comprising the following steps:
step 1: filtering the milbemycin fermentation liquor to obtain mushroom dregs; adding acetone or ethanol into the fungus residue for extraction to obtain milbemycin extract; concentrating the milbemycin extracting solution until the volume content of acetone or the volume content of ethanol is 20-30% to obtain a milbemycin extract; dissolving the milbemycin extract by using a first solvent to obtain a first milbemycin solution;
step 2: adding a second solvent into the first milbemycin dissolving solution obtained in the step (1), and then stirring for crystallization to obtain crude crystal powder;
and step 3: dissolving the coarse crystal powder obtained in the step (2) by using a first solvent to obtain a second milbemycin solution;
and 4, step 4: adding a second solvent into the second milbemycin dissolving solution obtained in the step (3) for stirring and recrystallizing to obtain milbemycin recrystallization powder;
wherein, the addition amount of the second solvent, the flow rate of the second solvent, the stirring time and the reaction temperature in the stirring recrystallization in the step 4 are the same as those in the stirring crystallization in the step 2;
the first solvent is acetone; the second solvent is any one of n-hexane, n-heptane and n-octane.
2. The method for producing milbemycins with a shortened production cycle as claimed in claim 1, wherein in step 1, acetone or ethanol is added to the mushroom dregs for stirring extraction, the liquid-material ratio of the acetone or ethanol to the mushroom dregs is 6-10L: 3kg, the stirring time is 5-7 h, and then the mixture is filtered to obtain the milbemycins extract.
3. The method for producing milbemycins with shortened production cycle as claimed in claim 1, wherein the flow rate of the second solvent added in step 2 and step 4 is controlled to be 5.3-8.7L/min, and the stirring time of step 2 and step 4 is 4.5-5.5 h; controlling the reaction temperature of the step 2 and the step 4 to be 20-30 ℃.
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| WO2000042047A1 (en) * | 1999-01-15 | 2000-07-20 | Novartis Ag | 4-phenoxymethyl-substituted milbemycins |
| CN1732174A (en) * | 2002-12-24 | 2006-02-08 | 三共农业株式会社 | Method for purification of milbemycins |
| CN103772458A (en) * | 2012-10-25 | 2014-05-07 | 北大方正集团有限公司 | Purification method for Nemadectin |
| CN104557967A (en) * | 2014-12-24 | 2015-04-29 | 北大医药重庆大新药业股份有限公司 | Production method of high-purity milbemycins |
| EP2886640A1 (en) * | 2013-12-18 | 2015-06-24 | Riga Technical University | Process for isolation of milbemycins A3 and A4 |
| CN106146531A (en) * | 2016-07-07 | 2016-11-23 | 李丽倩 | A kind of production method of high-purity mibemycin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS62155281A (en) * | 1985-12-27 | 1987-07-10 | Sankyo Co Ltd | Antibiotic milbemycin compound |
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| WO2000042047A1 (en) * | 1999-01-15 | 2000-07-20 | Novartis Ag | 4-phenoxymethyl-substituted milbemycins |
| CN1732174A (en) * | 2002-12-24 | 2006-02-08 | 三共农业株式会社 | Method for purification of milbemycins |
| CN103772458A (en) * | 2012-10-25 | 2014-05-07 | 北大方正集团有限公司 | Purification method for Nemadectin |
| EP2886640A1 (en) * | 2013-12-18 | 2015-06-24 | Riga Technical University | Process for isolation of milbemycins A3 and A4 |
| CN104557967A (en) * | 2014-12-24 | 2015-04-29 | 北大医药重庆大新药业股份有限公司 | Production method of high-purity milbemycins |
| CN106146531A (en) * | 2016-07-07 | 2016-11-23 | 李丽倩 | A kind of production method of high-purity mibemycin |
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| CN110437248A (en) | 2019-11-12 |
| CN106946905A (en) | 2017-07-14 |
| CN106946905B (en) | 2019-09-20 |
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